epidemiology

Primary cutaneous lymphomas (PCLs) are defined as non-Hodgkin lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. After the gastrointestinal lymphomas, PCLs are the second most common group of extranodal non-Hodgkin lymphomas with an estimated annual incidence of 1/100 000. PCL must be distinguished from nodal or systemic malignant lymphomas involving the skin secondarily, which often have another clinical behaviour, have a different prognosis and require a different therapeutic approach. In recent lymphoma classifications PCLs are therefore included as separate entities. Within the group of PCL distinct types of cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma (CBCL) can be distinguished. In Europe, CTCLs constitute ∼75%–80% of all PCLs, CBCLs 20%–25%, but different distributions have been observed in other parts of the world.

diagnosis

The diagnosis and classification of PCL should always be based on a combination of clinical, histological and immunophenotypical data. Demonstration of clonal T-cell receptor or immunoglobulin gene rearrangements in lesional skin or peripheral blood may be a valuable adjunct in selected cases. However, clinical features are in general the most important decision makers for therapeutic planning. PCLs should be classified according to the criteria of the WHO-EORTC classification.

staging

In all cases, except for patients with early stage mycosis fungoides (MF) or its variants and patients with lymphomatoid papulosis, adequate staging should be performed to exclude the presence of extracutaneous disease. Adequate staging includes complete physical examination, complete and differential blood cell count and serum biochemistry, appropriate imaging techniques and optionally a bone marrow biopsy and aspirate. Prognosis is extremely variable depending on the type of PCL and the stage of disease. For clinical staging of MF and Sézary syndrome (SS) the revised TNM staging system should be used. For PCLs other than MF/SS a separate TNM classification system has recently been published. This staging system is primarily meant to document extent of disease and cannot be used as a prognostic guide.

therapy

The choice of treatment depends on the type of PCL and the stage of disease. Due to their heterogeneity and rarity controlled clinical trials in PCLs are virtually lacking, with few exceptions mainly concerning recently marketed drugs. Recommendations are therefore largely based on (retrospective) cohort studies and expert opinions discussed during consensus meetings of the EORTC Cutaneous Lymphoma Group and the International Society for Cutaneous Lymphomas (ISCL).

mycosis fungoides and variants

Since early aggressive chemotherapy is associated with considerable side effects, but does not improve survival, a stage-adapted conservative therapeutic approach is recommended for MF and its variants. Patients with only patches and/or plaques covering <10% (stage IA) or ≥10% (stage IB) of the skin surface should be treated with skin-directed therapies including topical steroids, PUVA (psoralens + UVA), narrow-band UVB and topical cytostatic agents, such as mechlorethamine or carmustine (BCNU). Narrow-band UVB should only be used in patients with patches or very thin plaques. In patients developing one or a few tumours (stage IIB) additional local radiotherapy suffices. Local radiotherapy can be curative in patients with early localized disease and in patients with pagetoid reticulosis. Patients with more extensive plaques and tumours or patients refractory to skin-directed therapies a combination of PUVA and interferon or PUVA and retinoids, including bexarotene, or total skin electron beam irradiation can be considered. In patients with advanced and refractory disease alternative approaches, such as gemcitabine, liposomal doxorubicin, the histone deacetylase (HDAC) inhibitor vorinostat or the fusion toxin denileukin diftitox may be applied. However, the exact place of these new drugs in the treatment of MF, either alone or in combination with other treatment modalities, has still to be defined. Multi-agent chemotherapy is only indicated in patients with effaced lymph nodes or visceral involvement (stage IV), or in patients with widespread tumour stage MF that cannot be controlled with skin-targeted and immunomodulating therapies. In young patients with refractory, progressive MF or SS allogeneic stem cell transplantation may be considered. Durable responses have been reported, but experience is still limited and the optimal conditioning regimen and optimal timing for an allogeneic transplant are currently unknown. Results with autologous stem cell transplantation in MF and SS have been disappointing.

Sezary syndrome

Being a systemic disease (leukaemia) by definition, systemic treatment is required. Skin-directed therapies like PUVA or potent topical steroids may be used as adjuvant therapy. Extracorporeal photopheresis (ECP), either alone or in combination with other treatment modalities, has been suggested as the treatment of choice in SS and erythrodermic MF, with overall response rates of 30%–80%, or complete response rates of 14%–25%. However, the suggested superiority of ECP over the traditional low-dose chemotherapy regimens has not yet been substantiated by controlled randomized trials. Prolonged treatment with a combination of low-dose chlorambucil and prednisone is often effective in controlling the disease, but is unlikely to give complete response. Low-dose methotrexate, bexarotene, denileukin diftitox, (low-dose) alemtuzumab, liposomal doxorubicin and multi-agent chemotherapy have been recommended as second-line treatment of SS. It should be emphasized that comparison of treatment results in the different studies is almost impossible, because of differences in diagnostic criteria used for SS.

primary cutaneous CD30-positive lymphoproliferative disorders

The group of primary cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes primary cutaneous anaplastic large lymphoma (C-ALCL) and lymphomatoid papulosis (LyP), which form a spectrum of disease. Patients with C-ALCL generally present with solitary or localized (ulcerating) tumours or nodules and should be treated with radiotherapy or surgical excision. Patients presenting with multifocal skin lesions can best be treated with radiotherapy in the case of only a few lesions, or with low-dose methotrexate as in LyP. Multi-agent chemotherapy is only indicated in patients presenting with or developing extracutaneous disease and rare patients with rapidly progressive skin disease.

subcutaneous panniculitis-like T-cell lymphoma

The term subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is nowadays only used for cases with an α/β T-cell phenotype, which have an excellent prognosis in particular if not associated with a haemophagocytic syndrome (HPS), which is frequently an extremely aggressive clinical syndrome requiring immediate intervention. A recent study reports a 5-year overall survival of 91% and 46% in SPTCL patients without and with a HPS, respectively. In SPTCL without associated HPS systemic steroids or other immunosuppressive agents should be considered first, whereas in cases of solitary skin lesions radiotherapy is advised. Only in cases with progressive disease not responding to immunosuppressive therapy and in cases with HPS is multi-agent chemotherapy required.

extranodal NK/T-cell lymphoma, nasal type

Extranodal NK/T-cell lymphoma, nasal type is a nearly always Epstein–Barr virus-positive lymphoma which characteristically presents with a mid-facial ulceronecrotic tumour, and uncommonly with (ulcerating) skin lesions at other sites. In patients with stage I disease radiotherapy is the first choice of treatment. In case of more advanced disease these lymphomas show an aggressive clinical behavior and are often resistant to chemotherapy.

primary cutaneous peripheral T-cell lymphoma, not otherwise specified

Within the group of primary cutaneous peripheral T-cell lymphomas, not otherwise specified (PTCLs, NOS) three somewhat better defined subgroups have been included as provisional entities (see Table 1). However, all cases have in common a generally aggressive clinical course and poor survival, and should therefore be treated with multi-agent chemotherapy. Since the results are often disappointing, early allogeneic stem cell transplantation may be considered. The only exception is the group of CD4-positive small–medium pleomorphic CTCLs. These patients often present with a solitary tumour, preferentially on the head, should be treated with local radiotherapy or excision and have an excellent prognosis.

Table 1.

WHO-EORTC classification

Cutaneous T-cell lymphoma 
Mycosis fungoides (MF) 
Variants of MF 
    Folliculotropic MF 
    Pagetoid reticulosis 
    Granulomatous slack skin 
Sézary syndrome 
Primary cutaneous CD30-positive 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, NOS 
    Aggressive epidermotropic CD8+ CTCLa 
    Cutaneous γ/δ T-cell lymphomaa 
    CD4+ small/medium-sized pleomorphic CTCLa 
Cutaneous T-cell lymphoma 
Mycosis fungoides (MF) 
Variants of MF 
    Folliculotropic MF 
    Pagetoid reticulosis 
    Granulomatous slack skin 
Sézary syndrome 
Primary cutaneous CD30-positive 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, NOS 
    Aggressive epidermotropic CD8+ CTCLa 
    Cutaneous γ/δ T-cell lymphomaa 
    CD4+ small/medium-sized pleomorphic CTCLa 
Cutaneous B-cell lymphoma 
    Primary cutaneous marginal zone B-cell lymphoma 
    Primary cutaneous follicle center lymphoma 
    Primary cutaneous diffuse large B-cell lymphoma, leg type 
Cutaneous B-cell lymphoma 
    Primary cutaneous marginal zone B-cell lymphoma 
    Primary cutaneous follicle center lymphoma 
    Primary cutaneous diffuse large B-cell lymphoma, leg type 
a

Provisional entities.

cutaneous B-cell lymphoma

In the WHO-EORTC classification three main types of CBCL are distinguished: primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle centre lymphoma (PCFCL) and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT). PCMZL and PCFCL are indolent types of CBCL with a disease-related 10-year survival exceeding 90%, while PCLBCL-LT has a more unfavourable prognosis (disease-related 5-year survival, ∼50%). Recently, EORTC/ISCL consensus recommendations for the management of these three types of CBCL have been formulated, which are summarized in Table 2.

Table 2.

Recommendations for the initial management of CBCL

 Extent First-line therapy Alternative therapies 
PCMZL Solitary/localized Local radiotherapy IFN-α i.l. 
  Excision (antibiotics)a Rituximab i.l. 
   Intralesional steroids 
 Multifocal Wait-and-see IFN-α i.l. 
·  Local radiotherapy Rituximab i.v 
  Chlorambucilb Topical or intralesional steroids 
  Rituximab i.l. (antibiotics)a  
PCFCL Solitary/localized Local radiotherapy IFN-α i.l. 
  Excision Rituximab i.l. 
 Multifocal Wait-and-see R-CVP/CHOPc 
  Local radiotherapy  
  Rituximab i.v.  
PCLBCL, LT Solitary/ localized R-CHOP +/- IFRT Local radiotherapy 
   Rituximab i.v. 
 Multifocal R-CHOP Rituximab i.v. 
 Extent First-line therapy Alternative therapies 
PCMZL Solitary/localized Local radiotherapy IFN-α i.l. 
  Excision (antibiotics)a Rituximab i.l. 
   Intralesional steroids 
 Multifocal Wait-and-see IFN-α i.l. 
·  Local radiotherapy Rituximab i.v 
  Chlorambucilb Topical or intralesional steroids 
  Rituximab i.l. (antibiotics)a  
PCFCL Solitary/localized Local radiotherapy IFN-α i.l. 
  Excision Rituximab i.l. 
 Multifocal Wait-and-see R-CVP/CHOPc 
  Local radiotherapy  
  Rituximab i.v.  
PCLBCL, LT Solitary/ localized R-CHOP +/- IFRT Local radiotherapy 
   Rituximab i.v. 
 Multifocal R-CHOP Rituximab i.v. 
a

In case of evidence for B. burgdorferi infection.

b

Or other single or combination regimens appropriate for low-grade B-cell lymphomas.

c

In exceptional cases or for patients developing extracutaneous disease.

i.l.: intralesional; i.v.: intravenous; IFRT: involved field radiotherapy.

follow-up

The frequency of follow-up visits depends on the type of PCL and stage of disease. It may vary from every 6 or 12 months in patients with indolent types of PCL and stable disease or patients in complete remission to every 4–6 weeks in patients with active or progressive disease. Follow-up visits should focus on history and physical examination, and additional testing (histology, blood examination, imaging, etc.) should only be performed if required.

note

Levels of Evidence [I–V] and Grades of Recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading are considered justified standard clinical practice by the experts and the ESMO Faculty.

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Author notes

Approved by the ESMO Guidelines Working Group: December 2006, last update December 2009. This publication supercedes the previously published version—Ann Oncol 2009; 20 (Suppl 4): iv115–iv118.
Conflict of interest: The authors have reported no conflicts of interest.