Approach

Cutaneous T-cell lymphomas (CTCL) is a heterogeneous group of malignancies, and presentation can be diverse. Establishing the correct diagnosis is often difficult and requires expertise located in specialist centers. Diagnosis is based on a combination of clinical, histologic, immunophenotypic, and genetic data.[5][31][32]

History and physical exam

Patients with suspected primary CTCL are usually older. The incidence rates for mycosis fungoides (MF)/Sézary syndrome (SS), the two most common forms of CTCL, peak in the 50- to 74-year age group, with men more frequently affected than women.[3][4][30]​​ Higher incidence rates are also found in African-Americans compared with other racial groups.[3]​ Evidence suggests that MF is twice as common in African-American populations, while higher rates of SS are seen in white Americans.[7][8][9][10]

Pruritus is one of the most frequent and debilitating symptoms of CTCL, especially for patients with SS.[2] One retrospective analysis demonstrated that not only is pruritus present in over 50% of patients, but the severity of the pruritus increased with more advanced disease.[33]

All patients should undergo a complete skin exam assessing the percentage of body surface area (BSA) and type of skin lesion, palpation of the peripheral lymph node regions, and palpation of organomegaly/masses.[31][32]

MF and its variants are characterized by heterogeneous cutaneous manifestations including:[5][32][34][35][36]

  • Polymorphic patches or plaques

  • Tumors and erythroderma (associated with advanced cutaneous stage)

  • Folliculotropic MF (FMF) may present as folliculocentric papules, nodules, or areas of alopecia

  • Hypopigmented lesions

  • Hyperpigmentation, mostly seen in children, adolescents, and patients with darker skin

  • Granulomatous slack skin (redundant skin resembling cutis laxa on flexural areas)

  • Unilesional, pagetoid reticulosis

  • Peripheral adenopathy may or may not be present

Any body surface can be affected, including the palms and the soles of the feet, but in most early presentations of MF the lesions are limited to the chest, abdomen, pelvis, and back.[37][38] Facial involvement is uncommon in the early stages, except in the folliculotropic variant of mycosis fungoides. Patients with mycosis fungoides presenting in the later stages may have generalized skin lesions. Many patients will have had the skin lesions for a number of years and been treated for other skin disorders such as psoriasis, eczema, or an allergic reaction.[Figure caption and citation for the preceding image starts]: ErythrodermaFrom the collection of the Christie NHS Foundation Trust, Manchester, UK; used with permission [Citation ends].com.bmj.content.model.Caption@78f02ef9[Figure caption and citation for the preceding image starts]: Cutaneous T-cell lymphoma: early patch diseaseFrom the collection of the Christie NHS Foundation Trust, Manchester, UK; used with permission [Citation ends].com.bmj.content.model.Caption@268775c7[Figure caption and citation for the preceding image starts]: Cutaneous T-cell lymphoma: extensive patch diseaseFrom the collection of the Christie NHS Foundation Trust, Manchester, UK; used with permission [Citation ends].com.bmj.content.model.Caption@2e5ebd85[Figure caption and citation for the preceding image starts]: Tumor plus ulceration in a patient with folliculotropic mycosis fungoidesFrom the collection of the Christie NHS Foundation Trust, Manchester, UK; used with permission [Citation ends].com.bmj.content.model.Caption@c3f2dea

SS is a rare (<5% cases) leukemic type of CTCL, defined by:[2][5][32]

  • Pruritic erythroderma

  • Generalized lymphadenopathy

  • Clonally related neoplastic T cells with cerebriform nuclei (Sézary cells) in the skin, lymph nodes, and peripheral blood.

As the clinical and histologic presentation of SS may be similar to MF, demonstration of peripheral blood involvement may be crucial for the diagnosis of SS.[2][5] For a definitive diagnosis of SS, in addition to peripheral clonally related neoplastic T cells in skin and peripheral blood, one of the following should be present:[2][5]

  • Absolute Sézary cell count of >1000/microliter

  • An expanded CD4+ T-cell population resulting in a CD4/CD8 ratio ≥10, CD4+/CD7- cells ≥30%, or CD4+/CD26- cells ≥40%.

Correlation of clinical features with the histopathologic findings of blood are essential for a definitive diagnosis of SS.[5][32]

Biopsy

Biopsy of suspicious lesions is essential for all patients.[31][32] Multiple biopsies may be necessary to capture the pathologic variability of disease. Analysis of the tumor should be done by a pathologist with expertise in the diagnosis of CTCLs.

Repeated biopsy may be necessary if the analysis of the consult material in conjunction with the clinical features is not diagnostic.[5][32]

Immunohistochemical (IHC) panel of skin biopsy should include:[32]

  • CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30

  • Molecular analysis to detect clonal T-cell receptor (TCR) gene rearrangements, or other assessment of clonality.

Tumor cells are usually CD3+, CD4+, and CD8-, although CD8+ variants are not uncommon. CTCL lesions often lose CD7.[5][32]

Repeated biopsy of skin should be done if the presence of large cell transformation (histologically as greater than 25% of the tumor cells displaying large size) or folliculotropism is suspected, but not previously confirmed pathologically.[32] The presence of either of these variants may have important implications for selection of therapy and outcome, and should be included in pathology reports.[32]  

IHC panel of skin biopsy should include:[32]

  • CD25, CD56, TIA1, granzyme B, TCRß, TCRẟ; CXCL13, inducible T-cell co-stimulator (ICOS), and PD-1

If the skin biopsy is not diagnostic, biopsy of enlarged lymph nodes or suspected extracutaneous sites may be needed.[31][32]​ Excisional or incisional biopsy is the preferred method of lymph node biopsy.[32]​ A fine needle biopsy alone is not sufficient for the initial diagnosis of lymphoma. Bone marrow biopsy may be helpful in patients with unexplained hematologic abnormality. Repeated biopsy may be necessary if results are not diagnostic.[32]

Bone marrow biopsy may be helpful in patients with unexplained hematologic abnormality.[5][32]

Laboratory evaluation

Essential laboratory studies for all patients include:[5][31][32]

  • Complete blood count (CBC) with differential and determination of absolute lymphocyte count

  • Flow cytometric studies to assess and quantitate an expanded T-cell population with aberrant phenotype: recommended for patients with T2-4 skin classification, or any suspected extracutaneous disease including adenopathy, but optional for patients with T1 stage disease

  • Clonal TCR gene rearrangement in peripheral blood lymphocytes if blood involvement suspected

  • Comprehensive metabolic panel

  • Lactate dehydrogenase (LDH)

For patients with extensive skin disease where the skin biopsy is not diagnostic of advanced-stage disease, assessment of peripheral blood for Sézary cells with flow cytometry and molecular analysis is recommended.[32] Sézary cell preparation is less useful than flow cytometry due to the subjective nature of the process, but can be useful where flow cytometry is not available.[5][31][32]

Human T-cell lymphotropic virus (HTLV)-I/2 serology should be performed in all patients with MF or SS, to distinguish those with HTLV-I-associated adult T-cell leukemia/lymphoma from those with other T-cell leukemias, such as T-prolymphocytic leukemia. This will have an impact on therapy.[5][32]

In the UK, it is recommended that in all new patients with lymphoma, HIV status should be checked.[5] 

Liver function should be assessed in all patients prior to treatment.

Imaging

Computed tomography (CT) with contrast of the neck, chest, abdomen, and pelvis or integrated whole body (including legs and arms) with positron emission tomography (PET) or CT is recommended for patients with T3 or T4 disease.[32] Imaging should be considered for patients with T2a, T2b, folliculotropic MF, large-cell transformed MF, palpable adenopathy, or abnormal laboratory studies.[32]

Patients with cutaneous lymphomas may have extranodal disease, which may be inadequately imaged by CT. PET scan may be preferred in these circumstances.[32] However, PET scans are not routinely recommended for patients with MF/SS in the UK.[5]

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