Cutaneous T cell lymphoma

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Overview
Classification Mycosis fungoides Sezary syndrome
Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2]

Synonyms and keywords: CTCL; Mycosis fungoides; Sezary syndrome; Sezary's disease; Alibert-Bazin syndrome; Granuloma fungoides

Overview

Cutaneous T-Cell lymphoma (CTCL) is a class of non-Hodgkin's lymphoma, which is a type of cancer of the immune system. Cutaneous T-cell lymphoma (CTCL) is infiltration of malignant T cells and activated T cells in the skin. Cutaneous T cell lymphoma arises from T-cell lymphocytes, which are normally involved in the cell mediated immune response. The malignant T cells in the body are pushed to the surface of the skin in a biological process used to rid the body of offending material, causing various lesions to appear on the skin. These lesions change shape as the disease progresses, typically beginning as what appears to be a rash and eventually forming plaques and tumors before metastatizing to other parts of the body. Early-stage of Cutaneous T-cell lymphoma (CTCL) limited to the skin, tumor cells in later stage disease can populate blood or lymph nodes. There are 3 classification methods used to classify cutaneous T cell lymphoma into several subtypes. Mycosis Fungoides was first described in 1806 by French dermatologist Jean-Louis-Marc Alibert. Sezary's disease was first described by Albert Sézary. On microscopic histopathological analysis, atypical lymphoid cells, polymorphous inflammatory infiltrate in the dermis, and lymphocytes with cerebroid nuclei are characteristic findings of mycosis fungoides. Cutaneous T cell lymphoma is caused by a mutation in the T cells. Cutaneous T cell lymphoma must be differentiated from other diseases such as eczema and psoriasis. Mycosis fungoides commonly affects 45 and 55 years. Sézary syndrome commonly affects 60 years. In the United States, males are more commonly affected with cutaneous T cell lymphoma than females. In the United States, cutaneous T cell lymphoma usually affects individuals of the African American race.There are no established risk factors for cutaneous T cell lymphoma. If left untreated, cutaneous T cell lymphoma may progress to develop patches , plaque, and tumors. Depending on the extent of the lymphoma at the time of diagnosis, the prognosis may vary. According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for cutaneous T cell lymphoma.The staging of cutaneous T cell lymphoma is based on skin, lymph node, visceral and blood involvement.The most common symptoms of cutaneous T cell lymphoma include fever, weight loss, skin rash, night sweats, itching, chest pain, abdominal pain, and bone pain. Common physical examination findings of cutaneous T cell lymphoma include fever, rash, pruritus, ulcer, chest tenderness, abdominal tenderness, bone tenderness, peripheral lymphadenopathy, and central lymphadenopathy.Laboratory tests for cutaneous T cell lymphoma include complete blood count (CBC), blood chemistry studies, flow cytometry, immunohistochemistry, and immunophenotyping. The definitive diagnosis of cutaneous T cell lymphoma is confirmed by either a or multiple skin biopsy or a lymph node biopsy. CT scan may be helpful in the diagnosis of cutaneous T cell lymphoma. MRI may be helpful in the diagnosis of cutaneous T cell lymphoma. PET scan may be helpful in the diagnosis of cutaneous T cell lymphoma.Other diagnostic studies for cutaneous T cell lymphoma include bone marrow aspiration and bone marrow biopsy.The predominant therapy for cutaneous T cell lymphoma is PUVA. Adjunctive chemotherapy, radiotherapy, biological therapy, retinoid therapy, and photophoresis may be required.

Classification

According to world Health Organization (WHO) and European Organization for Research and Treatment of Cancer (EORTC) classification, cutaneous T cell and NK cell lymphomas may be classified into the following types:

• Mycosis fungoides
• Mycosis fungoides variants and subtypes
  • Folliculotropic mycosis fungoides
  • Pagetoid reticulosis
  • Granulomatous slack skin
• Sezary syndrome
• Adult T cell leukemia/lymphoma
• Primary cutaneous CD30+ lymphoproliferative disorders
  • Primary cutaneous anaplastic large cell lymphoma
  • Lymphomatoid papulosis
• Subcutaneous panniculitis like T cell lymphoma
• Extranodal NK/T cell lymphoma, nasal type
• Primary cutaneous peripheral T cell lymphoma, rare subtypes
  • Primary cutaneous gamma-delta T cell lymphoma
  • Primary cutaneous aggressive epidermotropic CD8+ T cell lymphoma (provisional)
  • Primary cutaneous CD4+ small/medium-sized pleomorphic T cell lymphoproliferative disorder (provisional)
  • Primary cutaneous acral CD8+ T cell lymphoma (provisional)
• Primary cutaneous peripheral T cell lymphoma, not otherwise specified

Cutaneous T cell lymphoma classification

Name	Description
Primary or cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma	Characterized by localized or disseminated eruptive papules, nodules with tumors showing central ulceration, and necrosis or by superficial hyperkeratotic patches and plaques Dissemination to other visceral sites (lung, testis, CNS, and oral mucosa) Lymph nodes are seldom affected Aggressive clinical course with median survival rate of 32 months
Primary cutaneous CD4-positive small/medium T-cell lymphoma	Clinical presentation is usually a solitary plaque or nodule, commonly on the face, neck, or upper trunk The involvement of lower extremities is rare Cutaneous patches are generally absent

Pathophysiology

• Cutaneous T cell lymphoma arises from T-cell lymphocytes, which are normally involved in the cell mediated immune response.
• The tumor cells originate from memory T cells or skin homing CD4+ T cells expressing cutaneous lymphocyte antigen (CLA) and chemokine receptors CCR4 and CCR7.
• It is understood that cutaneous T cell lymphoma (maycosis fungoides, Sezary sydrome ) is the result of malignant T cell that derived from a mature CD41 CD45RO1 memory T cells.
• Malignant T cell express adhesion molecules such as CCR4 and CLA.
• Malignant T cell in Sezary syndrome (Sezary cells) have a different phenotype, they express CCR7 and L-selectin 4.
• Immunohistochemistry shows expression T-cell antigens such as CD7, CD5, CD26, CD2 and CD3.
• Malignant T cell express adhesion molecules such as CCR4 and CLA.
• The exact pathogenesis and mechanism of pruritus in CTCL is not completely understood.

Genetics

• Cutaneous T cell lymphoma is chromosomal changes event linked to DNA repair deficiencies, which in a subpopulation of T cells leads to CTCL development over years pattern.

• Development of cutaneous T cell lymphoma disease is the result of multiple genetic mutations.

• Genes involved in the pathogenesis of mycosis fungoides include:
  • Deletions or translocations involving a gene, NAV3, at 12q2 (helicaselike activity)
  • Deletion in 42 regions and amplification in 21 observed with meaningful amplifications of 8q (MYC) and 17q (STAT3) and deletions of 17p (TP53) and 10 (PTEN, FAS)

• Other deletion such as:
  • ZEB1
  • ARID1A
  • DNMT3A
  • CDKN2A
  • FAS
  • ATM
  • CTCF
  • STAT5B
  • PRKCQ
  • somatic mutations (NFKB2, CD28, RHOA) observed in gene sequencing.

• The development of cutaneous T cell lymphoma is the result of multiple genetic mutations such as:

• • There is not a classic chromosomal translocation in cutaeous T cell lymphoma( MF and SS ) significant
  • chromosomal instability has been noted. Losses on 1p, 10q, 13q, and 17p and gains of 4, 17q, and 18 have been identified
  • Deletions and translocations in different chromosomes or chromosomal segments
  • Chromosomal amplification of JunB at 19p12 observed in mycosis fungoides and Sezary syndrome.

Differentiating Cutaneous T cell lymphoma from other Diseases

• Mycosis fangoides must be differentiated from any diseases with cutaneous patch or plaque that not respond to first- and second-line treatment ssuch as:
  • Sezaruy syndrome
    • Sezaruy syndrome is more symptoI contrast to patch or plaque MF, SS is much more symptomatic. Sezary syndrome patients tend to present with diffuse skin involvement,not like mycosis fungoides usually evolve through patches and plaques to erythroderma
  • Sezaruy syndrome
    • In Sezary syndrome infiltration of skin is generally much less dense than plaque in mycosis fungoides (MF)
  • Eczema
  • Adult T cell leukemia/lymphma
  • Psoriasis
  • Pityriasis rubra pilaris
  • dermatitis
  • Hypereosinophilic syndrome
  • Adult T-cell leukemia
  • Atopic dermatitis
  • Contact dermatitis ( Allergic, irritant)
  • Chronic actinic dermatitis
  • Scabies
  • Subcutaneous panniculitis like T cell lymphoma (SPTCL)
  • Drug eruption
  • Graft versus host disease
  • Lichen planus
  • Pediatric atopic dermatitis
  • Tinea corporis
  • Primary cutaneous anaplastic large cell lymphoma (ALCL)
  • Cutaneous gamma/delta T cell lymphoma (G/D TCL)