Classification of primary cutaneous lymphomas

INTRODUCTION — Primary cutaneous lymphomas are a heterogeneous group of T cell and B cell neoplasms that present in the skin without any evidence of extracutaneous disease at the time of diagnosis. In the last two decades, multiple classification systems have been used for these conditions. These include:

●Kiel classification

●European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lymphomas

●World Health Organization (WHO) classification of hematolymphoid tumors (2001)

●WHO-EORTC classification of primary cutaneous lymphomas (2005)

●WHO classification of hematolymphoid tumors (2008)

●Revised WHO classification of hematolymphoid tumors (2016)

●Revised WHO-EORTC classification of primary cutaneous lymphomas (2018)

●WHO classification of hematolymphoid tumors 5^th edition (2022)

In the early 1980s, mycosis fungoides (MF), Sézary syndrome (SS), and some related disorders, collectively termed cutaneous T cell lymphoma (CTCL), were the only types of cutaneous lymphomas that were recognized. Cutaneous lymphomas other than MF/SS were firmly believed to represent skin manifestations of a systemic lymphoma and treated accordingly [1].

The development and application of immunophenotyping and cytogenetic and molecular testing had a major impact on the diagnosis and classification of cutaneous lymphomas. Collaborative studies by dermatologists and pathologists using these new diagnostic techniques demonstrated that malignant lymphomas other than MF/SS can present primarily in the skin without detectable extracutaneous disease. Based upon these studies, several new types of CTCL and cutaneous B cell lymphomas (CBCL) were defined [2]. It became clear that primary cutaneous lymphomas had distinctive immunophenotypic and genetic features, a different clinical behavior, and often a much better prognosis than histologically similar nodal lymphomas with secondary skin involvement.

Since in the past primary CTCL and CBCL were not recognized by the classification systems used by hematopathologists for nodal lymphomas (eg, Kiel classification, Working Formulation), they were often inappropriately treated as systemic lymphomas with unnecessarily aggressive therapeutic regimens. This observation prompted the EORTC Cutaneous Lymphoma Group to formulate a separate classification for primary cutaneous lymphomas [2].

The 1997 EORTC classification simply listed the different types of CTCL and CBCL that had been defined as separate entities in the decade before. It included a limited number of well-defined types of CTCL and CBCL and some provisional entities. A distinction was made among cutaneous lymphomas with indolent, intermediate, or aggressive clinical behavior. The clinical significance of this classification has been validated by several large studies including more than 1300 patients with a primary cutaneous lymphoma [2-4].

The 3^rd edition of the WHO classification for tumors of hematopoietic and lymphoid tissues, published in 2001, included most types of CTCL but did not recognize different types of CBCL [5]. The combined efforts of the EORTC Cutaneous Lymphoma Group and the WHO group resulted in a new consensus classification for primary cutaneous lymphomas, the 2005 WHO-EORTC classification [6]. Several large studies have validated the clinical significance of this new classification [6-9].

The 4^th edition of the WHO classification, published in 2008, and subsequent editions have adopted the terminology and definitions of the WHO-EORTC classification with only minor modifications and now include all types of CTCL and CBCL relevant for dermatologists [10-13]. The 2018 update of the WHO-EORTC classification of primary cutaneous lymphomas is for the most part identical to the 2016 revision of the WHO classification for tumors of hematopoietic and lymphoid tissues [14,15]. The relative frequency and prognosis of the different types of CTCL and CBCL included in the 2018 update of the WHO-EORTC classification are presented in the table (table 1).

This topic will briefly discuss the types of primary cutaneous T cell and B cell lymphomas included in the 2018 update of the WHO-EORTC classification of primary cutaneous lymphomas and the 5^th edition of the WHO classification of hematolymphoid tumors [16]. The classification of other hematopoietic neoplasms is presented separately. (See "Classification of hematopoietic neoplasms".)

CUTANEOUS T CELL LYMPHOMAS — The term cutaneous T cell lymphoma (CTCL) describes a heterogeneous group of neoplasms of skin-homing T cells that show considerable variation in clinical presentation, histologic appearance, immunophenotype, and prognosis (table 1). In the Western world, CTCL represent approximately 75 to 80 percent of all primary cutaneous lymphomas [6]. Mycosis fungoides (MF) and primary cutaneous CD30⁺ lymphoproliferative disorders (LPD) account for approximately 90 percent of CTCL.

Mycosis fungoides — Classic MF is an epidermotropic CTCL clinically characterized by the progression from patch stage to plaques stage and lastly to tumor stage. It is the most common type of CTCL and accounts for approximately 40 percent of all primary cutaneous lymphomas and 60 percent of all CTCL. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

In addition to the classic type, three variants of MF with distinctive clinicopathologic features have been recognized:

●Folliculotropic mycosis fungoides – This variant of MF is characterized by folliculotropic infiltrates, often with sparing of the epidermis, and preferential involvement of the head and neck area. (See "Variants of mycosis fungoides", section on 'Folliculotropic mycosis fungoides'.)

●Pagetoid reticulosis – Variant of MF characterized by the presence of solitary patches or plaques, usually on the extremities, showing histologically an intraepidermal proliferation of neoplastic T cells. (See "Variants of mycosis fungoides", section on 'Pagetoid reticulosis'.)

●Granulomatous slack skin – Granulomatous slack skin is a very rare variant of MF characterized clinically by the development of folds of lax skin in the intertriginous areas and histologically by a granulomatous infiltrate with clonal T cells. (See "Variants of mycosis fungoides", section on 'Granulomatous slack skin'.)

Sézary syndrome — Sézary syndrome (SS) is a leukemic type of CTCL presenting with erythroderma and peripheral lymphadenopathy and characterized by the presence of neoplastic T cells (Sézary cells) in skin, lymph nodes, and peripheral blood. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".)

Adult T cell leukemia-lymphoma — Adult T cell leukemia-lymphoma (ATLL) is defined as a peripheral T cell neoplasm associated with the human T cell leukemia virus 1 (HTLV-1). ATLL is endemic in areas with a high prevalence of HTLV-1 in the population, such as southwest Japan, the Caribbean islands, and parts of South and Central America. Approximately 25 percent of ATLL patients present with skin lesions mimicking MF or Sézary syndrome. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma".)

Primary cutaneous CD30+ lymphoproliferative disorders — Primary cutaneous CD30⁺ lymphoproliferative disorders (LPDs) are the second most common group of CTCL, accounting for approximately 30 percent of CTCL (table 1). This group includes primary cutaneous anaplastic large cell lymphoma (C-ALCL), lymphomatoid papulosis (LyP), and borderline cases. These conditions show overlapping clinical and histologic features and form a spectrum of disease:

●Primary cutaneous anaplastic large cell lymphoma – Primary C-ALCL is characterized histologically by the presence of large cells with an anaplastic or pleomorphic cytomorphology and expression of the CD30 antigen by the majority (greater than 75 percent) of tumor cells. It presents with solitary or localized (ulcerating) skin tumors and has an excellent prognosis in most cases. Unlike systemic ALCL, the vast majority of C-ALCL are anaplastic lymphoma kinase (ALK) negative and do not show the t(2;5) chromosomal translocation. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)

●Lymphomatoid papulosis – LyP is defined as a chronic, recurrent, self-healing papulonecrotic or papulonodular skin disease with histologic features suggestive of a CD30⁺ malignant lymphoma. Several histologic subtypes of LyP mimicking other types of CTCL have been described. Although these variants do not have therapeutic or prognostic implications, it important that pathologists recognize them and include LyP in the differential diagnosis of certain types of CTCL. (See "Lymphomatoid papulosis".)

Subcutaneous panniculitis-like T cell lymphoma — Subcutaneous panniculitis-like T cell lymphoma (SPTCL) was originally defined as an aggressive cytotoxic T cell lymphoma that preferentially infiltrates subcutaneous tissue and is often complicated by a hemophagocytic syndrome [2,5]. In the 2001 World Health Organization (WHO) classification, SPTCL included cases with an alpha-beta T cell phenotype (75 percent) and cases with a gamma-delta T cell phenotype (25 percent) [5]. Studies have shown clinical, histologic, and immunophenotypic differences between cases of SPTCL with an alpha-beta T cell phenotype and those with a gamma-delta T cell phenotype, suggesting that they may represent different entities [17]. While most SPTCL with an alpha-beta T cell phenotype show an indolent clinical behavior, SPTCL with a gamma-delta T cell phenotype runs a very aggressive clinical course, similar to other types of gamma-delta T cell lymphoma.

Therefore, in the 2005 WHO-European Organization for Research and Treatment of Cancer (EORTC) classification and in more recent classifications, the term SPTCL is only used for cases with an alpha-beta T cell phenotype, whereas cases with a gamma-delta T cell phenotype are included in the category of primary cutaneous gamma-delta T cell lymphoma (PCGD-TCL). (See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma".)

EBV-positive T cell and NK cell lymphoproliferations of childhood — Epstein-Barr virus (EBV)-positive T cell and natural killer (NK) cell lymphoproliferations of childhood include hydroa vacciniforme lymphoproliferative disorder (formerly hydroa vacciniforme-like lymphoproliferative disorders), severe hypersensitivity reactions to mosquito bites, and systemic EBV-positive T cell lymphoma of childhood [18]. Two forms of hydroa vacciniforme lymphoproliferative disorder are recognized: the classic form and the systemic form. These disorders are seen mainly in children and adolescents from Asia or in indigenous populations from Central and South America and Mexico. Both conditions are rare in adults. (See "Infectious mononucleosis", section on 'Chronic active EBV infection' and "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Hydroa vacciniforme'.)

Extranodal NK/T cell lymphoma, nasal type — Extranodal NK/T cell lymphoma, nasal type is nearly always an EBV-positive lymphoma composed of small, medium, or large cells, usually with an NK or, more rarely, a cytotoxic T cell phenotype. The skin is the second most common site of involvement after the nasal cavity/nasopharynx, and skin involvement may be a primary or secondary manifestation of the disease. This lymphoma is more common in Asia, Central America, and South America. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type".)

Primary cutaneous peripheral T cell lymphoma, rare subtypes

Primary cutaneous gamma-delta T cell lymphoma — PCGD-TCL is a rare and most often aggressive CTCL composed of a clonal proliferation of mature, activated gamma-delta T cells with a cytotoxic phenotype. In previous classifications, cases with panniculitis-like lesions were classified as SPTCL with a gamma-delta phenotype. (See "Primary cutaneous T cell lymphomas, rare subtypes", section on 'Primary cutaneous gamma-delta T cell lymphoma'.)

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T cell lymphoma — Primary cutaneous CD8⁺ aggressive epidermotropic cytotoxic T cell lymphoma (CD8⁺ AECTCL) is a rare and very aggressive type of CTCL characterized by a proliferation of epidermotropic CD8⁺ cytotoxic T cells. CD8⁺ AECTCL is included as a provisional entity in the 2016 revision of the WHO classification of hematopoietic neoplasms [11]. (See "Primary cutaneous T cell lymphomas, rare subtypes", section on 'Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T cell lymphoma'.)

Primary cutaneous acral CD8+ T cell lymphoproliferative disorder — Primary cutaneous acral CD8⁺ T cell lymphoma, initially designated as "indolent CD8⁺ lymphoid proliferation of the ear," has been included as a new provisional entity in the 2018 revision of the WHO-EORTC classification. It is histologically characterized by a diffuse infiltrate of medium-sized CD8⁺ cytotoxic T cells, suggesting a high-grade malignant lymphoma, and clinically by a solitary skin lesion affecting acral sites (most commonly, the ear) and an indolent clinical behavior. Because of its very indolent clinical behavior, this condition is now classified as primary cutaneous acral CD8+ T cell lymphoproliferative disorder [13,19]. (See "Primary cutaneous T cell lymphomas, rare subtypes", section on 'Primary cutaneous acral CD8+ T cell lymphoma'.)

Primary cutaneous CD4+ small/medium T cell lymphoproliferative disorder — In the WHO-EORTC and WHO 2008 classification, primary cutaneous CD4⁺ small/medium T cell lymphoma (PCSM-TCL) was included as a provisional type of CTCL defined by a predominance of small to medium size CD4⁺ pleomorphic T cells without prior or concurrent patches and plaques typical of MF [6,12]. Almost all cases present with a solitary plaque or tumor, which have the same clinicopathologic features and benign clinical course as cutaneous T cell pseudolymphomas with a nodular growth pattern. Therefore, in the 2018 update of the WHO-EORTC classification, the term primary cutaneous CD4⁺ small/medium T cell lymphoproliferative disorder, rather than lymphoma, is preferred [11]. (See "Primary cutaneous T cell lymphomas, rare subtypes", section on 'Primary cutaneous CD4+ small/medium T cell lymphoproliferative disorder'.)

CUTANEOUS B CELL LYMPHOMAS — The term cutaneous B cell lymphoma (CBCL) refers to those cases of B cell lymphoma that present primarily in the skin when there is no evidence of extracutaneous disease at the time of diagnosis and after the completion of an initial staging evaluation. In the 2018 update of the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification for cutaneous lymphomas, three main types of CBCL are recognized. In the Western world, CBCL make up approximately 25 percent of primary cutaneous lymphomas.

Primary cutaneous marginal zone lymphoma — Primary cutaneous marginal zone lymphoma (PCMZL) is an indolent lymphoma composed of small B cells, including marginal zone (centrocyte-like) cells, lymphoplasmacytoid cells, and plasma cells. It includes cases previously designated as primary cutaneous immunocytoma, cutaneous follicular lymphoid hyperplasia with monotypic plasma cells, and primary cutaneous plasmacytoma without underlying multiple myeloma (extramedullary plasmacytoma of the skin).

Within the group of PCMZL, distinction is made between heavy chain class-switched cases (immunoglobulin G [IgG] positive), which are the most common and most typical type of PCMZL, and non-class-switched cases (immunoglobulin M [IgM] positive), which are uncommon, share many features with mucosa-associated lymphoid tissue (MALT) lymphomas at other extranodal sites, and are more likely to have extracutaneous disease [11,14,15]. In the 2016 revision of the 4^th edition of the WHO classification, PCMZL was not yet listed separately but was included in the broad group of extranodal marginal zone lymphoma of MALT [10,11].

However, in the 5^th edition of the WHO classification, PCMZL is recognized as a distinct entity, separate from other MALT lymphomas [13]. In the published International Consensus Classification of mature lymphoid neoplasms, the term "primary cutaneous marginal zone lymphoproliferative disorder" (rather than "primary cutaneous marginal zone lymphoma") was suggested because of the extremely indolent clinical behavior, with disease-specific survival rates approaching 100 percent [19]. PCMZL make up approximately 7 percent of all cutaneous lymphomas and approximately 30 to 40 percent of primary CBCL. (See "Primary cutaneous marginal zone lymphoma".)

Primary cutaneous follicle center lymphoma — Primary cutaneous follicle center lymphoma (PCFCL), previously called primary cutaneous follicle center cell lymphoma, is a tumor of neoplastic follicle center cells with a predominance of large centrocytes (large cleaved cells) admixed with variable numbers of centroblasts (large noncleaved cells with prominent and usually paracentral nucleoli). PCFCL generally presents with localized lesions on the head, particularly the scalp, or trunk. PCFCL may show a follicular, a follicular and diffuse, or a diffuse growth pattern. In contrast to nodal follicular lymphomas, most PCFCL are B cell lymphoma 2 (BCL2) negative and lack the t(14;18) translocation. In previous classifications, PCFCL with a diffuse growth pattern were commonly classified as diffuse large B cell lymphoma. PCFCL accounts for approximately 10 percent of all cutaneous lymphomas and approximately 40 to 50 percent of primary CBCL. (See "Primary cutaneous follicle center lymphoma".)

Primary cutaneous diffuse large B cell lymphoma, leg type — Primary cutaneous diffuse large B cell lymphoma, leg type (PCDLBCL, LT) shows histologically a predominance of confluent sheets of centroblasts and immunoblasts. It typically presents with skin lesions on the lower legs in older adult patients, particularly females. PCDLBCL, LT makes up approximately 4 percent of all cutaneous lymphomas and approximately 20 percent of primary CBCL. (See "Primary cutaneous large B cell lymphoma, leg type".)

EBV-positive mucocutaneous ulcer — Epstein-Barr virus (EBV)-positive mucocutaneous ulcer was included as a new entity in the 2018 revision of the WHO-EORTC classification [11]. It affects patients with age-related and iatrogenic immunosuppression and usually has a self-limited, indolent course. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'EBV-positive mucocutaneous ulcer'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary cutaneous lymphoma".)

SUMMARY

●Primary cutaneous lymphomas as separate entities in the group of hematopoietic neoplasms – Primary cutaneous lymphomas are a heterogeneous group of T cell and B cell neoplasms that present in the skin without any evidence of extracutaneous disease at the time of diagnosis. Because of their distinctive immunophenotypic and genetic features, clinical behavior, and prognosis, primary cutaneous lymphomas were included as separate entities in the 2018 update of the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification and the WHO classification of hematolymphoid tumors 5^th edition (table 1). (See 'Introduction' above.)

●Cutaneous T cell lymphomas – In the Western world, cutaneous T cell lymphomas (CTCL) represent approximately 75 percent of all primary cutaneous lymphomas. Mycosis fungoides and primary cutaneous CD30⁺ lymphoproliferative disorders account for approximately 90 percent of all CTCL. Other types of CTCL are rare and may run a very aggressive clinical course. (See 'Cutaneous T cell lymphomas' above and 'Primary cutaneous peripheral T cell lymphoma, rare subtypes' above.)

●Cutaneous B cell lymphomas – Cutaneous B cell lymphomas represent approximately 25 percent of all primary cutaneous lymphomas. Three main types recognized are primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous diffuse large B cell lymphoma, leg type. (See 'Cutaneous B cell lymphomas' above.)