Cutaneous T-Cell Lymphoma
Introduction
Cutaneous T-cell lymphoma (CTCL) is a type of extranodal non-Hodgkin’s lymphoma (NHL), which is a clonal proliferation of T lymphocytes originating in the skin and consists of a group of diseases with different clinical manifestations, histological features, and prognosis [1]. Cutaneous T-cell lymphomas account for 75-80% of all primary cutaneous lymphomas. In the last decade, as the understanding of lymphoma has improved, some new types have been discovered, while the staging of lymphoma is constantly updated and progressing. Compared with other sites of lymphoma, skin lymphoma lesions are easy to detect and can be biopsied in a timely manner, playing an important role in the diagnosis, classification and treatment of the disease.
Classification
With the increasing understanding of cutaneous T-cell lymphoma, the proper classification of such a complex and diverse spectrum of the disease has become an important issue. The latest classification system combines two sets of classifications from the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC) based on the clinical manifestations of the disease, the morphology of the tumor cells, and the biology of the cells, and a new classification of cutaneous T-cell lymphoma was developed in 2005 (WHO-EORTC classification) [2], as shown in Table 1. In the new classification, the Sézary syndrome, which was once classified as a subtype in MF, was separated into a new type.
Table 1. 2005 WHO-EORTC classification of cutaneous T-cell lymphomas
Mycosis fungoides granulomatosis
Variant subtypes of mycosis fungoides
Mycosis fungoides pro-follicular granuloma
Paget-like reticulocytic hyperplasia
Granulomatous skin laxity
Sézary’s syndrome
Adult T-cell leukemia/lymphoma
Primary cutaneous CD30+ lymphoproliferative disorder
Primary cutaneous progressive large cell lymphoma
Lymphomatoid papulosis
Subcutaneous lipofuscinosis-like T-cell lymphoma
Extranodal NK/T-cell lymphoma, nasal type
Primary cutaneous peripheral T-cell lymphoma, unspecified type
Primary cutaneous aggressive pro-epidermal CD8+ T-cell lymphoma*
Cutaneous gamma/δ T-cell lymphoma*
Primary cutaneous CD4+ small/moderate size pleomorphic T-cell lymphoma*
* Tentative classification
Based on the above classification, WHO-EROTC further classified cutaneous T-cell lymphomas into two categories: “inert” and “aggressive” [2]. The incidence and 5-year survival rates of the two types of cutaneous T-cell lymphoma are shown in Table 2.
Table 2: Incidence and survival rates of cutaneous T-cell lymphoma
WHO-EORTC classification
Percentage of cutaneous lymphoma frequency (%)
5-year survival rate (%)
Inert biological features of
Mycosis fungoides
54
88
Variant of mycosis fungoides
Follicle-friendly mycosis fungoides
6
80
Paget-like reticulocytic hyperplasia
1
100
granulomatous skin laxity
< 1
100
Primary cutaneous CD30+ lymphoproliferative disorders
Primary cutaneous mesenchymal large cell lymphoma
10
95
Lymphomatoid papulosis
16
100
Subcutaneous lipofuscinosis-like T-cell lymphoma
1
82
Primary cutaneous CD4+ small/moderate pleomorphic T-cell lymphoma
3
75
Aggressive biological features of
Sézary’s syndrome
4
24
Adult T-cell leukemia/lymphoma
unclear
unclear
Extranodal NK/T-cell lymphoma, nasal type
1
< 5
primary cutaneous aggressive pro-epidermal CD8+ T-cell lymphoma
< 1
18
cutaneous gamma/δ T-cell lymphoma
1
< 5
Primary cutaneous peripheral T-cell lymphoma, undetermined type
3
16
Pathogenesis
The pathogenesis of cutaneous T-cell lymphoma is currently unknown. With the exception of adult T-cell leukemia/lymphoma, which is thought to be associated with human T-cell-loving virus (HTLV), and extranodal NK/T-cell lymphoma, the nasal type, which is thought to be associated with Epstein-Barr virus (EBV), no clear environmental factors have been identified for other types of cutaneous T-cell lymphoma. Immunological abnormalities of skin homing T cells, cytogenetic abnormalities, and cellular resistance to apoptosis are important mechanisms in the pathogenesis of cutaneous T-cell lymphoma.
Diagnosis
1. Histopathology
Patients suspected of having cutaneous T-cell lymphoma should first undergo a skin biopsy for histopathologic diagnosis to exclude benign lymphoproliferative disorders. Some cutaneous T-cell lymphomas, such as mycosis fungoides, progress slowly and can be clinically and histologically unspecific for many years, so multiple multi-point sampling is required to obtain the most representative lesions for the disease, if necessary.
2. Immunophenotyping
Immunohistochemical examination using paraffin or frozen sections plays an extremely important role in the diagnosis and classification of lymphoma. The use of antigen-antibody reactions can distinguish the origin of tumor cells and play an important role in the classification and staging of the disease.
3. T-cell receptor gene rearrangement analysis
In recent years, T cell receptor (TCR) gene rearrangement analysis has been increasingly used in the diagnosis and classification of lymphoma, and currently Southern blotting or PCR methods are commonly used. This method can identify whether the proliferating cells in the skin lesions are clonal T cells, which plays an important role in the diagnosis of benign and malignant diseases. However, the presence of clonal T-cell subsets is not an absolute indicator of the benignity or malignancy of the disease, and should be combined with clinical and histological manifestations to make a correct diagnosis.
4. Classification and staging
Once the diagnosis of cutaneous T-cell lymphoma is confirmed, the type must be defined. The diagnosis of the disease is clarified based on clinical manifestations, histopathological manifestations, immunophenotype and T-cell receptor gene rearrangement analysis. In addition, a correct staging method is needed to distinguish cutaneous T-cell lymphoma from systemic lymphoma with involvement. The staging method depends on the specific type of cutaneous T-cell lymphoma. Routine analysis often involves a complete blood count, blood biochemistry, lymph node biopsy, bone marrow biopsy, and CT examination of the chest and abdomen [3].