AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

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

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

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

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

Pagetoid reticulosis is a variant of MF and is characterized by the presence of localized patches or plaques with an intraepidermal proliferation of neoplastic T cells. The term pagetoid reticulosis should be restricted to the localized type (Woringer-Kolopp type) and should not be used to describe the disseminated type (Ketron-Goodman type). Generalized cases should probably be classified as aggressive epidermotropic CD8⁺ CTCL, CGD-TCL, or tumor-stage MF.⁵

GSS syndrome is a rare subtype of CTCL characterized by the slow development of folds of lax skin in the major skin folds and, histologically, by an infiltrate of clonal T cells, with exceptionally large multinucleated giant cells sometimes showing inclusion of fragmented elastic fibers.

Sézary syndrome (SS) has been defined historically by the triad of erythroderma, generalized lymphadenopathy, and the presence of neoplastic T cells (Sézary cells) in skin, lymph nodes, and peripheral blood. Some authorities believe the diagnosis of SS should include one or more of the following⁶:

• An absolute Sézary cell count of least 1000/µL
• Demonstration of immunophenotypical abnormalities (an expanded CD4⁺ T-cell population resulting in a CD4/CD8 ratio of more than 10:1; loss of any or all of the T-cell antigens CD2, CD3, CD4, CD5; or loss of both CD4 and CD5)
• Demonstration of a T-cell clone in the peripheral blood by molecular or cytogenetic methods

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

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell neoplasm etiologically linked with the human T-cell leukemia virus 1 (HTLV-1). Cutaneous lesions are usually a manifestation of widely disseminated disease, although a slowly progressive form that may only involve the skin may occur.⁷

Subcutaneous panniculitislike T-cell lymphoma (SPTL) is a cytotoxic T-cell lymphoma characterized by the presence of primarily subcutaneous infiltrates of small, medium, or large pleomorphic T cells and many macrophages, predominantly affecting the legs and often complicated by a hemophagocytic syndrome.⁸ At least 2 groups of SPTL with different histologies, phenotypes, and prognoses can be distinguished. Cases with an alpha/beta-positive T-cell phenotype are usually CD8⁺, are restricted to the subcutaneous tissue (with no dermal or epidermal involvement), and tend to run an indolent clinical course.^{9, 10} The SPTL designation is only used for patients with an alpha/beta-positive T-cell phenotype, whereas those with a gamma/delta T-cell phenotype are now categorized as having CGD-TCL.^{1, 2, 3, 10, 11}

Extranodal NK/T-cell lymphoma, nasal type, is an Epstein-Barr virus (EBV)–positive lymphoma of small, medium, or large cells, usually with an NK-cell, or, more rarely, a cytotoxic T-cell phenotype. The skin is the second most common site of involvement, with the nasal cavity/nasopharynx being the most common and the reason why it was once known as a legal midline granuloma. Cutaneous involvement may be primary or secondary. Because both primary and secondary involvement are clinically aggressive and require the same type of treatment, distinction between the 2 cutaneous involvements seems unnecessary.^{10, 12, 13}

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

• Primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma, a provisional entity, is characterized by a proliferation of epidermotropic CD8⁺ cytotoxic T cells and aggressive clinical behavior.⁵
• CGD-TCL is composed of a clonal proliferation of mature, activated gamma/delta T cells with a cytotoxic phenotype.^{11, 14, 15} It may be primary or secondary cutaneous lymphoma.
• Primary cutaneous CD4⁺ small/medium-sized pleomorphic T-cell lymphoma is the diagnosis used when a predominance of small- to medium-sized CD4⁺ pleomorphic T cells are present without a history of patches and plaques typical of MF.¹⁶

For additional information from other eMedicine articles, see T-Cell Disorders, Mycosis Fungoides, and Lymphoma, Cutaneous T-Cell. Additionally, see Medscape's Biologic Therapies in Cancer Resource Center and Skin Cancer Resource Center.

Pathophysiology

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

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

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

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

Frequency

United States

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

International

CTCLs account for 65% of cutaneous lymphomas. CTCLs have a worldwide distribution, with no well-identified increase in prevalence in any region. Some studies have identified an increase in prevalence in industrial populations (eg, among workers who use machine cutting oils). ATLL is endemic in areas with a high prevalence of HTLV-1 infection, such as southwest Japan, the Caribbean islands, South America, and parts of Central Africa. ATLL occurs in 1-5% of seropositive individuals after more than 2 decades of viral persistence.⁷ Nasal NK/T-cell lymphoma, which is associated with EBV infection, is more common in Asia, Central America, and South America.

Race

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

Sex

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

Age

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

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Classic MF

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

Stages IA and IB

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

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

Stages IIA and IIB

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

D'emblee MF

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

Stage IVA and stage IVB

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

Transformation of MF

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

Pagetoid reticulosis, localized (Woringer-Kolopp) type

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

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

Erythrodermic (stage III) MF

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

Variants of MF

• Folliculotropic MF (FMF) is commonly first evident clinically with alopecia, follicular cysts, or comedolike lesions and is usually associated with follicular mucinosis and strong epidermotropism.¹⁷ When mucin is present, the disease is also called alopecia mucinosa. However, the benign form of alopecia mucinosa, not associated with MF, must be distinguished from MF associated with mucinosis. The most relevant feature, with and without associated follicular mucinosis, is the deep follicular and perifollicular localization of the neoplastic infiltrates, which makes them less accessible to skin-targeted therapies.
• Hypopigmented MF tends to occur in young, slightly to moderately dark-skinned people of Indian, Latin American, or sub-Saharan African American heritage. It manifests as irregular but fairly well-demarcated hypopigmented or white patches. They are asymptomatic or are slightly pruritic and may appear with or without other lesions typical of MF.
• A granulomatous reaction pattern occasionally is seen in MF and its variants.
• Bullous MF manifests with flaccid, tense, or ruptured bullae arising on normal skin, an erythematous base, or within typical patch- or plaque-stage lesions of MF. It tends to arise on the trunk and extremities. Rarely, it may clinically resemble pemphigus vulgaris or even erythema multiforme.
• Pustular MF is often limited to the palms, but the lesions may occur elsewhere.
• Hyperpigmented MF is diffuse macular hyperpigmentation accompanied by typical MF, or, rarely, the hyperpigmentation may be the only manifestation. These lesions may resemble ashy dermatosis or may appear as more or less well-defined macules. Ultrastructural studies have revealed atypical lymphocytes and keratinocytes, macrophages, and Langerhans cells that contain giant melanosomes within lysosomes.
• Unilesional MF manifests as a single area of otherwise typical MF that, by definition, comprises a single lesion. Histological changes are identical to those that occur with multiple disseminated lesions of MF. The prognosis is excellent following treatment, although it may recur after surgical excision. In addition to hair follicles, atypical cells in MF may rarely be tropic to eccrine glands. In the even rarer syringotropic MF (syringolymphoid hyperplasia), these are the principal or only lesions observed. Both the eccrine duct and the eccrine gland are typically involved and eccrine epithelium may appear hyperchromatic and atypical, mimicking eccrine carcinoma. Lesions manifest as red to skin-colored papules, red-to-brown patches, or red scaly plaques. Hair loss without mucinous degeneration in the affected areas is common. All reported cases to date have been in men.
• Pagetoid reticulosis (Woringer-Kolopp disease) arises preferentially on acral skin as a single, slowly growing psoriasiform plaque. Dissemination or extracutaneous manifestation does not occur. The histologic hallmark of the disease is the pagetoid spread of haloed lymphoid cells in the epidermis.
• Poikilodermic MF is when poikiloderma (ie, poikiloderma vasculare atrophicans, which is a combination of atrophic, dry, dyspigmented skin and telangiectasia) develops in cases of otherwise typical MF; this is not an infrequent occurrence. Occasionally, it may predominate or even be the only presenting manifestation of the disease. It may rarely involve skin over the entire body.
• Other variants of MF include hyperkeratotic/verrucous and vegetating/papillomatous MF, typically arising in the axillae, perineum, cervical area (neck), and sometimes on the breasts near the areolae, resembling acanthosis nigricans or multiple seborrheic keratosis.
• Persistent pigmented purpuralike-to-lichenoid processes also may be a manifestation of MF.
• Mucosal involvement by MF is rare and may occur as part of generalized involvement in advanced cases, particularly those that have undergone large cell transformation; it is a poor prognostic sign.
• GSS syndrome is a distinct subtype of MF characterized by ponderous, more-or-less infiltrated folds of skin that arise slowly in intertriginous areas, especially the axillae and groin. GSS syndrome may give rise to Hodgkin disease.

Sézary syndrome

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

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

Extranodal NK/T-cell lymphoma, nasal type

Extranodal nasal-type NK/T-cell lymphoma is an EBV-positive lymphoma of small, medium, or large cells with an NK-cell or cytotoxic T-cell phenotype.¹⁸

Physical

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

• Initially, MF has a predilection for the buttocks and other sun-protected areas. In tumor-stage MF, the usual presentation is a combination of patches, plaques, and tumors; the tumors often show ulceration. However, if only tumors are present, without preceding or concurrent patches or plaques, a diagnosis of MF is highly unlikely and another type of CTCL should be considered.^{1, 2}
• SS occurs almost exclusively in adults. It is characterized by erythroderma, often associated with marked pruritus and exfoliation, edema, and lichenification. Lymphadenopathy, alopecia, onychodystrophy, and palmoplantar hyperkeratosis are commonly associated.
• GSS syndrome shows circumscribed areas of pendulous lax skin with a predilection for the axillae and groin. An association with Hodgkin lymphoma or with classic MF may be apparent.¹⁹ Most patients have an indolent clinical course.
• Acute ATLL is characterized by the presence of leukemia, lymphadenopathy, organomegaly, hypercalcemia, and, in approximately 50%, skin lesions. Skin lesions most commonly include nodules or tumors (33%), generalized papules (22%), or plaques (19%).⁷ Chronic and smoldering variants frequently manifest as skin lesions that closely resemble MF, whereas circulating neoplastic T cells are few or absent.
• SPTL is a rare form of CTCL; only alpha/beta-types are included. Patients are usually first seen with solitary or multiple nodules and plaques, mainly involving the legs, although they may be more generalized. Ulceration is uncommon, but systemic symptoms such as fever, fatigue, and weight loss may be present. A hemophagocytic syndrome may be present and is generally associated with a rapidly progressive course.²⁰ Dissemination to extracutaneous sites is unusual. SPTL may be preceded for years or decades by a seemingly benign panniculitis suggestive of chronic erythema nodosum. Rarely, it may produce scalp alopecia.²¹
• Primary cutaneous PTL, unspecified, is a heterogeneous group of diseases for which the common characteristic is a lack of typical features of MF.
• Cutaneous gamma/delta T-cell lymphoma¹¹ belongs to the PTL group.^{2, 3} It usually has an aggressive course and manifests with disseminated plaques and/or ulceronecrotic nodules or tumors, particularly on the extremities.²²
• Primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma, provisional entity, manifests localized or disseminated eruptive papules, nodules, and tumors that show central ulceration and necrosis or superficial, hyperkeratotic patches and plaques.^{5, 23}
• Primary cutaneous CD4⁺ small/medium-sized pleomorphic T-cell lymphoma tends to be first apparent as a solitary plaque or tumor, generally on the face, neck, or upper trunk, although it may less commonly appear as one or several papules, nodules, or tumors.^{16, 24}
• Extranodal NK/T-cell lymphoma, nasal type, usually appears as a midfacial destructive tumor or multiple plaques or tumors, often with ulceration, preferentially on the trunk and extremities. Systemic symptoms such as fever, malaise, and weight loss may be present, and some cases are accompanied by a hemophagocytic syndrome. Extranodal NK/T-cell lymphoma, nasal type, has a variant that clinically resembles hydroa vacciniforme in which children, mainly in Latin America and Asia, have a papulovesicular eruption that typically occurs on sun-exposed areas such as the face and upper extremities.^{25, 26}

Causes

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

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Erythroderma, nonlymphomatous
Erythema neurolyticum migrans

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

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Clinical features, the history of the disease, and histomorphology and cytomorphology findings yield clues that lead to a diagnosis in most cases. However, demonstration of a dominant T-cell clone in skin biopsy specimens by a molecular assay (ie, Southern blot, polymerase chain reaction) constitutes an additional diagnostic criterion to distinguish CTCLs from inflammatory dermatoses.
• The diagnosis of SS should include one or more of the following⁶:
• • An absolute Sézary cell count of least 1000 cells/µL
  • Demonstration of immunophenotypical abnormalities (an expanded CD4⁺ T-cell population resulting in a CD4/CD8 ratio of more than 10; loss of any or all of the T-cell antigens CD2, CD3, CD4, CD5; or loss of both CD4 and CD5)
  • Demonstration of a T-cell clone in the peripheral blood by molecular or cytogenetic methods: Flow cytometry may be useful for differential diagnosis of precursor and peripheral T-cell and NK-cell lymphomas.²⁷
• Following a diagnostic algorithm for the evaluation and diagnosis of erythroderma due to CTCL versus "reactive" causes of erythroderma may be helpful.²⁸
• See Histologic Findings.¹

Other Tests

• Neoplastic MF cells have a mature CD3⁺, CD4⁺, CD45RO⁺, CD8^- memory T-cell phenotype. Rarely, otherwise-classic MF may have a CD4^-, CD8⁺ mature T-cell phenotype.²⁹ An aberrant phenotype, such as loss of pan–T cell antigens (eg, CD2, CD3, CD5), is not unusual.
• An identical phenotype is seen in GSS syndrome and SS. Clonal T-cell receptor gene rearrangements are detected in most MF cases.³⁰ Many structural and numerical chromosomal abnormalities have been described in the advanced stages of MF, but recurrent, MF-specific chromosomal translocations have not been identified. Chromosomal loss at 10q and abnormalities in P15, P16, and TP53 tumor suppressor genes are often evident with MF.
• The neoplastic T cells in pagetoid reticulosis may have either a CD3⁺, CD4⁺, CD8^- phenotype or a CD3⁺, CD4^-, CD8⁺ phenotype, with CD30 often being expressed.³¹
• Genetic features show T-cell receptor genes to be clonally rearranged in persons with MF, GSS syndrome, or SS. Demonstration of clonal T cells in the peripheral blood is an important diagnostic criterion that allows differentiation between SS and benign forms of erythroderma.⁶ Recurrent chromosomal translocations are not detected in persons with SS, but complex karyotypes are common, as is a consistent pattern of identical chromosomal abnormalities in SS as seen in MF.³²
• The neoplastic T cells in ATLL express a CD3⁺, CD4⁺, CD8^- phenotype, with CD25 being highly expressed.⁷ T-cell receptor genes (TCR) are clonally rearranged; clonally integrated HTLV-1 genes are present and are useful in differentiating between chronic or smoldering variants of ATLL and classic MF or SS.
• Panniculitislike T-cell lymphoma shows an alpha/beta⁺, CD3⁺, CD4^-, CD8⁺ T-cell phenotype, with expression of cytotoxic proteins.¹⁰ CD30 and CD56 are not expressed. Neoplastic T cells do show clonal TCR gene rearrangements, although neither specific genetic abnormalities nor EBV has been identified.
• Extranodal NK/T-cell lymphoma, nasal type, has neoplastic cells that express CD2, CD56, and cytoplasmic CD3.

Histologic Findings

In the early stages of MF, the histopathology is nonspecific,^{33, 34, 35, 36} and the condition is often misdiagnosed as an inflammatory disorder. Early-patch MF 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,³⁰ especially at the tips of the rete ridges.

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

Folliculocentric MF shows a primarily perivascular and periadnexal localization of the dermal infiltrate with variable involvement of the follicular epithelium by small, medium, or sometimes large hyperchromatic cells with cerebriform nuclei and sparing of the epidermis (folliculotropism instead of epidermotropism).¹ Most have mucinous degeneration of the follicular epithelium (follicular mucinosis), best demonstrated with Alcian blue staining, and an admixture of eosinophils and sometimes plasma cells. Prominent infiltration of both follicular epithelium and eccrine sweat glands is often observed. Similar cases with prominent infiltration of eccrine sweat glands, often seen with alopecia, have been called syringotropic MF.³⁷ Basaloid folliculolymphoid hyperplasia is a distinctive finding in follicular MF.³⁸

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

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

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

The histology of SS may be nonspecific, but it is often similar to MF, although the cellular infiltrates in SS are more often monotonous,^{39, 40} 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.⁴¹

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

In SPTL, subcutaneous infiltrates simulate a panniculitis and show small, medium, or sometimes large pleomorphic T cells with hyperchromatic nuclei and often many macrophages.¹¹ The overlying epidermis and dermis are typically not involved.⁴² Rimming of individual fat cells by neoplastic T cells is a helpful, although not completely specific, diagnostic feature.¹⁰ Necrosis, karyorrhexis, and cytophagocytosis are common.

Primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma, characterized by a proliferation of epidermotropic CD8⁺ cytotoxic T cells, has an acanthotic or atrophic epidermis, necrotic keratinocytes, ulceration, and variable spongiosis, sometimes with blister formation.^{5, 23} Epidermotropism tends to be marked, ranging from a linear distribution to a pagetoid pattern throughout the epidermis.

CGD-TCL has 3 major histologic patterns of involvement that can be present in the skin: epidermotropic, dermal, and subcutaneous.¹¹ More than 1 is often present in the same patient in different biopsy specimens or within a single biopsy specimen.²² The lymphoma cells are generally medium to large with coarsely clumped chromatin, with large blastic cells with vesicular nuclei and prominent nucleoli being infrequent and apoptosis and necrosis common, often with angioinvasion. The subcutaneous involvement may demonstrate rimming of fat cells.

Primary cutaneous CD4⁺ small/medium-sized pleomorphic T-cell lymphoma shows dense, diffuse, or nodular infiltrates within the dermis with a tendency to infiltrate the subcutis, and epidermotropism is often present focally. A predominance of small/medium-sized pleomorphic T cells may be seen, with a smaller proportion of large pleomorphic cells present.⁴³

Extranodal NK/T-cell lymphoma, nasal type, has dense dermal and often subcutaneous infiltrates with prominent angiocentricity and angiodestruction, often accompanied by extensive necrosis.^{44, 45}

Primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma has a beta-F1⁺, CD3⁺, CD8⁺, granzymes-B⁺, perforin⁺, TIA-1⁺, CD45RA⁺, CD45RO, CD2^-, CD4^-, CD5^-, CD7^+/- phenotype.^{16, 23} It is usually associated with EBV seronegativity. The lymphoma cells show clonal TCR gene rearrangements, although specific genetic abnormalities have not been described.

CGD-TCL¹¹ lymphoma cells are generally of beta-F1^-, CD3⁺, CD2⁺, CD5^-, CD7^+/-, CD56⁺ phenotype with strong expression of cytotoxic proteins. Most lack both CD4 and CD8, although CD8 may be expressed in some cases.^{22, 46} 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.⁴⁷ The lymphoma cells show clonal rearrangement of the TCR-gamma gene, while TCR-beta may be rearranged or deleted, but it is not expressed. EBV test results are usually negative.²²

Primary cutaneous CD4⁺ small/medium-sized pleomorphic T-cell lymphoma, a CD3⁺, CD4⁺, CD8^-, CD30^- phenotypic lymphoma, sometimes has loss of pan–T-cell markers. Cytotoxic proteins are generally not expressed.¹⁶ The TCR genes are clonally rearranged.²⁴

Primary cutaneous PTL, type unspecified, shows an aberrant CD4⁺ T-cell phenotype with variable loss of pan–T-cell antigens. CD30 staining is negative or restricted to a few scattered tumor cells. Rare cases may show coexpression of CD56. Expression of cytotoxic proteins is uncommon.¹⁶

Staging

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

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

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

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

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

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

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• When MF is confined to the skin, skin-targeted therapies such as topical corticosteroids, heliotherapy, photochemotherapy (eg, psoralen plus UV-A [PUVA]), topical application of nitrogen mustard (mechlorethamine) or carmustine (BCNU), or radiotherapy, including total skin electron beam irradiation, are often effective a controlling manifestations.⁴⁸ Bexarotene is also sometimes used for disease confined to the skin. Psoriatic doses of methotrexate have been used, but some concern exists relating to large cell transformation occasionally observed in these patients.
• Treatment of stages T1 and T2 MF with total skin electron beam therapy is highly effective in early-stage MF without adjuvant therapy. Management of relapses with local radiotherapy or a second round of total skin electron beam irradiation is feasible, timesaving, and cost-effective.⁴⁹ In patients with limited patch-stage MF, topical steroids or bexarotene gel can be used.
• Tazarotene, long-term and low-dose oral etoposide, and imiquimod may be of value in the treatment of early CTCL.^{50, 51} One small pilot study showed tazarotene 0.1% gel to be a well-tolerated and effective adjuvant topical therapy for the treatment of refractory MF.⁵²
• Biological agents such as interferon alfa and other cytokines (eg, interleukin 2 [IL-2]), traditional and new retinoids such as bexarotene, and receptor-targeted cytotoxic fusion proteins (eg, DAB389I-2; denileukin diftitox) are increasingly being used. Combination therapy with bexarotene and PUVA should be considered for patients with treatment-resistant CTCL refractory to monotherapy.⁵³ However, the precise use of these new treatments, either as single-agent therapy or in combination with other therapies (eg, PUVA) in the treatment of MF, remains to be established.
• Multiagent chemotherapy is used with unequivocal lymph node or systemic involvement or in cases with widespread tumor-stage MF that is refractory to skin-targeted therapies and is not early patch/plaque-stage disease.
• Perifollicular localization of the dermal infiltrates in FMF is often less responsive to skin-targeted therapies (eg, PUVA, topical nitrogen mustard) than classic plaque-stage MF, and total skin electron beam irradiation is superior.⁵⁴ However, because sustained complete remissions are rarely achieved with electron beam therapy, PUVA combined with retinoids or interferon alfa should be considered, although persistent tumors can be effectively treated with local radiotherapy. Follicular CTCL may benefit from isotretinoin for persistent cysts and comedones.⁵⁵
• Extracorporeal photopheresis, either alone or in combination with other treatment modalities (eg, interferon alfa), is an effective treatment for SS and erythrodermic MF, with overall response rates of 30-80% and complete response rates of 14-25%.⁵⁶ The alleged superiority of extracorporeal photopheresis over the traditional low-dose chemotherapy regimens has not been proven. Beneficial results have also been described with interferon alfa, either alone or in combination with PUVA therapy, prolonged treatment with a combination of low-dose chlorambucil (2-4 mg/d) and prednisone (10-20 mg/d), or with methotrexate (MTX) (5-25 mg/wk), but complete responses are uncommon. Skin-directed therapies such as PUVA or potent topical steroids are good adjuvant therapies. Beneficial effects of bexarotene and alemtuzumab (anti-CD52) have been noted, but the long-term effects of these therapies remain to be established.⁵⁷

Surgical Care

Localized MF may benefit from a number of therapeutic modalities, including radiotherapy, intralesional steroids, or surgical excision. One option is to excise a patch or plaque with a 0.5-cm margin and then control subsequent disease with either irradiation or photochemotherapy with PUVA, photodynamic therapy, or carbon dioxide laser surgery.⁵⁸ Localized radiation or a surgical approach to localized MF can be used, with the latter having the advantage that a full dose of radiation can be delivered in the same location at a later time, thus preserving options for future therapy.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

CTCLs are a heterogeneous group of entities. One should distinguish indolent, low-risk MF and SS from aggressive HTLV-1–associated ATLL.⁵⁹ Treatment for early-stage CTCL includes topical therapies with or without interferon alfa or oral agents, while advanced-stage patients often progress and are treated with chemotherapy and novel agents. Multiagent cytotoxic regimens may be palliative, but they seem to lack a demonstrated survival benefit.⁶⁰ Novel therapies for CTCL include bexarotene, which has demonstrated efficacy in advanced refractory CTCL. Other novel agents include the IL-2 fusion toxin (Ontak), IL-12, pentostatin (a potent adenosine deaminase inhibitor), histone deacetylase inhibitors (eg, depsipeptide), NF-kappa-B inhibitors, cytokine-receptor antagonists, immunomodulatory therapies, and allogeneic stem cell therapy. The value of new therapeutic approaches to CTCL needs to be critically assessed in regard to overall survival and disease-specific survival.

Drug Category: Chemotherapy agents

Inhibit neoplastic growth.

Drug Category: Fusion proteins

Drug Category: Biological response modulators

Immunomodulator/biologic agents.

Drug Category: Antineoplastic agents

Monoclonal antibody against antigen on T cells.

Drug Category: Topical chemotherapy agents

Drug Category: Topical immune response modifiers

Drug Category: Retinoids

Regulate genes that control cellular differentiation and proliferation.

Drug Category: Steroids

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Prognosis

• The prognosis for patients with MF is dependent on stage and, in particular, the type and extent of skin lesions and the presence of extracutaneous disease.² Patients with limited patch/plaque-stage MF seem to have similar life expectancies to age-, sex-, and race-matched control populations. Ten-year disease-specific survival rates were 97-98% for patients with limited patch/plaque disease (covering <10% of the skin surface), 83% for patients with generalized patch/plaque disease (covering >10% of the skin surface), 42% for patients with tumor-stage disease, and approximately 20% for patients with histologically docu