Cutaneous T-Cell Lymphoma 

Updated: Aug 15, 2018
Author: Lauren C Pinter-Brown, MD; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

Cutaneous T-cell lymphoma (CTCL) (see the image below) is a group of lymphoproliferative disorders characterized by localization of neoplastic T lymphocytes to the skin. Collectively, CTCL is classified as a type of non-Hodgkin lymphoma (NHL).

Early patch-stage cutaneous T-cell lymphoma. Early patch-stage cutaneous T-cell lymphoma.

WHO-EORTC classification of CTCLs

The World Health Organization–European Organization for Research and Treatment of Cancer (WHO-EORTC) classification of CTCLs is divided into those with indolent clinical behavior and those with aggressive subtypes. A third category is that of precursor hematologic neoplasms that are not T-cell lymphomas (CD4+/CD56+ hematodermic neoplasm [blastic natural killer (NK)-cell lymphoma]).[1]

CTCLs with indolent clinical behavior include the following[1] :

  • Mycosis fungoides

  • Mycosis fungoides variants and subtypes (eg, folliculotropic mycosis fungoides, pagetoid reticulosis, granulomatous slack skin)

  • Primary cutaneous CD30+ lymphoproliferative disorder (eg, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis)

  • Subcutaneous panniculitis-like T-cell lymphoma (provisional)

  • Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)

CTCLs with aggressive clinical behavior include the following[1] :

  • Sézary syndrome

  • Adult T-cell leukemia/lymphoma

  • Extranodal NK/T-cell lymphoma, nasal type

  • Primary cutaneous peripheral T-cell lymphoma, unspecified

  • Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional)

  • Cutaneous gamma/delta-positive T-cell lymphoma (provisional)

Signs and symptoms

The signs and symptoms of CTCL vary depending on the type. The two most common types are mycosis fungoides and Sézary syndrome.

Classic mycosis fungoides is divided into the following 3 stages:

  • Patch (atrophic or nonatrophic): Nonspecific dermatitis, patches on lower trunk and buttocks; minimal/absent pruritus

  • Plaque: Intensely pruritic plaques, lymphadenopathy

  • Tumor: Prone to ulceration

Sézary syndrome is defined by erythroderma and leukemia. Signs and symptoms include the following:

  • Edematous skin

  • Lymphadenopathy

  • Palmar and/or plantar hyperkeratosis

  • Alopecia

  • Nail dystrophy

  • Ectropion

  • Hepatosplenomegaly may be present

Ocular involvement may be evident in advanced CTCL.[2]

See Clinical Presentation for more detail.

Diagnosis

In most cases of mycosis fungoides, the diagnosis is reached owing to its clinical features, disease history, and histomorphologic and cytomorphologic findings. An additional diagnostic criterion to distinguish CTCL from inflammatory dermatoses is demonstration of a dominant T-cell clone in skin biopsy specimens by a molecular assay (ie, Southern blot, polymerase chain reaction [PCR]). Genetic testing may also be considered.

The following laboratory tests are included in the diagnostic workup of mycosis fungoides:

  • Complete blood count with differential; review the buffy coat smear for Sézary cells

  • Liver function tests: Look for liver-associated enzyme abnormalities

  • Uric acid and lactate dehydrogenase levels: These are markers of bulky and/or biologically aggressive disease

  • 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

  • Human immunodeficiency virus (HIV) and human T-lymphotropic virus type 1 (HTLV-I) testing

For a diagnosis of Sézary syndrome, one or more of the following criteria should be met[3] :

  • Absolute Sézary cell count of at least 1000 cells/µL

  • Immunophenotypic abnormalities (expanded CD4+ T-cell population resulting in CD4/CD8 ratio of >10; loss of any or all of T-cell antigens CD2, CD3, CD4, and CD5; or loss of both CD4 and CD5)

  • T-cell clone in the peripheral blood shown by molecular or cytogenetic methods: Flow cytometry may be useful for differential diagnosis of precursor and peripheral T-cell and NK-cell lymphomas[4]

Imaging studies

  • Chest radiography: To determine whether there is lung involvement

  • Abdominal/pelvic computed tomography (CT) scanning: In patients with advanced mycosis fungoides (stage IIB to IVB) or those with clinically suspected visceral disease

  • Positron emission tomography (PET) scanning: To determine visceral involvement

Staging

Although mycosis fungoides and Sézary syndrome are types of NHL, a different staging system is used, based on the particular skin findings and findings of extracutaneous disease, as follows:

  • Stage IA disease (as defined by the tumor, node, metastases blood [TNMB] system): Patchy or plaquelike skin disease involving less than 10% of skin surface area (T1 skin disease)

  • Stage IB: Patchy/plaquelike skin disease involving 10% or more of the skin surface area (T2 skin disease)

  • Stage IIB disease: Tumors are present (T3 skin lesions)

  • Stage III disease: Generalized erythroderma is present

  • Stage IVA1 disease: Erythroderma and significant blood involvement occur[5]

  • Stage IVA2 disease: Lymph node biopsy result shows total effacement by atypical cells (LN4 node)[5]

  • Stage IVB disease: Visceral involvement (eg, liver, lung, bone marrow) occurs

See Workup for more detail.

Management

Treatment for early stage CTCLs includes topical therapies with or without interferon alpha (IFN-α) or oral agents, whereas advanced-stage patients are treated with chemotherapy and novel agents. Multiagent cytotoxic regimens may be palliative but seem to lack a demonstrated survival benefit.[6]

Mycoses fungoides

Symptomatic treatments, emollients, or antipruritics, plus specific topical and systemic treatment, are used to manage mycosis fungoides. Generally, 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 refractory stage I disease.[7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17]

Localized mycosis fungoides therapy may include radiotherapy, intralesional steroids, or surgical excision, as well as the following:

  • Extracorporeal photopheresis, alone or in combination with other treatment modalities (eg, IFN-α)[18] : Sézary syndrome, erythrodermic mycosis fungoides

  • Unrelated cord blood transplantation[19] : Mycosis fungoides

  • Allogeneic stem cell transplantation: Treatment-refractory mycosis fungoides[7]

  • Multiagent chemotherapy: Unequivocal lymph node or systemic involvement, or widespread tumor-stage mycosis fungoides that is refractory to skin-targeted therapies and is not early patch or plaque-stage disease

Topical therapies include topical steroids, topical retinoids, topical chemotherapy, psoralen-enhanced light therapy, and total body electron beam radiation. Systemic therapy includes oral retinoids, recombinant IFN-α, fusion toxins, monoclonal antibodies, single-agent chemotherapy, histone deacetylase inhibitors, and extracorporeal photopheresis.

Sézary syndrome

Sézary syndrome therapy is based on disease burden and rapidity of progression.[20] Preserve immune response to prevent infection, use immunomodulatory therapy before chemotherapy (unless disease burden or therapeutic failure requires otherwise), and consider combination therapy over monotherapy, particularly systemic immunomodulatory therapy plus skin-directed treatments.

Pharmacotherapy

The following agents are used in the management of CTCL:

  • Antineoplastics (eg, chlorambucil, vorinostat, methotrexate, etoposide, romidepsin, denileukin diftitox, carmustine, mechlorethamine, bexarotene)

  • Immunomodulators (eg, IFN-α 2b)

  • Monoclonal antibody antineoplastics (eg, alemtuzumab)

  • Topical skin products (eg, Imiquimod 5% cream, topical mechlorethamine)

  • Retinoid-like agents (eg, alitretinoin, tazarotene gel)

  • Corticosteroids (eg, prednisone, prednisolone)

See Treatment and Medication for more detail.

Background

Cutaneous T-cell lymphoma 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. (For lymphomas in general, the skin is actually the second most common extranodal site; gastrointestinal sites are first.)[21, 5, 7, 8, 22]

When the term was first coined, it most often referred to mycosis fungoides/Sézary syndrome, the most common cutaneous T-cell lymphoma.[23, 24] Subsequently, however, the many entities that make up the cutaneous T-cell lymphomas were found to differ widely in biologic course, histologic appearance, and, in some cases, immunologic and cytogenetic features and in their response to appropriate treatment (see the images below). (See Pathophysiology, Etiology, Presentation, and Workup.)

Patch-stage mycosis fungoides. Patch-stage mycosis fungoides.
Plaque-stage mycosis fungoides. Plaque-stage mycosis fungoides.
Hypopigmented cutaneous T-cell lymphoma. Courtesy Hypopigmented cutaneous T-cell lymphoma. Courtesy of Jeffrey Meffert, MD.

Classification of cutaneous T-Cell lymphomas

Cutaneous T-cell lymphomas have been defined in the past by an integration of histologic, biologic, immunologic, and cytogenetic characteristics in two classification systems[25, 26] : the European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lymphomas[25] and the World Health Organization (WHO) classification of hematologic malignancies. (See Pathophysiology, Etiology, Presentation, and Workup.)[26]

A tumor, node, metastases (TNM) classification system for primary cutaneous lymphomas other than mycosis fungoides and its variant Sézary syndrome has also been proposed.[27]

The EORTC classification focused on primary cutaneous lymphomas, which may vary from their nodal counterparts in clinical behavior, prognosis, and appropriate therapeutic approaches.[25] 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 may instead be a differential diagnosis that requires clinicopathologic correlation. (See Prognosis, DDx, Treatment, and Medication.)

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.[26] The WHO classification allowed oncologists, dermatologists, and pathologists to use a common language.

In 2005, during consensus meetings, representatives of both systems reached an agreement on a new classification system, the WHO-EORTC Classification of Cutaneous Lymphomas. (See Table 1, below.)[1]

Table 1. WHO-EORTC Classification of Cutaneous T-Cell Lymphoma (Open Table in a new window)

WHO-EORTC Classification

Frequency (%)

5-Year Survival Rate (%)

Indolent Clinical Behavior

Mycosis fungoides

44

88

Mycosis fungoides variants and subtypes

—Folliculotropic mycosis fungoides

4

80

—Pagetoid reticulosis

< 1

100

—Granulomatous slack skin

< 1

100

Primary cutaneous CD30+ lymphoproliferative disorder

—Primary cutaneous anaplastic large cell lymphoma

8

95

—Lymphomatoid papulosis

12

100

Subcutaneous panniculitis-like T-cell lymphoma (provisional)

1

82

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

2

75

Aggressive Clinical Behavior

Sézary syndrome

3%

24%

Adult T-cell leukemia/lymphoma

NR

NR

Extranodal NK/T-cell lymphoma, nasal type

NR

NR

Primary cutaneous peripheral T-cell lymphoma, unspecified

2

16

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional)

< 1

18

Cutaneous gamma/delta-positive T-cell lymphoma (provisional)

< 1

NR

Precursor Hematologic Neoplasm (not a T-cell lymphoma)

CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma)

 

NR

 

NR

Source: Adapted from Willemze et al. Blood. 2005;105(10):3768-85.[1]

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

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

Table 2. Cluster Designations (Open Table in a new window)

CD Type

Representative Cells

Also Known As

CD2

T, NK

Sheep RBC

CD3

T

 

CD4

T subset

Helper

CD5

T

 

CD7

T, NK

Prothymocyte

CD8

T subset, NK

Suppressor

CD25

Active T, B, M

IL-2R (Tac)

CD30

Active T, B

Ki-1

CD45

T subset

CLA

CD56

NK

NCAM

B = B cell; CD = cluster designation; 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.

Cutaneous T-cell lymphomas with indolent clinical behavior

Mycosis fungoides is not discussed in this subsection but is addressed further on.

Primary cutaneous CD30-positive lymphoproliferative disorder

The term CD30-positive lymphoproliferative disorders encompasses 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.

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 and without evidence of extracutaneous disease. Extracutaneous dissemination, mainly to regional nodes, occurs 10% of the time.

The disease is multifocal in skin approximately 30% of the time. CD30-positive (75% or more) membrane staining of the large lymphocytes or large clusters of CD30-positive atypical lymphocytes with pleomorphic or multiple nuclei and nucleoli are seen. Numerous mitotic figures can be observed. Unlike systemic anaplastic large cell lymphoma, anaplastic lymphoma kinase (ALK) staining is usually negative.

A helpful tool for distinguishing cutaneous from systemic anaplastic large cell lymphoma is to test for the presence of the t(2;5) translocation. This 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, using 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; these can evolve to papulovesicular or pustular lesions. These lesions are much smaller than those of 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. (See the image below.)

A 40-year-old woman complained of a recurrent skin 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 that was CD30 positive. The clinical picture and pathologic findings were consistent with lymphomatoid papulosis. This condition has a benign natural history, despite clonal gene rearrangement in some cases. Skin eruptions occur in self-limited crops, which do not require treatment.

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 may develop in 20% of cases.

Subcutaneous panniculitis-like T-cell lymphoma

In subcutaneous panniculitis-like 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.

At least 2 groups of subcutaneous panniculitis-like T-cell lymphoma with different histologies, phenotypes, and prognoses can be distinguished. Cases with an alpha/beta-positive T-cell phenotype are usually CD8+, are characterized by recurrent lesions that are restricted to the subcutaneous tissue (with no dermal or epidermal involvement), and tend to run an indolent clinical course.[28, 29]

The WHO-EORTC term subcutaneous panniculitis-like T-cell lymphoma refers only to the alpha/beta type.[1] 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 gamma/delta 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 gamma/delta-positive lymphomas in a provisional category.[1] Clinically, this lymphoma is more aggressive, with dissemination to mucosal and other extranodal sites.[1, 29, 30, 31, 32]

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

This condition 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.

Aggressive subtypes of cutaneous T-cell lymphoma

In this section, the following are reviewed:

  • Adult T-cell lymphoma/leukemia (human T-cell lymphotropic virus [HTLV]–positive)

  • Nasal-type extranodal natural killer (NK)/T-cell lymphoma

  • Primary cutaneous peripheral T-cell lymphoma, unspecified (PTCL-U)

Provisional categories, such as primary aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma and primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma, are also discussed. Cutaneous gamma/delta-positive T-cell lymphoma (discussed earlier) also belongs in this category. Sézary syndrome is discussed in the subsection on mycosis fungoides.[33]

Adult T-cell lymphoma/leukemia

Most patients with adult T-cell lymphoma/leukemia are those with antibodies to HTLV-1, a retrovirus 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 hyperlobate 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 patients 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, a disease characterized by small, medium, and large cells, the nasal cavity/nasopharynx and the skin of the trunk and extremities are involved by multiple plaques and tumors (see the image below). These lesions are frequently accompanied by systemic symptoms such as fever and weight loss, and an associated hemophagocytic syndrome may be observed.

A 42-year-old woman who had moved to the United St A 42-year-old woman who had moved to the United States from Peru several year ago presented with an ulcerative lesion on her face near her nose, and destruction of her hard palate. Tissue biopsy revealed NK/T-cell lymphoma. Image courtesy of Jason Kolfenbach, MD, and Kevin Deane, MD, Division of Rheumatology, University of Colorado Denver School of Medicine.

Cutaneous involvement may be primary or secondary. Because both primary involvement and secondary involvement are clinically aggressive and require the same type of treatment, distinction between them seems unnecessary.[29, 34, 35, 36]

This condition is more common in males and geographically 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 WHO-EORTC classification.[1]

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

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

Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma

Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma is a clinically aggressive, (sometimes) disseminated disease that 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.

Mycosis fungoides

Mycosis fungoides is the most common type of cutaneous T-cell lymphoma (44%), which has led some authors to use this term synonymously with cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma 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.

Mycosis fungoides itself is often an epidermotropic disorder and is characterized by the evolution of patches into plaques and tumors composed of small to medium-sized skin-homing T cells; some (or, rarely, all) of these T cells have convoluted, cerebriform nuclei. (See the images below.)

Patch-stage cutaneous T-cell lymphoma. Courtesy of Patch-stage cutaneous T-cell lymphoma. Courtesy of Jeffrey Meffert, MD.
Early patch-stage cutaneous T-cell lymphoma. Early patch-stage cutaneous T-cell lymphoma.

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. Approximately 1000 new cases of mycosis fungoides occur annually in the United States (ie, 0.36 cases per 100,000 population).

This condition is more common in blacks than in whites (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 approximately 50 years; however, mycosis fungoides can also be diagnosed in children and adolescents and apparently has similar outcomes.[37]

Variants of mycosis fungoides that are recognized by WHO/EORTC include the following[1] :

  • Sézary syndrome

  • Folliculotropic mycosis fungoides

  • Granulomatous slack skin

  • Pagetoid reticulosis (Woringer-Kolopp disease)

Sézary syndrome

Sézary syndrome accounts for about 5% of all cases of mycosis fungoides. The patient with Sézary syndrome has generalized exfoliative dermatitis or erythroderma and lymphadenopathy, as well as atypical T lymphocytes with cerebriform nuclei (more than 1000 per mm3) 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. (See the images below.)

Erythroderma of Sézary syndrome. Erythroderma of Sézary syndrome.
Nail changes of Sézary syndrome. Nail changes of Sézary syndrome.

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 one 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 WHO-EORTC classification for cutaneous lymphoma considers its behavior "aggressive."[1]

Folliculotropic mycosis fungoides

Folliculotropic mycosis fungoides manifests as 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.

Pagetoid reticulosis

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

The term pagetoid reticulosis should be restricted to the localized type and should not be used to describe the disseminated type (Ketron-Goodman type).[38]

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 an almost 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 with it in this disease is limited. One third of patients have been reported to have concomitant Hodgkin lymphoma or mycosis fungoides.

Granulomatous cutaneous T-cell lymphomas are rare, so limited data on their clinicopathologic and prognostic features are available.[39] Patients with either granulomatous mycosis fungoides or granulomatous slack skin display overlapping histologic features. The development of bulky skin folds in granulomatous slack skin differentiates this condition clinically from granulomatous mycosis fungoides.

Patient education

For patient education information, see Lymphoma (Hodgkin's Disease and Non-Hodgkin's Lymphoma) and Skin Cancer.

Pathophysiology

Of all primary cutaneous lymphomas, 65% are of the T-cell type. The most common immunophenotype is CD4 positive. There is no common pathophysiology for these diseases, as the term cutaneous T-cell lymphoma encompasses a wide variety of disorders.

Mycosis fungoides

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 on the skin.[5] The malignant clone frequently lacks normal T-cell antigens such as CD2, CD5, or CD7.

The normal and malignant cutaneous T cells home in on the skin through 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.[40]

Further promoting the proclivity of the cutaneous T cell to home in on 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 CC chemokine receptor 4 (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.

Etiology

The primary etiologic mechanisms for the development of cutaneous T-cell lymphoma (eg, mycosis fungoides) have not been elucidated. Mycosis fungoides 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 1 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 mycosis fungoides. It would also predict that each patient would likely have a unique malignant clone, which, in fact, has been found to be the case.

Environmental factors

Chemical, physical, and microbial irritants have been discussed as causes for cutaneous T-cell lymphoma or mycosis fungoides, but evidence related to an etiology is not convincing.[30] 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.[32] Various theories also implicate occupational or environmental exposures (eg, Agent Orange).

Epidemiology

Cutaneous T-cell lymphoma has a worldwide distribution; some studies have identified a higher prevalence of the disease in industrial populations (eg, among workers who use machine cutting oils). The incidence of cutaneous T-cell lymphoma in the United States was reported to be 6.4 persons per million population annually (for the overall, age-adjusted incidence) between 1973 and 2002, with the disease’s incidence increasing over that time period.[41]

Adult T-cell lymphoma/leukemia 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. This disease occurs in 1-5% of seropositive individuals after more than 2 decades of viral persistence.[42]

Nasal-type NK/T-cell lymphoma, which is associated with Epstein-Barr virus (EBV) infection, is more common in Asia, Central America, and South America.

A study in Kuwait found that the annual incidence rate of mycosis fungoides there was 0.43 case per 100,000 persons.[43]

Race-, sex-, and aged-related demographics

In the United States, cutaneous T-cell lymphoma is more common among persons of sub - Saharan African lineage than among those of European background, in a ratio of approximately 2:1. In Kuwait, a study found that the annual incidence rate of mycosis fungoides was significantly higher among Arabs than among non-Arab Asians.[43]

Cutaneous T-cell lymphoma has a sex predilection, being more common in men than women by a ratio of approximately 2:1.[43]

Most patients with cutaneous T-cell lymphoma are middle-aged or elderly. Sézary syndrome, for example, occurs almost exclusively in adults. Many patients have had a poorly defined form of dermatitis for many years prior to the onset of the disease. In a significant proportion of cases, the onset of the disease, or of a dermatitic precursor of the disease, occurs in childhood.

However, cutaneous T-cell lymphoma is exceedingly rare in children younger than 10 years, and in such cases it does not show a male predominance; one series even reported a strong female predilection. Similar to adult patients, 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 mycosis fungoides are described as having Woringer-Kolopp disease (pagetoid reticulosis). These patients are usually middle-aged, with an age distribution in one series ranging from 13-68 years and with a mean age of 55 years.

Prognosis

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 disease stage at diagnosis, as well as to the type and extent of skin lesions and the whether or not extracutaneous disease is present, as demonstrated by the following[1, 44] :

  • Patients diagnosed with stage IA mycosis fungoides (patch or plaque skin disease limited to < 10% of the skin surface area) who undergo treatment have an overall life expectancy similar to age-, sex-, and race-matched controls (10-year survival rate of 97-98%)

  • Patients who have stage IIB disease with cutaneous tumors have a median survival rate of 3.2 years (10-year survival rate of 42%)

  • Patients who have stage III disease (generalized erythroderma) have a median survival rate of 4-6 years (10-year survival rate of 83%)

  • Patients with extracutaneous disease stage IVA (lymph nodes) or stage IVB (viscera) have a survival rate of less than 1.5 years (10-year survival rate of 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 cutaneous T-cell lymphoma.[45]

Univariate analysis has shown that the following factors are also associated with reduced survival and increased risk of disease progression[44] :

  • Increased age

  • Male sex

  • Increased lactate dehydrogenase (LDH)

An analysis of 20-year trends reporting on incidence and associated mortality of patients with mycosis fungoides showed a decline in the mortality rate in the United States, perhaps related to increased recognition and earlier diagnosis of the disease.[46] 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.

Sézary syndrome

Late-stage mycosis fungoides or Sézary syndrome is associated with declining immunocompetence.[47] Death most often results from systemic infection, especially with Staphylococcus aureus or Pseudomonas aeruginosa.[48] 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.

Median survival for patients with Sézary syndrome has been reported to be 2-4 years,[49] although the median survival was 2.9 years among patients defined by 2011 criteria for the disease.[20] The disease-specific 5-year survival rate has been reported to be 24%.

Folliculotropic mycosis fungoides

The prognosis associated with folliculotropic mycosis fungoides is worse than that for classic patch- and plaque-stage mycosis fungoides and corresponds more closely with tumor-stage disease (stage IIB). For this reason, some authors have proposed that the disorder be staged with tumor-stage disease (stage IIB). Folliculotropic mycosis fungoides reportedly has a disease-specific 5-year survival rate of approximately 70-80%.[50]

Adult T-cell leukemia/lymphoma

In patients with adult T-cell leukemia/lymphoma, 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 period, but transformation into an acute phase with an aggressive course may occur.[42, 51]

Subcutaneous panniculitis-like T-cell lymphoma

Subcutaneous panniculitis-like T-cell lymphoma (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.[29] The 5-year survival rate for such patients may be greater than 80%.

Unilesional pagetoid reticulosis

Unilesional pagetoid reticulosis progresses slowly. Patients usually have an excellent prognosis.

PTCL-U

Primary cutaneous peripheral T-cell lymphoma, unspecified (PTCL-U), is associated with a poor prognosis. The 5-year survival rate is less than 20%,[52] regardless of whether the disease manifests with solitary/localized lesions or generalized skin lesions.[53]

Nasal-type NK/T-cell lymphoma

Nasal-type NK/T-cell lymphoma manifesting in the skin is highly aggressive, and patients have a median survival period of less than 12 months.[54, 55] The most important factor in 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.[55]

CD30+, CD56+ patients seem to have a better prognosis, possibly being examples of cutaneous anaplastic large cell lymphoma with coexpression of CD56.[56]

Granulomatous disease

Granulomatous cutaneous T-cell lymphomas tend to be therapy resistant, with a slowly progressive course that is apparently worse than that of classic nongranulomatous mycosis fungoides.[39]

Provisional entities

Primary cutaneous CD4+ small/medium pleomorphic T-cell lymphoma is associated with a relatively favorable prognosis, with an estimated 5-year survival rate of approximately 60-80%.[53] 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 period of 32 months.[38]

Cutaneous gamma/delta-positive T-cell lymphoma patients tend to have aggressive disease resistant to multiagent chemotherapy and/or radiation, with a median survival in 1 study of only 15 months.[57] A trend toward decreased survival was noted for patients with subcutaneous fat involvement, in comparison with patients who had epidermal or dermal disease only.

Complications

Potential complications of mycosis fungoides include the following:

  • Infection, particularly from indwelling intravenous catheters or from lymph node biopsy sites

  • High-output cardiac failure

  • Anemia of chronic disorders

  • Edema

  • Secondary malignancies - Eg, skin cancer, melanoma, colon cancer, Hodgkin lymphoma, and non-Hodgkin lymphomas

 

Presentation

History

The skin rash of mycosis fungoides may consist of 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 patients who have progressive chronic dermatosis or whose condition is refractory to topical treatments.

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

Classic mycosis fungoides

Classic mycosis fungoides 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, which usually consists of patches and is often found 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.[58]

Classic mycosis fungoides 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 mycosis fungoides. Some regard large-plaque parapsoriasis as patch-stage mycosis fungoides. (See the images below.)

Plaque-stage parapsoriasis. Plaque-stage parapsoriasis.
Patch-stage mycosis fungoides progressing to plaqu Patch-stage mycosis fungoides progressing to plaque stage, with cutaneous cigarette-paper appearance evident.

In many cases, the disease never progresses beyond this stage, and the diagnosis of mycosis fungoides 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. In children, early stage disease and unusual forms, such as the hypopigmented variant, tend to predominate.[59]

Stages IA and IB

While well-developed plaques that are clinically diagnostic for mycosis fungoides are usually intensely pruritic, less characteristic ones typically are not, and the development of pruritus in such lesions is a sign of progression towards mycosis fungoides. Depending on whether the lesions involve up to 10% of the body surface 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'embleemycosis fungoides

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

Stage III (erythrodermicmycosis fungoides)

Mycosis fungoides that is evident as an erythroderma but with too few circulating lymphocytes to warrant a diagnosis of Sézary syndrome is designated erythrodermic mycosis fungoides. Dermatopathic lymphadenopathy is present in these cases. Rarely, such patients may present with a nodulotumorous eruption.[60]

Stages IVA and IVB

Development of lymph nodes that are 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 ofmycosis fungoides

Mycosis fungoides in any stage may suddenly become much more aggressive, progressing rapidly to more advanced stages (see the images below). This is associated with the histologic appearance of large, atypical cells; often, these are CD30+, and the process is termed large cell transformation. It may be evident as a new, solitary nodule within a classic mycosis fungoides patch or plaque, as abrupt onset of multiple scattered papules and/or nodules without spontaneous resolution, or within new or enlarging tumors.[61]

Middle-aged woman with mycosis fungoides showing u Middle-aged woman with mycosis fungoides showing ulceration and marked depigmentation of advanced disease.
Middle-aged woman with mycosis fungoides showing u Middle-aged woman with mycosis fungoides showing ulceration and marked depigmentation of advanced disease.

Variants of mycosis fungoides

Pagetoid reticulosis

Pagetoid reticulosis arises preferentially on acral skin. The histologic hallmark of the disease is the pagetoid spread of haloed lymphoid cells in the epidermis.

Patients with localized pagetoid reticulosis 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 mycosis fungoides, extracutaneous dissemination and disease-related deaths rarely occur. (Ketron-Goodman disease, which is multilesional, has a clinical course similar to that of mycosis fungoides. Some cases may actually represent primary cutaneous epidermotropic CD8+ (cytotoxic) T-cell lymphoma.)

Folliculotropic mycosis fungoides

Folliculotropic mycosis fungoides is commonly first evident clinically with alopecia, follicular cysts, or comedolike lesions and is usually associated with follicular mucinosis and strong epidermotropism.[62] It is most commonly seen on the head and neck, often showing infiltrated plaques together with acneiform comedolike papules, epidermal cysts, and keratosis pilaris–like papules.[63] When mucin is present, the disease is also called alopecia mucinosa.

However, the benign form of alopecia mucinosa, which is not associated with mycosis fungoides, must be distinguished from mycosis fungoides 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 mycosis fungoides

Hypopigmented mycosis fungoides 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 mycosis fungoides. (See the images below.)

Hypopigmented cutaneous T-cell lymphoma. Courtesy Hypopigmented cutaneous T-cell lymphoma. Courtesy of Jeffrey Meffert, MD.
Hypopigmented cutaneous T-cell lymphoma. Courtesy Hypopigmented cutaneous T-cell lymphoma. Courtesy of Jeffrey Meffert, MD.

Pustular mycosis fungoides

A granulomatous reaction pattern occasionally is seen in mycosis fungoides and its variants. Pustular mycosis fungoides also can occur; it is often limited to the palms, but the lesions may occur elsewhere.

Bullous mycosis fungoides

Bullous mycosis fungoides manifests with flaccid, tense, or ruptured bullae arising on normal skin or an erythematous base or within typical patch- or plaque-stage lesions of mycosis fungoides. It tends to arise on the trunk and extremities. Rarely, it may clinically resemble pemphigus vulgaris or even erythema multiforme.

Hyperpigmented mycosis fungoides

Hyperpigmented mycosis fungoides is diffuse macular hyperpigmentation accompanied by typical mycosis fungoides, although in rare cases 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 mycosis fungoides

Unilesional mycosis fungoides manifests as a single area of otherwise typical mycosis fungoides that, by definition, manifests as a single lesion. Histologic changes are identical to those that occur with multiple disseminated lesions of mycosis fungoides. The prognosis is excellent following treatment, although it may recur after surgical excision.

Syringotropic mycosis fungoides

In addition to hair follicles, atypical cells in mycosis fungoides may rarely be tropic to eccrine glands. In the even rarer syringotropic mycosis fungoides (syringolymphoid hyperplasia), these are the principal or only lesions observed. 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. Most reported cases have been in men; in one series, only 4 of 14 patients were female.[64]

Poikilodermic mycosis fungoides

Poikilodermic mycosis fungoides occurs when poikiloderma (ie, poikiloderma vasculare atrophicans, which is a combination of atrophic, dry, dyspigmented skin and telangiectasia) develops in cases of otherwise typical mycosis fungoides; 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.

Granulomatous slack skin syndrome

Granulomatous slack skin syndrome is a distinct subtype of mycosis fungoides that is characterized by ponderous, more-or-less infiltrated folds of skin that arise slowly in intertriginous areas, especially the axillae and groin. Granulomatous slack skin syndrome may give rise to Hodgkin disease.

Additional variants and characteristics

Other variants of mycosis fungoides include hyperkeratotic/verrucous and vegetating/papillomatous mycosis fungoides, typically arising in the axillae, perineum, and cervical area (neck), as well as, 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 mycosis fungoides.

Mucosal involvement by mycosis fungoides 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.

Sézary syndrome

The combination of erythroderma and leukemia is defined as Sézary syndrome. 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 mycosis fungoides, 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.

Physical Examination

The following signs of cutaneous T-cell lymphoma are discussed in this section:

  • Patches and plaques

  • Skin tumors

  • Erythroderma (exfolliative dermatitis)

  • Lymphadenopathy

Ocular involvement may be evident in advanced cutaneous T-cell lymphoma.[2] Direct tumor infiltration may produce or contribute to corneal ulceration in such patients.

Cutaneous patches and plaques

The patch stage of mycosis fungoides is characterized by 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 infiltrative, they evolve into palpable plaques.

Patch-stage mycosis fungoides. Patch-stage mycosis fungoides.

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

Plaque-stage mycosis fungoides. Plaque-stage mycosis fungoides.
Partially confluent, erythematous plaques in advan Partially confluent, erythematous plaques in advancing mycosis fungoides.
Close-up view of advancing plaque-stage mycosis fu Close-up view of advancing plaque-stage mycosis fungoides with partially confluent, erythematous plaques.

Patches and plaques may affect any area of the skin, but they are often distributed asymmetrically in the sun-protected 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. However, if only tumors are present, without preceding or concurrent patches or plaques, a diagnosis of mycosis fungoides is highly unlikely and another type of cutaneous T-cell lymphoma should be considered.[30, 1] (See the images below.)

Tumor-stage cutaneous T-cell lymphoma. Tumor-stage cutaneous T-cell lymphoma.
Tumor-stage mycosis fungoides. Tumor-stage mycosis fungoides.

Skin erythroderma

Sézary syndrome is characterized by erythroderma, which is often associated with marked pruritus and exfoliation, edema, and lichenification. Lymphadenopathy, onychodystrophy, and palmoplantar hyperkeratosis are also commonly associated. In addition, patients experience thickening of the facial skin folds (leonine facies) and ectropion of the eyelids. Sun exposure may be painful, as well as pruritic. (See the image below.)

Erythroderma of Sézary syndrome. Erythroderma of Sézary syndrome.

A few patients with Sézary syndrome have patchy, total-scalp, or universal alopecia. Follicular mycosis fungoides may present with alopecia; total-body hair loss may be evident in some patients with generalized erythroderma and Sézary syndrome.[65] The alopecia may also appear clinically identical to alopecia areata. However, skin biopsy specimens may reveal atypical T lymphocytes within the follicular epithelium or epidermis, sometimes with follicular mucinosis.

Lymphadenopathy

Extracutaneous involvement in mycosis fungoides becomes more clinically evident as the stages and extent of the disease progress. 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.

Other signs of cutaneous T-cell lymphoma

Granulomatous slack skin syndrome shows circumscribed areas of pendulous, lax skin with a predilection for the axillae and groin. An association with Hodgkin lymphoma or with classic mycosis fungoides may be apparent.[66] Most patients have an indolent clinical course.

Acute adult T-cell leukemia/lymphoma is characterized by the presence of leukemia, lymphadenopathy, organomegaly, hypercalcemia, and, in approximately 50% of cases, skin lesions. Skin lesions most commonly include nodules or tumors (33%), generalized papules (22%), or plaques (19%).[42] Chronic and smoldering variants frequently manifest as skin lesions that closely resemble mycosis fungoides, whereas circulating neoplastic T cells are few or absent.

Subcutaneous panniculitis-like T-cell lymphoma is a rare form of cutaneous T-cell lymphoma. Patients are usually first seen with solitary or multiple nodules and plaques; these mainly involve 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.[67] Dissemination to extracutaneous sites is unusual. Subcutaneous panniculitis-like T-cell lymphoma may be preceded for years or decades by a seemingly benign panniculitis suggestive of chronic erythema nodosum. Rarely, it may produce scalp alopecia.[68]

Primary cutaneous peripheral T-cell lymphomas, unspecified, are a heterogeneous group of diseases for which the common characteristic is a lack of typical features of mycosis fungoides. Cutaneous gamma/delta-positive T-cell lymphoma,[31] which belongs to this group,[1, 32] usually has an aggressive course and manifests with disseminated plaques and/or ulceronecrotic nodules or tumors, particularly on the extremities.[57]

Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, a provisional entity, is characterized by localized or disseminated eruptive papules, nodules, and tumors that show central ulceration and necrosis or superficial, hyperkeratotic patches and plaques.[38, 69]

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 1 or several papules, nodules, or tumors.[70, 53]

Nasal-type extranodal NK/T-cell lymphoma usually appears as a destructive midfacial tumor or as 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.

Nasal-type extranodal NK/T-cell lymphoma 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.[71, 72]

 

DDx

Diagnostic Considerations

Cutaneous T-cell lymphomas are 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.

At times, disseminated infections such as leishmaniasis, leprosy, South American blastomycosis, coccidioidomycosis, and other deep fungal infections may mimic and require distinction from cutaneous T-cell lymphoma. Acne vulgaris, epidermal inclusion cysts, and insect bites may resemble folliculotropic mycosis fungoides.

Granulomatous mycosis fungoides with hypohidrosis may mimic lepromatous leprosy.[73] Other conditions to consider in the differential diagnosis of cutaneous t-cell lymphoma include nonlymphomatous erythroderma and erythema neurolyticum migrans.

Differential Diagnoses

 

Workup

Approach Considerations

For mycosis fungoides, clinical features, the history of the disease, and histomorphologic and cytomorphologic 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 [PCR]) constitutes an additional diagnostic criterion to distinguish cutaneous T-cell lymphoma from inflammatory dermatoses.

For a diagnosis of Sézary syndrome, one or more of the following criteria should be present[3] :

  • An absolute Sézary cell count of least 1000 cells/µL

  • Demonstration of immunophenotypic abnormalities (an expanded CD4+ T-cell population that results in a CD4/CD8 ratio of more than 10; loss of any or all of the T-cell antigens CD2, CD3, CD4, and 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 the differential diagnosis of precursor and peripheral T-cell and NK-cell lymphomas[4]

Following a diagnostic algorithm for the evaluation and diagnosis of erythroderma due to cutaneous T-cell lymphoma, versus erythroderma resulting from "reactive" causes, may be helpful.[74]

Perform the following tests in the diagnostic workup of mycosis fungoides:

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

  • Look for liver-associated enzyme abnormalities; abnormal transaminase values may indicate hepatic involvement

  • Obtain uric acid and lactate dehydrogenase (LDH) levels, since uric acid and LDH are markers of bulky and/or biologically aggressive disease

  • Conduct a 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 HTLV-I testing

Reflectance confocal microscopy

Reflectance confocal microscopy as an investigational technique in mycosis fungoides may highlight junctional atypical lymphocytes, architectural disarray, and spongiosis.[75]

Imaging studies

Chest radiography

Perform chest radiography to determine whether there is lung involvement.

CT scanning

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.

PET scanning

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

Polymerase Chain Reaction Assay

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.

Genetic Testing

Neoplastic mycosis fungoides cells have a mature CD3+, CD4+, CD45RO+, CD8- memory T-cell phenotype. Rarely, otherwise-classic mycosis fungoides may have a CD4-, CD8+ mature T-cell phenotype.[76] An aberrant phenotype, such as a loss of pan–T cell antigens (eg, CD2, CD3, CD5), is not unusual.

An identical phenotype is seen in granulomatous slack skin syndrome and Sézary syndrome. Clonal T-cell receptor gene rearrangements are detected in most mycosis fungoides cases.[77]

Many structural and numerical chromosomal abnormalities have been described in the advanced stages of mycosis fungoides, but recurrent, mycosis fungoides–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 mycosis fungoides.

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.[78]

Genetic features show T-cell receptor genes to be clonally rearranged in persons with mycosis fungoides, granulomatous slack skin syndrome, or Sézary syndrome. Demonstration of clonal T cells in the peripheral blood is an important diagnostic criterion that allows differentiation between Sézary syndrome and benign forms of erythroderma.[3]

Recurrent chromosomal translocations are not detected in persons with Sézary syndrome, but complex karyotypes are common, as is a consistent pattern of identical chromosomal abnormalities in Sézary syndrome as seen in mycosis fungoides.[79]

The neoplastic T cells in adult T-cell leukemia/lymphoma express a CD3+, CD4+, CD8- phenotype, with CD25 being highly expressed.[42] T-cell receptor genes are clonally rearranged; clonally integrated HTLV-1 genes are present and are useful in differentiating between chronic or smoldering variants of adult T-cell leukemia/lymphoma and classic mycosis fungoides or Sézary syndrome.

Panniculitis-like T-cell lymphoma shows an alpha/beta+, CD3+, CD4-, CD8+ T-cell phenotype, with expression of cytotoxic proteins.[29] CD30 and CD56 are not expressed. Neoplastic T cells do show clonal T-cell receptor gene rearrangements, although neither specific genetic abnormalities nor EBV has been identified.

Nasal-type extranodal NK/T-cell lymphoma has neoplastic cells that express CD2, CD56, and cytoplasmic CD3.

Biopsy

Perform a skin punch biopsy, which is submitted on sodium chloride–soaked gauze to allow for 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) assay was “significantly useful” in evaluating lymphadenopathy in patients with mycosis fungoides or, specifically, Sézary syndrome, “especially for triaging lymph nodes that would otherwise not be sampled or for evaluating multiple lymph nodes."[80]

In the study, the investigators assessed a series of 11 FNA biopsy specimens from 10 patients with mycosis fungoides or Sézary syndrome and performed flow cytometric immunophenotyping and TCR-gamma PCR assay on the FNA biopsy material. These were correlated with cytologic findings.[80]

Seven of 10 patients in the study demonstrated "lymph node involvement by cutaneous T-cell lymphoma, with 3 cases exhibiting large-cell transformation and 4 cases exhibiting a small-cell pattern."

Another 6 patients in the study were identified, using flow cytometric immunophenotyping, as having an abnormal T-cell population. In 2 cases—one in which insufficient events were present for evaluation by flow cytometry and one in which flow cytometry was not diagnostic of T-cell lymphoma—TCR-gamma PCR assay demonstrated a clonal T-cell rearrangement. Immunohistochemistry on cell block material revealed classic Hodgkin lymphoma in 2 cases.

Histology

In the early stages of mycosis fungoides, the histopathology is nonspecific,[81, 82, 83, 84] and the condition is often misdiagnosed as an inflammatory disorder. Early patch mycosis fungoides shows superficial bandlike or lichenoid infiltrates, mainly consisting of lymphocytes and histiocytes.

A few atypical cells with small to medium, highly indented (cerebriform), and sometimes hyperchromatic nuclei are present and are mostly confined to the epidermis (epidermotropism). They tend to colonize the basal layer of the epidermis either as single, often haloed cells or in a linear configuration,[77] especially at the tips of the rete ridges. (See the image below.)

Mycosis fungoides with large, atypical T lymphocyt Mycosis fungoides with large, atypical T lymphocytes in the epidermis and dermis.

When a clear halo surrounds an intraepidermal mononuclear cell singly or in clumps, it is called a Pautrier microabscess. Its presence is suggestive of mycosis fungoides, but it is not necessary for the diagnosis. (See the image below.)

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

To summarize, the histologic criteria for the diagnosis of mycosis fungoides include the following[85] :

  • A bandlike upper dermal infiltrate of lymphocytes and other inflammatory cells, with no grenz zone, is present

  • Epidermotropism of mononuclear cells occurs

  • Little spongiosis of the epidermis is found.

  • Lymphocytes have nuclei that are hyperchromatic and convoluted or cerebriform

Plaque and tumor stages

In mycosis fungoides plaques, the histologic changes are diagnostic; epidermotropism is generally more pronounced than in mycosis fungoides 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.

Folliculotropic mycosis fungoides

Folliculotropic mycosis fungoides 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).[30]

Most patients have mucinous degeneration of the follicular epithelium (follicular mucinosis)—which is 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 mycosis fungoides.[86] Basaloid folliculolymphoid hyperplasia is a distinctive finding in follicular mycosis fungoides.[87]

Granulomatous mycosis fungoides

Granulomatous mycosis fungoides shows sarcoidal, granuloma annulare–like, or giant cell–rich reactions. Granulomatous slack skin 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

Pagetoid reticulosis 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.

Sézary syndrome

The histology of Sézary syndrome may be nonspecific, but it is often similar to mycosis fungoides, although the cellular infiltrates in Sézary syndrome are more often monotonous,[88, 89] 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. (See the image below.)[90]

Electron micrograph of a Sézary cell. Electron micrograph of a Sézary cell.

Adult T-cell leukemia/lymphoma

In adult T-cell leukemia/lymphoma, 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 that seen with mycosis fungoides. In the smoldering type of adult T-cell leukemia/lymphoma, dermal infiltrates may be sparse, with only slightly atypical cells.

Subcutaneous panniculitis-like T-cell lymphoma

In subcutaneous panniculitis-like T-cell lymphoma, subcutaneous infiltrates simulate a panniculitis and show small, medium, or sometimes large pleomorphic T cells with hyperchromatic nuclei and often many macrophages.[31] The overlying epidermis and dermis are typically not involved.[91] Rimming of individual fat cells by neoplastic T cells is a helpful, although not completely specific, diagnostic feature.[29] Necrosis, karyorrhexis, and cytophagocytosis are common.

Primary cutaneous aggressive epidermotropic CD8

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.[38, 69] Epidermotropism tends to be marked, ranging from a linear distribution to a pagetoid pattern throughout the epidermis.

This disorder has a beta-F1+, CD3+, CD8+, granzymes-B+, perforin+, TIA-1+, CD45RA+, CD45RO, CD2-, CD4-, CD5-, CD7+/- phenotype.[53, 69] It is usually associated with EBV seronegativity. The lymphoma cells show clonal TCR gene rearrangements, although specific genetic abnormalities have not been described.

Cutaneous gamma/delta-positive T-cell lymphoma

Cutaneous gamma/delta-positive T-cell lymphoma has 3 major histologic patterns of involvement that can be present in the skin; specifically, epidermotropic, dermal, and subcutaneous.[31] More than 1 is often present in the same patient in different biopsy specimens or within a single biopsy specimen.[57] The lymphoma cells are generally medium to large, with coarsely clumped chromatin; large blastic cells with vesicular nuclei and prominent nucleoli are infrequent and apoptosis and necrosis are common, often with angioinvasion. The subcutaneous involvement may demonstrate rimming of fat cells.

Cutaneous gamma/delta-positive T-cell lymphoma cells are generally of beta-F1-, CD3+, CD2+, CD5-, CD7+/-, CD56+ phenotype with strong expression of cytotoxic proteins.[31] Most lack both CD4 and CD8, although CD8 may be expressed in some cases.[57, 92] 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.[93]

The lymphoma cells show clonal rearrangement of the TCR -gamma gene, while TCR -beta may be rearranged or deleted but is not expressed. EBV test results are usually negative.[57]

Primary cutaneous CD4

Histologically, this disorder shows dense, diffuse, or nodular infiltrates within the dermis that have a tendency to infiltrate the subcutis. 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.[94]

Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma is a CD3+, CD4+, CD8-, CD30- phenotypic lymphoma. Cytotoxic proteins are generally not expressed, and sometimes there is a loss of pan–T-cell markers.[53] The TCR genes are clonally rearranged.[70]

Nasal-type extranodal NK/T-cell lymphoma

Nasal-type extranodal NK/T-cell lymphoma has dense dermal and often subcutaneous infiltrates with prominent angiocentricity and angiodestruction, often accompanied by extensive necrosis.[54, 95]

Primary cutaneous peripheral T-cell lymphoma, unspecified

Primary cutaneous peripheral T-cell lymphoma, 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.[53]

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 for these disorders. The system is based on the particular skin findings and findings of extracutaneous disease that are observed in affected patients, with the stages defined as follows:

  • Stage IA disease (as defined by the tumor, node, metastases, blood [TNMB] system) - Patchy or plaquelike skin disease involving less than 10% of the skin surface area (T1 skin disease)

  • Stage IB - Patchy or plaquelike skin disease involving 10% or more of the skin surface area (T2 skin disease)

  • Stage IIB disease - Tumors are present (T3 skin lesions)

  • Stage III disease - Generalized erythroderma is present

  • Stage IVA1 disease - Erythroderma and significant blood involvement occur[5]

  • Stage IVA2 disease - Lymph node biopsy result shows total effacement by atypical cells (LN4 node)[5]

  • Stage IVB disease - Visceral involvement (eg, liver, lung, bone marrow) occurs

These definitions are denoted in Table 3. Table 4 lists the TNMB stage definitions. Table 5 is a comparison of the 2 systems.

Table 3. Staging of Cutaneous T-Cell Lymphoma (Open Table in a new window)

Stage

Skin Lesions

Lymphadenopathy

Erythroderma

Histology

Patches/

plaques

(less than10%)

Plaques/

plaques

(10% or more)

Tumors

Lymph Nodes

Viscera

IA

+

-

-

-

-

-

-

IB

+ or -

+

-

-

-

-

-

IIA

+ or -

+ or -

+ or -

+

-

-

-

IIB

+ or -

+ or -

+

+ or -

-

-

-

III

+ or -

+ or -

+ or -

+ or -

+

-

-

IVA

+ or -

+ or -

+ or -

+ or -

+ or -

+

-

IVB

+ or -

+ or -

+ or -

+ or -

+ or -

+ or -

+

Table 4. TNMB Staging of Cutaneous T-Cell Lymphoma (Open Table in a new window)

Stage Class

Stage

Definition

T

(tumor)

T1

Patches/plaques involving less than 10% of body surface

T2

Patches/plaques involving 10% or more of body surface

T3

Tumor(s) present on skin

T4

Erythroderma

N

(nodes)

N0

No enlarged lymph node present

N1

Enlarged lymph nodes, histologically uninvolved

N2

No enlarged lymph node; 1 or more nodes histologically involved*

N3

Enlarged lymph nodes, histologically involved

M

(metastasis to viscera)

M0

No visceral lesion present

M1

Visceral involvement

B

(blood involvement)

B0

Circulating atypical lymphocytes (Sézary cells) less than 5% of lymphocytes

B1

Circulating atypical lymphocytes 5% or more of lymphocytes (Sézary syndrome)

*Uncommon finding, usually not considered/investigated.

 

Table 5. Comparison of Staging Systems for CTCL (Open Table in a new window)

Clinical Stage

TNM (B) Stage

IA

T1 N0 M0

IIB

T2 N0 M0

IIA

T1 N1 M0

T2 N1 M0

 

IIB

T3 N0 M0

T3 N1 M0

 

III

T4 N0 M0

T4 N1 M0

 

IVA

T1 N2 M0

T2 N2 M0

T3 N2 M0

T4 N2 M0

T1 N3 M0

T2 N3 M0

T3 N3 M0

T4 N3 M0

IVB

T1 N0 M1

T2 N0 M1

T3 N0 M1

T4 N0 M1

T1 N1 M1

T2 N1 M1

T3 N1 M1

T4 N1 M1

T1 N2 M1

T2 N2 M1

T3 N2 M1

T4 N2 M1

T1 N3 M1

T2 N3 M1

T3 N3 M1

T4 N3 M1

 

Treatment

Approach Considerations

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

Mycosis fungoides treatment selection should be based on the stage and previous treatment history. 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 who are intolerant of topical treatments or whose condition has failed to respond to such treatments.[7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17]

Sequential therapies that are stage appropriate are selected on the basis of 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 respond and on the rapidity of onset of that response.

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

Treatment of localized mycosis fungoides

Localized mycosis fungoides 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 using one of the following treatment modalities[96] :

  • Irradiation
  • Photochemotherapy using ultraviolet A (UV-A) light treatment enhanced with psoralen (PUVA)
  • Photodynamic therapy
  • Carbon dioxide laser surgery

Localized radiation or a surgical approach to localized mycosis fungoides can be used. The advantage of using surgery first is that a full dose of radiation can be delivered in the same location at a later time, thus preserving options for future therapy.

A retrospective review by Thomas et al indicated that the use of a single dose of radiation (700-800 cGy) in place of multiple-fraction radiation treatment still results in excellent palliation in patients with cutaneous T-cell lymphoma. The investigators reviewed the results of radiation treatment in 270 lesions in a total of 58 patients (most of whom had mycosis fungoides); 97% of the lesions had been treated with 700 cGy or more of radiation.[97]

Over a mean follow-up period of 41.3 months, Thomas et al noted a complete response occurred in 255 (94.4%) lesions and a partial response rate occurred in 10 (3.7%) lesions. Four lesions (1.5%) demonstrated a partial response that, following a second treatment, became a complete response. Only one lesion (0.4%) showed no response.[97]

The investigators also found the following results:

  • A lower complete-response rate in the lower extremities than in other parts of the body

  • A lower complete-response rate in lesions treated with photons than in those treated with electrons

  • A lower complete-response rate in patients whose lesions demonstrated large-cell transformation and tumor morphology

  • A significantly lower overall survival rate in patients with Sézary syndrome and erythroderma than in other patients

Thomas et al also determined that the cost of multiple-fraction radiation treatment was more than 200% greater than it was for single-fraction therapy.

See also the clinical guideline summary, Guidelines for topical photodynamic therapy: update, from the British Association of Dermatologists.

Extracorporeal photophoresis

Extracorporeal photopheresis, either alone or in combination with other treatment modalities (eg, interferon alfa), is an effective treatment for Sézary syndrome and for erythrodermic mycosis fungoides, with overall response rates of 30-80% and complete response rates of 14-25%.[18] The alleged superiority of extracorporeal photopheresis over the traditional low-dose chemotherapy regimens has not been proven.

Cord blood transplantation

Unrelated cord blood transplantation is a possible therapeutic option.[19] In one patient, it was performed following myeloablative conditioning and brought a complete remission. Although a relapse occurred 3 months later, discontinuation of immunosuppressant therapy led to mycosis fungoides regression and a second complete remission that continued for more than 23 months. Reduced-intensity umbilical cord blood transplantation is another option for advanced mycosis fungoides.[98]

Bone marrow transplantation

Allogeneic transplants are reported in the literature as case reports or in small groups of patients.[99, 7] A German study suggested that allogeneic stem cell transplantation may be an important alternative option for young patients with treatment-refractory mycosis fungoides, because "complete clinical remission can be obtained even in advanced stages."[7]

Combination chemotherapy

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

However, multiagent chemotherapy is used with unequivocal lymph node or systemic involvement or in cases with widespread tumor-stage mycosis fungoides that is refractory to skin-targeted therapies and is not early patch/plaque-stage disease.

Consultations

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

Topical Therapy

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. In the patch or plaque stage of the disease, the following topical treatments are generally used:

  • Topical steroids

  • Topical retinoids

  • Topical chemotherapy - Eg, nitrogen mustard or bischloroethylnitrosourea (BCNU)

  • Ultraviolet B (UV-B) light treatment or UV-A light treatment enhanced with psoralen (PUVA)

  • Total-body electron beam radiation

These modalities are also used in combination with systemic modalities (eg, PUVA plus interferon) for higher-stage disease.

A majority of patients in the patch stage 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-stage disease will respond to PUVA (76-90% complete responses); psoralens inhibit DNA synthesis in tissues exposed to psoralen and UV-A. In addition, most cases of patch- or plaque-stage disease will respond to topical chemotherapy agents, which inhibit cell growth and proliferation (complete response rate, 60%).

Retinoids are vitamin A analogues involved in the modulation of cell growth, division, reproduction, and differentiation.[100] Their biologic effects result from alterations in gene expressions that are mediated through 2 major types of nuclear receptors, the retinoic acid receptor and the retinoic X receptor. Each receptor subtype likely controls the expression of unique and common genes. Subclass-specific retinoids are available.

Mechlorethamine topical (Valchlor) was approved in August 2013 for mycosis fungoides–type cutaneous T-cell lymphoma (MF-type CTCL). Approval was based on a trial in patients with refractory stage IA-IIA MF-type CTCL, in which 60% of patients treated with mechlorethamine had a confirmed response at 12 months, compared with 48% of those treated with a pharmacy-compounded mechlorethamine preparation.[101, 102, 103]

Systemic Therapy

Systemic treatment, such as oral retinoids, recombinant interferon alfa, fusion toxins, monoclonal antibodies, and single-agent chemotherapy, can be used sequentially to palliate symptoms from more advanced mycosis fungoides. Many active agents exist, including antimetabolites, alkylating agents, topoisomerase II inhibitors, anthracyclines, and purine analogues. The most extensive data exist for the use of methotrexate.[104]

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

  • Extracorporeal photopheresis - Leukapheresis with UV-A light treatment enhanced with psoralen (PUVA) for the collected white blood cells, with reinfusion of treated cells

  • Oral retinoids

  • Fusion toxin treatment - Recombinant toxins are generated by fusion of a plant or bacterial toxin gene to a receptor ligand; the first such toxin to enter clinical trial was DAB-interleukin 2 (DAB-IL2)

  • Histone deacetylase inhibitor treatment - These agents may inhibit gene transcription

  • CC chemokine receptor type 4 (CCR4)–directed monoclonal antibody

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.

Mogamulizumab, a CCR4-directed monoclonal antibody, was approved by the FDA in August 2018 for adults with mycosis fungoides or Sézary syndrome who have received at least 1 prior systemic therapy. Approval was based on the MAVORIC (Mogamulizumab anti-CCR4 Antibody Versus ComparatOR In CTCL) phase 3 clinical trial that compared mogamulizumab with vorinostat. Significantly superior progression-free survival (PFS) was observed with mogamulizumab (7.7 months) compared with vorinostat (3.1 months) (P < 0.0001).[105]

Specific Therapies

When mycosis fungoides is confined to the skin (cutaneous T-cell lymphoma [CTCL]), skin-targeted therapies, such as the following, are often effective in controlling manifestations[106] :

  • Topical corticosteroids

  • Heliotherapy

  • Photochemotherapy - Eg, psoralen plus UV-A (PUVA)

  • Topical application of nitrogen mustard (mechlorethamine) or carmustine (BCNU)

  • Radiotherapy - Including total skin electron beam irradiation

Bexarotene is also sometimes used for disease confined to the skin. Beneficial effects of bexarotene and of alemtuzumab (anti-CD52) have been noted, but the long-term effects of these therapies remain to be established.[107]

Psoriatic doses of methotrexate have been used, but some concern exists relating to large cell transformation occasionally observed in these patients. Narrowband UV-B therapy is another option.[108]

Treatment of stages T1 and T2 mycosis fungoides with total skin electron beam therapy is highly effective 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.[109] In patients with limited patch-stage mycosis fungoides, 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 cutaneous T-cell lymphoma.[110, 111] One small pilot study showed tazarotene 0.1% gel to be a well-tolerated and effective adjuvant topical therapy for the treatment of refractory mycosis fungoides.[112]

Biologic agents such as interferon alfa and other cytokines (eg, IL-2), traditional and newer retinoids such as bexarotene, and receptor-targeted cytotoxic fusion proteins (eg, DAB389IL-2) are increasingly being used. The fusion protein, denileukin, was discontinued in January 2014. Combination therapy with bexarotene and PUVA should be considered for patients with treatment-resistant cutaneous T-cell lymphoma that is refractory to monotherapy.[113] However, the precise use of these newer treatments, either as single-agent therapy or in combination with other therapies (eg, PUVA) in the treatment of mycosis fungoides, remains to be established.

Beneficial results have 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/day) and prednisone (10-20 mg/day), or methotrexate (MTX) (5-25 mg/wk), but complete responses are uncommon.

As previously mentioned, multiagent chemotherapy is used with unequivocal lymph node or systemic involvement or in cases with widespread tumor-stage mycosis fungoides that is refractory to skin-targeted therapies and is not early patch/plaque-stage disease.

Subcutaneous panniculitis-like T cell lymphoma usually responds poorly to chemotherapy. Cyclosporine A has shown some efficacy for cases that relapse after chemotherapy, and a case report of a long-term complete remission with cyclosporine A as a first-line therapy has been published.[114] Systemic corticosteroids have also been found effective for first-line single-agent therapy, inducing complete remission in four of five patients in one study.[115]

Treatment of Sézary Syndrome

The treatment of Sézary syndrome should be predicated on disease burden and rapidity of progression.[20] Because infection is the major cause of death in patients with mycosis Sézary syndrome, one should attempt to preserve immune response, use immunomodulatory therapy before chemotherapy unless the disease burden or therapeutic failure requires otherwise, and consider combination therapy, particularly systemic immunomodulatory therapy plus skin-directed treatments, as a better option than monotherapy.

Because Staphylococcus infection may be associated with a disease flare, systemic antibiotics should be administered when in doubt to prevent life-threatening sepsis. Pruritus treatment is an important quality-of-life consideration and should not be neglected.[116] It can be so severe that special itch-targeted therapies may need to be devised.

Mogamulizumab, a CCR4-directed monoclonal antibody, was approved by the FDA in August 2018 for adults with Sézary syndrome or mycosis fungoides who have received at least 1 prior systemic therapy.[105]  For more information, see Systemic Therapy. 

Treatment of Folliculotropic Mycosis Fungoides

Perifollicular localization of the dermal infiltrates in folliculotropic mycosis fungoides is often less responsive to skin-targeted therapies (eg, PUVA, topical nitrogen mustard) than is classic plaque-stage mycosis fungoides; total skin electron beam irradiation is superior.[117] 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 mycosis fungoides may benefit from isotretinoin for persistent cysts and comedones.[118] Many patients benefit from PUVA therapy, although they may not respond as well as patients with classic mycosis fungoides do.[63] Early syringotropic cutaneous T-cell lymphoma may be treated with local radiotherapy, with excellent local control.[119]

 

Guidelines

Guidelines Summary

Guidelines contributors: Priyank P Patel, MD, Hematology/Oncology Fellow, Roswell Park Cancer Institute, University at Buffalo; Francisco J Hernandez-Ilizaliturri, MD; Chief, Lymphoma and Myeloma Section; Professor of Medicine, Department of Medical Oncology; Director of The Lymphoma Translational Research Program; Associate Professor of Immunology, Roswell Park Cancer Institute 

NHL Classification Schemas

The three most commonly used classification schemas for non-Hodgkin lymphoma (NHL) are as follows:

  • National Cancer Institute’s Working Formulation (IWF)[120]

  • Revised European-American Classification of Lymphoid Neoplasms (REAL)[121]

  • World Health Organization (WHO) classification[122]

The Working Formulation, originally proposed in 1982, classified and grouped lymphomas by morphology and clinical behavior (ie, low, intermediate, or high grade) with 10 subgroups labeled A to J.[120] In 1994, the Revised European-American Lymphoma (REAL) classification attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic NHL entities.[121]

The World Health Organization (WHO) classification, first introduced in 2001 and updated in 2008, further elaborates upon the REAL approach. This classification divides NHL into two groups: those of B-cell origin and those of T-cell/natural killer (NK)–cell origin.[122]

Although considered obsolete, the National Cancer Institute’s Working Formulation (IWF) classification is still used mainly for historical data comparisons.[120]

The World Health Organization–European Organization for Research and Treatment of Cancer (WHO-EORTC) classification of cutaneous T-cell lymphoma (CTCL) is divided into CTCLs with indolent clinical behavior and those with aggressive subtypes. CTCLs with indolent clinical behavior include the following[1] :

  • Mycosis fungoides

  • Mycosis fungoides variants and subtypes (eg, folliculotropic mycosis fungoides, pagetoid reticulosis, granulomatous slack skin)

  • Primary cutaneous CD30+ lymphoproliferative disorder (eg, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis)

  • Subcutaneous panniculitis-like T-cell lymphoma (provisional)

  • Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)

Mycosis Fungoides/Sezary Syndrome

In addition to the guidelines from the National Comprehensive Cancer Network (NCCN)[123] , the European Organization for Research and Treatment of Cancer (EORTC) released consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome (MF/SS) in 2006.[124]  In 2013, the European Society for Medical Oncology (ESMO) included treatment recommendations in its guidelines for primary cutaneous lymphoma.[125]

Diagnosis

The NCCN considers the following studies essential for establishing a diagnosis of MF/SS[123] :

  • Biopsy of suspicious skin sites (multiple biopsies may be necessary to capture the pathologic variability of disease at diagnosis)

  • Dermatopathology review of slides (including evaluation for presence of transformation or areas of folliculotropism

  • Immunohistochemistry panel of skin biopsy (CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30, CD25, CD56, TIA1, granzyme B, ßF1, TCR-CγM1)

  • Molecular analysis to detect clonal T-cell antigen receptor (TCR) gene rearrangements or other assessment of clonality

Staging

In 2007, the ISCL/EORTC released a revised tumor-node-metastasis-blood (TNMB) classification of MF/SS based on particular skin findings and extracutaneous disease.[5]  See Table 4, below.

Table 4. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis-blood revised classification for mycosis fungoides and Sezary syndrome (Open Table in a new window)

Skin

Involvement

Node

Involvement

Viscera

Involvement

T1

Patchy or plaquelike skin disease involving ≤10% of the skin surface area

N0

No abnormal lymph nodes

M0

No visceral organ involvement

T2

Patchy or plaquelike skin disease involving ≥10% of the skin surface area

N1

Histopathology Dutch Gr 1 or NCI LN 0-2

M1

Visceral organ involvement

T3

Tumors are present ≥1 cm in diameter

N2

Histopathology Dutch Gr 2 or NCI LN 3

MX

Abnormal visceral site; no histologic confirmation

T4

Erythroderma ≥80% of body area

N3

Histopathology Dutch Gr 3-4 or NCI LN 4

Blood

Involvement

   

Nx

Abnormal lymph nodes; no histologic confirmation

B0

≤5% of peripheral blood lymphocytes are Sezary cells

       

B1

>5% of peripheral blood lymphocytes are Sezary cells but do met B2 criteria

       

B2

≥1000/mcL Sezary cells or CD4/CD8 ≥10 or ≥40% CD4+/CD7- or ≥30% CD4+/CD26- cells

The ISCL/EORTC system was further modified to update clinical staging classifications.[5]  See Table 5, below.

Table 5. Staging classifications for mycosis fungoides and Sezary syndrome (Open Table in a new window)

Clinical Stage

5-Year Survival[5]

TNM (B) Stage

IA

96-100%

T1N0M0B0

T1N0M0B1

     

IB

73-86%

T2N0M0B0

T2N0M0B1

     

IIA

49-73%

T1N1M0B0

T1N1M0B1

T1N2M0B0

T1N2M0B1

 

 

T2N1M0B0

T2N1M0B1

T2N2M0B0

T2N2M0B1

 

IIB

40-65%

T3N0M0B0

T3N0M0B1

T3N1M0B0

T3N1M0B1

 

 

T3N2M0B0

T3N2M0B1

     

IIIA

50-57%

T4N0M0B0

T4N1M0B0

T4N2M0B0

   

IIIB

T4N0M0B1

T4N1M0B1

T4N2M0B1

   

IVA

15-40%

T1N0M0B2

T2N0M0B2

T3N0M0B2

T4N0M0B2

 

 

T1N1M0B2

T2N1M0B2

T3N1M0B2

T4N1M0B2

 

 

T1N2M0B2

T2N2M0B2

T3N2M0B2

T4N2M0B2

 

 

T1N3M0B0

T2N3M0B0

T3N3M0B0

T4N3M0B0

 

 

T1N3M0B1

T2N3M0B1

T3N3M0B1

T4N3M0B1

 

 

T1N3M0B2

T2N3M0B2

T3N3M0B2

T4N3M0B2

 

IVB

0-15%

T1N0M1B0

T2N0M1B0

T3N0M1B0

T4N0M1B0

 

T1N1M1B1

T2N1M1B1

T3N1M1B1

T4N1M1B1

 

T1N2M1B2

T2N2M1B2

T3N2M1B2

T4N2M1B2

 

T1N3M1B3

T2N3M1B3

T3N3M1B3

T4N3M1B3

 

Treatment

The NCCN recommends that patients be treated at specialized centers with expertise in the management of MF/SS. Unlike other non-Hodgkin lymphoma subtypes, MF/SS criteria have not correlated with prognosis, and treatment decisions are made on a clinical basis.[123]

In 2011, the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the EORTC issued a joint consensus statement proposing new clinical end points and response criteria for use in clinical trials of MF/SS.[126]  The NCCN includes the new criteria in its current recommendations.[123]

All three guidelines recommend treatment selection based on clinical stage.[123, 124, 125]

Mycosis fungoides

In general, topical therapies are recommended for localized disease (stages IA, IB and IIA), with systemic or combination systemic and topical therapies beginning with stage IIB. Systemic therapies may also be considered in patients with early-stage disease that does not respond to topical treatments.[123, 124, 125]

Localized therapies endorsed by the guidelines include the following[123, 124, 125]

  • Psoralens + ultraviolet A (PUVA)—For thick plaques

  • Narrow-band ultraviolet B (UVB)—For patch or thin plaques

  • Topical corticosteroids

  • Localized radiation therapy (12-36 Gy)

  • Topical chemotherapy (ie, nitrogen mustard or carmustine)

  • Topical retinoids (ie, bexarotene)

Because of the high toxicity of total skin electron beam therapy (TSEBT), both NCCN and EOTRTC recommend TSEBT only after other treatments have failed.[123, 124]

Systemic therapies recommended for advanced stages include the following[123, 124, 125]

  • Retinoids (ie, bexarotene)

  • Interferons (IFN-alpha, IFN-gamma)

  • Histone deacetylase (HDAC)-inhibitors (vorinostat, romidenpsin)—not approved in Europe

  • Extracorporeal photopheresis (ECP)

  • Methotrexate (≤100 mg/wk)

All three guidelines recommend IFN-alpha and PUVA or PUVA and retinoids (including bexarotene) as second-line combination therapies for MF stages IA, IB, and IIA.[123, 124, 125]

Other NCCN recommended combination therapies for advanced disease include the following[123] :

  • PUVA and ECP

  • TSEBT and ECP

  • Retinoids and interferons

  • ECP and retinoids

  • ECP and interferons

  • ECP and retinoids and interferons

Sezary syndrome and erythrodermic mycosis fungoides

Participation in a clinical trial as a treatment option for all patients with SS or advanced-stage MF is recommended by both the NCCN and EOTRTC. [123, 124]  Treatment for SS or erythrodermic MF (stage IV) is palliative. The preferred modality is ECP, either alone or in combination with other treatments.[123, 124, 125]

Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders

In 2011, the the European Organization for Research and Treatment of Cancer (EORTC), the International Society for Cutaneous Lymphoma (ISCL), and the US Cutaneous Lymphoma Consortium (USCLC) published joint consensus recommendations for the management of primary cutaneous CD30+ T-Cell lymphoproliferative disorders (CD30+LPDs).[127]

Classification

Under the WHO-EORTC classification system for cutaneous lymphomas, primary CD30+LPDs represent a wide spectrum of disease, with lymphomatoid papulosis (LyP) at the benign end of the spectrum and primary cutaneous anaplastic large cell (PC-ALCL) lymphoma at the malignant end. Borderline lesions lie somewhere in between, with overlapping clinical and histopathologic features.[1]

Diagnosis

The National Comprehensive Cancer Network (NCCN) recommendations to establish a diagnosis of CD30+LPDs include the following[123] :

  • Differentiation of LyP and PC-ALCL from other forms of cutaneous T-cell lymphoma and secondary cutaneous involvement by nodal Hodgkin lymphoma or systemic ALCL requires careful clinicopathologic correlation

  • Mycosis fungoides can be comorbid

  • Clinical features include solitary or localized nodules or tumors (often ulcerated); multifocal lesions occur in about 20% of cases; extracutaneous disease occurs in about 10% of cases, usually involving regional lymph nodes

  • Immunohistochemistry (IHC) panel of skin biopsy specimen: CD3, CD4,CD8, CD20, CD30, CD56, βF1, ALK1

  • Expanded IHC: CD2, CD5, CD7, CD25,TIA1, granzyme B, perfornin, GM1, EBER-ISH

  • Histologically characterized by diffuse, cohesive sheets of large CD30-positive (in >75%) cells with anaplastic, pleomorphic, or immunoblastic appearance

  • Molecular analysis of skin biopsy: TCR gene rearrangements

  • Excisional or incisional biopsy of suspicious lymph nodes (in absence of definitive skin diagnosis)

  • Assessment of HTLV-1 serology in at-risk populations to identify CD30+ adult T-cell leukemia/lymphoma (ATLL)

  • Bone marrow biopsy only in cases of multifocal tumors, unexplained hematologic results, or presence of where extracutaneous disease

Staging

EORTC, ISCL, and USCLC guidelines recommend staging according to the 2007 tumor-node-metastasis (TNM) ISCL/EORTC staging of cutaneous lymphomas other than mycosis fungoides/Sezary syndrome.[27, 127]

Treatment

Both guidelines give similar treatment recommendations for PC-ALCL, as follows[123, 127] :

  • For solitary or grouped lesions, surgical excision or radiation therapy for first-line treatment

  • Relapses are equally frequent after both treatments; if confined to the skin, treatment can be repeated

  • For multifocal lesions, low-dose methotrexate may be used, based on expert consensus; retinoids and interferon alpha are alternative treatments for multifocal disease that is not responsive to other therapies, but data are limited on effectiveness. Newer promising agents include pralatrexate and CD30 antibody-drug conjugate brentuximab vedotin[104, 128]

  • Multi-agent chemotherapy is not recommended for multifocal or relapsing PC-ALCL limited to the skin; it is recommended only for extracutaneous spread

 

Medication

Medication Summary

Cutaneous T-cell lymphomas are a heterogeneous group of entities. One should distinguish indolent, low-risk mycosis fungoides and Sézary syndrome from aggressive HTLV-1–associated adult T-cell leukemia/lymphoma.[129]

Treatment for early stage cutaneous T-cell lymphomas includes topical therapies with or without interferon alfa or oral agents, while advanced-stage patients are treated with chemotherapy and novel agents. Multiagent cytotoxic regimens may be palliative, but they seem to lack a demonstrated survival benefit.[6]

Novel therapies for cutaneous T-cell lymphoma include bexarotene, which has demonstrated efficacy in advanced refractory cases of the disease. Other novel agents include the following:

  • IL-2 fusion toxin (Ontak)

  • IL-12

  • Pentostatin (a potent adenosine deaminase inhibitor)

  • Forodesine

  • Gemcitabine[130]

  • Histone deacetylase inhibitors (eg, romidepsin,[131] depsipeptide)

  • NF-kappa-B inhibitors

  • Cytokine-receptor antagonists

  • Immunomodulatory therapies

  • Allogeneic stem cell therapy

  • Mogamulizumab[105]

Mogamulizumab was approved by the FDA in August 2018 for adults with 2 rare forms of CTCL (ie, mycosis fungoides, Sézary syndrome).

Forodesine is a potent inhibitor of purine nucleoside phosphorylase that promotes apoptosis in T- and B- cells through intracellular accumulation of deoxyguanosine triphosphate. In a phase II study of oral forodesine therapy in 144 patients with CTCL who had already failed three or more systemic therapies, no patients achieved complete remission but 11% achieved partial remission and 50% had stabilization of disease.[132]

The value of new therapeutic approaches to cutaneous T-cell lymphoma needs to be critically assessed with regard to overall survival and disease-specific survival.

Antineoplastics, Other

Class Summary

These agents inhibit cell growth and proliferation.

Chlorambucil (Leukeran)

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

Vorinostat (Zolinza)

Vorinostat is a histone deacetylase (HDAC) inhibitor. HDAC inhibition causes hypoacetylation of core nucleosomal histones, condenses chromatin structure, and represses gene transcription. This agent is indicated for treatment of progressive, persistent, or recurrent cutaneous T-cell lymphoma.

Methotrexate (Trexall, Otrexup, Rasuvo)

Methotrexate is a folic acid antagonist that inhibits dihydrofolate reductase, an enzyme needed to make DNA.

Etoposide (Toposar)

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

Romidepsin (Istodax)

Romidepsin is a histamine deacetylase (HDAC) inhibitor. It is indicated for cutaneous T-cell lymphoma in patients who have received at least one prior systemic therapy.

Denileukin diftitox (Ontak)

This product was discontinued in January 2014. This is a 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. Denileukin diftitox is used only in T-cell lymphoma in which malignant cells express the CD25 component of the IL-2 receptor. It interacts with the high-affinity IL-2 receptor on the surface of malignant cells to inhibit intracellular protein synthesis, which in turn causes cell death.

Carmustine (BiCNU)

Carmustine alkylates and cross-links DNA strands, inhibiting cell proliferation.

Mechlorethamine (Mustargen)

This is a topical nitrogen mustard that, as an alkylating agent, inhibits DNA replication.

Bexarotene (Targretin)

Bexarotene (Targretin) is an X-receptor–specific retinoid. The receptor works as transcription factors that regulate genes that control cellular differentiation and proliferation. It may inhibit sebaceous gland differentiation and abnormal keratinization.

Immunomodulators

Class Summary

These agents may modulate the host immune system to inhibit the growth and proliferation of malignant cells.

Interferon alfa 2b (Intron-A)

Interferon alfa 2b is a protein product manufactured by recombinant DNA technology. Its mechanism of antitumor activity is not clearly understood. However, direct antiproliferative effects against malignant cells and modulation of the host immune response may play important roles.

Antineoplastics, Monoclonal Antibody

Class Summary

Monoclonal antibodies against a T-cell antigen may inhibit cell growth and proliferation of malignant cells.

Alemtuzumab (Campath, Lemtrada)

Alemtuzumab is a monoclonal antibody against CD52, an antigen found on B cells, T cells, and almost all CLL cells. It binds to the CD52 receptor of lymphocytes, slowing the proliferation of leukocytes.

Mogamulizumab (mogamulizumab-kpkc, Poteligeo)

CC chemokine receptor type 4 (CCR4)-directed monoclonal antibody indicated for adults with relapsed or refractory mycosis fungoides or Sézary syndrome after at least 1 prior systemic therapy.

Topical Skin Products

Class Summary

Agents that induce secretion of interferon and other cytokines have shown efficacy. The topical alkylating agent, mechlorethamine, has also been shown to be effective.

Imiquimod 5% cream (Aldara, Zyclara)

This agent binds to Toll-like receptors 7 and 8 and induces the secretion of interferon alfa and other cytokines. Its mechanism of action is unknown.

Mechlorethamine topical (Valchlor)

Mechlorethamine topical is an alkylating agent that inhibits rapidly proliferating cells. It is indicated for mycosis fungoides-type cutaneous T-cell lymphoma.

Retinoid-like Agents

Class Summary

Retinoids regulate genes that control cellular differentiation and proliferation.

Alitretinoin topical (Panretin)

Off-label use. Alitretinoin is a retinoid, related to vitamin A. It has immunomodulating and anti-inflammatory effects. Binds to both retinoid acid receptor and retinoid X receptor.

Tazarotene gel (Avage, Fabior, Tazorac)

This agent is a retinoid prodrug with an active metabolite that modulates the differentiation and proliferation of epithelial tissue. It may also have anti-inflammatory and immunomodulatory properties.

Corticosteroids

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisone (Rayos)

Prednisone is an immunosuppressant; it should be used together with other agents such as low-dose chlorambucil and interferon alfa. Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body.

Prednisolone (Orapred, Pediapred, Millipred)

It is an immunosuppressant; it should be used together with other agents such as low-dose chlorambucil and interferon alfa. Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body.

 

Questions & Answers

Overview

What is cutaneous T-cell lymphoma (CTCL)?

What are the signs and symptoms of Sézary syndrome cutaneous T-cell lymphoma (CTCL)?

How is Sézary syndrome cutaneous T-cell lymphoma (CTCL) treated?

What are the WHO classifications for cutaneous T-cell lymphoma (CTCL)?

Which types of cutaneous T-cell lymphoma (CTCL) have indolent clinical behavior?

Which types of cutaneous T-cell lymphoma (CTCL) have aggressive clinical behavior?

What are the stages of classic mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

How is mycosis fungoides cutaneous T-cell lymphoma (CTCL) diagnosed?

Which lab tests are indicated in the workup of mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What are the diagnostic criteria for Sézary syndrome cutaneous T-cell lymphoma (CTCL)?

Which imaging studies are indicated in the workup of cutaneous T-cell lymphoma (CTCL)?

Which staging system is used for the mycosis fungoides and Sézary syndrome types of cutaneous T-cell lymphoma (CTCL)?

How is early stage cutaneous T-cell lymphoma (CTCL) treated?

How is mycosis fungoides cutaneous T-cell lymphoma (CTCL) treated?

What topical therapies are available for mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

Which medications are used in the management of cutaneous T-cell lymphoma (CTCL)?

What is the historical background for cutaneous T-cell lymphoma (CTCL)?

How is primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma characterized?

How common is mycosis fungoides cutaneous T-cell lymphoma (CTCL) and how is it characterized?

What is the prevalence of Sézary syndrome in cutaneous T-cell lymphoma (CTCL)?

How are cutaneous T-cell lymphomas (CTCL) classified?

What is primary cutaneous CD30-positive lymphoproliferative disorder in cutaneous T-cell lymphoma (CTCL)?

What are the manifestations of cutaneous T-cell anaplastic large cell lymphoma (ALCL)?

How is CD30-positive primary cutaneous T cell lymphoproliferative disorder distinguished from systemic anaplastic large cell lymphoma (ALCL)?

What is the workup for staging primary cutaneous CD30-positive lymphoproliferative disorder in cutaneous T-cell lymphoma (CTCL)?

What is the manifestation of lymphomatoid papulosis cutaneous T-cell lymphoma (CTCL)?

How is subcutaneous panniculitis-like T-cell lymphoma characterized?

What are the histologic findings in subcutaneous panniculitis-like T-cell lymphoma?

What are the immunologic findings of subcutaneous panniculitis-like T-cell lymphoma?

What are the types of subcutaneous panniculitis-like T-cell lymphoma?

How is the presentation of primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma characterized?

What are the aggressive subtypes of cutaneous T-cell lymphoma (CTCL)?

How is adult cutaneous T-cell lymphoma (CTCL) characterized?

How is nasal-type extranodal NK/T-cell lymphoma characterized?

How is primary cutaneous peripheral T-cell lymphoma, unspecified (PTCL-U) characterized?

What is the historical background of mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What are the race-related demographics of mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What are the variants of mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

How does folliculotropic mycosis fungoides cutaneous T-cell lymphoma (CTCL) manifest?

How does pagetoid reticulosis cutaneous T-cell lymphoma (CTCL) manifest?

How does granulomatous slack skin cutaneous T-cell lymphoma (CTCL) manifest?

What is the patient education for cutaneous T-cell lymphoma (CTCL)?

What is the pathophysiology of cutaneous T-cell lymphoma (CTCL)?

What is the pathophysiology of mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What causes cutaneous T-cell lymphoma (CTCL)?

What environmental factors play a role in the etiology of cutaneous T-cell lymphoma (CTCL)?

What is the prevalence of cutaneous T-cell lymphoma (CTCL)?

What are the race-related demographics of cutaneous T-cell lymphoma (CTCL)?

Is cutaneous T-cell lymphoma (CTCL) more common in men or women?

Which age groups are most commonly affected by cutaneous T-cell lymphoma (CTCL)?

What is the mortality and prognosis of cutaneous T-cell lymphoma (CTCL)?

What are prognostic factors of cutaneous T-cell lymphoma (CTCL)?

Which factors are associated with poor outcomes in cutaneous T-cell lymphoma (CTCL)?

What is the prognosis of Sézary syndrome cutaneous T-cell lymphoma (CTCL)?

What is the prognosis of folliculotropic mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the prognosis of adult T-cell leukemia/lymphoma?

What is the prognosis of subcutaneous panniculitis-like T-cell lymphoma?

What is the prognosis of unilesional pagetoid reticulosis cutaneous T-cell lymphoma (CTCL)?

What is the prognosis of primary cutaneous peripheral T-cell lymphoma, unspecified (PTCL-U)?

What is the prognosis of nasal-type NK/T-cell lymphoma?

What is the prognosis of granulomatous cutaneous T-cell lymphomas (CTCL)?

What is the prognosis of the provisional entities of cutaneous T-cell lymphoma (CTCL)?

What are potential complications of mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

Presentation

What is the clinical history of hypopigmented mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of bullous mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of classic mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of stages IA and IB mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of stages IIA and IIB mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of D&#39;emblee mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of stage III mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of stages IVA and IVB mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the clinical history large cell transformation of mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of pagetoid reticulosis cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of folliculotropic mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of pustular mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of hyperpigmented fungoides cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of unilesional mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of syringotropic mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of poikilodermatous mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of granulomatous slack skin syndrome in cutaneous T-cell lymphoma (CTCL)?

What are additional variants and characteristics of the mycosis fungoides type of cutaneous T-cell lymphoma (CTCL)?

What is the clinical history of Sézary syndrome in cutaneous T-cell lymphoma (CTCL)?

How is erythroderma characterized in Sézary syndrome cutaneous T-cell lymphoma (CTCL)?

What are the signs of cutaneous T-cell lymphoma (CTCL)?

How are patches and plaques characterized in cutaneous T-cell lymphoma (CTCL)?

What are the physical findings of skin tumors in cutaneous T-cell lymphoma (CTCL)?

What are the physical findings of lymphadenopathy in cutaneous T-cell lymphoma (CTCL)?

What are the physical findings of granulomatous slack skin syndrome in cutaneous T-cell lymphoma (CTCL)?

What are the physical findings of acute adult T-cell leukemia/lymphoma?

What are the physical findings of subcutaneous panniculitis-like T-cell lymphoma?

What are the physical findings of primary cutaneous peripheral T-cell lymphoma?

What are the physical findings of primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma?

What are the physical findings of primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma?

What are the physical findings of nasal-type extranodal NK/T-cell lymphoma?

DDX

What are the diagnostic considerations in the workup of cutaneous T-cell lymphoma (CTCL)?

What are the differential diagnoses for Cutaneous T-Cell Lymphoma?

Workup

What are the approach considerations in the workup of mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What are the diagnostic criteria for Sézary syndrome in cutaneous T-cell lymphoma (CTCL)?

Which lab tests are indicated in the workup of mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the role of reflectance confocal microscopy in the workup of cutaneous T-cell lymphoma (CTCL)?

Which imaging studies are indicated in the workup of cutaneous T-cell lymphoma (CTCL)?

What is the role of polymerase chain reaction (PCR) assay in the workup of cutaneous T-cell lymphoma (CTCL)?

What is the role of genetic testing in the workup of cutaneous T-cell lymphoma (CTCL)?

What is the role of genetic testing in the workup of mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What are the genetic features of cutaneous T-cell lymphoma (CTCL)?

When is biopsy indicated in the workup of cutaneous T-cell lymphoma (CTCL)?

What are the biopsy findings in cutaneous T-cell lymphoma (CTCL)?

What are the histologic findings of mycosis fungoides in cutaneous T-cell lymphoma (CTCL)?

What are the histologic findings of primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma?

What are the histologic criteria for a diagnosis of mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

How are the histologic findings in mycosis fungoides plaques characterized in cutaneous T-cell lymphoma (CTCL)?

What are the histologic findings of folliculotropic mycosis fungoides in cutaneous T-cell lymphoma (CTCL)?

What are the histologic findings of granulomatous mycosis fungoides in cutaneous T-cell lymphoma (CTCL)?

What are the histologic findings of pagetoid reticulosis in cutaneous T-cell lymphoma (CTCL)?

What are the histologic findings of Sézary syndrome in cutaneous T-cell lymphoma (CTCL)?

What are the histologic findings of adult T-cell leukemia/lymphoma in cutaneous T-cell lymphoma (CTCL)?

What are the histologic findings of subcutaneous panniculitis-like T-cell lymphoma?

What are the histologic findings of cutaneous gamma/delta-positive T-cell lymphoma?

What are the histologic findings of primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma?

What are the histologic findings of nasal-type extranodal NK/T-cell lymphoma?

What are the histologic findings of primary cutaneous peripheral T-cell lymphoma?

What are the stages of mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

Treatment

What are the approach considerations in the treatment of cutaneous T-cell lymphoma (CTCL)?

How is localized mycosis fungoides cutaneous T-cell lymphoma (CTCL) treated?

How effective is the treatment of localized mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the role of extracorporeal photopheresis in the treatment of cutaneous T-cell lymphoma (CTCL)?

What is the role of cord blood transplantation in the treatment of cutaneous T-cell lymphoma (CTCL)?

What is the role of bone marrow transplantation in the treatment of cutaneous T-cell lymphoma (CTCL)?

What is the role of combination chemotherapy in the treatment of cutaneous T-cell lymphoma (CTCL)?

Which specialist consultations are indicated in the treatment of cutaneous T-cell lymphoma (CTCL)?

What topical therapies are indicated in the treatment of cutaneous T-cell lymphoma (CTCL)?

How effective is topical therapy for the treatment of cutaneous T-cell lymphoma (CTCL)?

What topical agents are available for the treatment of cutaneous T-cell lymphoma (CTCL)?

What systemic treatments are used in the management of cutaneous T-cell lymphoma (CTCL)?

What skin-targeted therapies are used in the treatment of cutaneous T-cell lymphoma (CTCL)?

What are the benefits of bexarotene or alemtuzumab in the treatment of cutaneous T-cell lymphoma (CTCL)?

What is the role of methotrexate in the treatment of cutaneous T-cell lymphoma (CTCL)?

How effective is total skin electron beam therapy for the treatment of stages T1 and T2 mycosis fungoides in cutaneous T-cell lymphoma (CTCL)?

What is the role of tazarotene, etoposide, or imiquimod in the treatment of early cutaneous T-cell lymphoma (CTCL)?

Which biologic agents are used in the treatment of cutaneous T-cell lymphoma (CTCL)?

When is multiagent chemotherapy indicated in the treatment of cutaneous T-cell lymphoma (CTCL)?

Which medications are indicated in the treatment of subcutaneous panniculitis-like T cell lymphoma?

How is Sézary syndrome cutaneous T-cell lymphoma (CTCL) treated?

How is follicular mycosis fungoides cutaneous T-cell lymphoma (CTCL) treated?

Guidelines

What are the classifications of cutaneous T-cell lymphoma (CTCL)?

What are the classification schemas for non-Hodgkin lymphoma (NHL) and cutaneous T-cell lymphoma (CTCL)?

When were consensus guidelines released for the treatment of mycosis fungoides and Sezary syndrome (MF/SS) in cutaneous T-cell lymphoma (CTCL)?

Which studies are recommended to establish a diagnosis of mycosis fungoides/Sezary syndrome (MF/SS) in cutaneous T-cell lymphoma (CTCL)?

What is the tumor-node-metastasis-blood (TNMB) classification of mycosis fungoides/Sezary syndrome (MF/SS) in cutaneous T-cell lymphoma (CTCL)?

What are the treatment guidelines for mycosis fungoides/Sezary syndrome (MF/SS) in cutaneous T-cell lymphoma (CTCL)?

What is the recommended treatment for mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What are the recommended localized therapies for mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What are the recommended systemic therapies for mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What are the recommended therapies for advanced mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

What is the role of participation in a clinical trial in the treatment of Sezary syndrome and erythrodermic mycosis fungoides cutaneous T-cell lymphoma (CTCL)?

Which organizations are represented in the joint consensus recommendations for the management of primary cutaneous CD30+ T-Cell lymphoproliferative disorders (CD30+LPDs)?

What is the classifications of primary cutaneous CD30+ T-Cell lymphoproliferative disorders (CD30+LPDs)?

What are the recommended diagnostic criteria for primary cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+LPDs)?

What are the stages of primary cutaneous CD30+ T-Cell lymphoproliferative disorders (CD30+LPDs)?

What are the treatment recommendations for primary cutaneous CD30+ T-Cell lymphoproliferative disorders (CD30+LPDs)?

Medications

What is the drug treatment for cutaneous T-cell lymphoma (CTCL)?

What are the novel therapies for cutaneous T-cell lymphoma (CTCL)?

Which medications in the drug class Corticosteroids are used in the treatment of Cutaneous T-Cell Lymphoma?

Which medications in the drug class Retinoid-like Agents are used in the treatment of Cutaneous T-Cell Lymphoma?

Which medications in the drug class Topical Skin Products are used in the treatment of Cutaneous T-Cell Lymphoma?

Which medications in the drug class Antineoplastics, Monoclonal Antibody are used in the treatment of Cutaneous T-Cell Lymphoma?

Which medications in the drug class Immunomodulators are used in the treatment of Cutaneous T-Cell Lymphoma?

Which medications in the drug class Antineoplastics, Other are used in the treatment of Cutaneous T-Cell Lymphoma?