After recognizing that T-cells predominate, a host of other CD markers are used to characterize the cells further (). Commonly, staining for CD2, CD4, CD5, CD7, and CD8 is done. Expression of CD2 and CD3 confirms the presence of a T-cell process. The type of T-cells, whether CD4 and/or CD8, provides insight into the nature of the disease as an inflammatory or malignant process or combination thereof. The expression of CD5 and CD7 is variable depending on the disease process. The absence or reduced presence of CD7 can be suggestive of a diagnosis of cutaneous T-cell lymphoma (CTCL), as CD7 is frequently the first CD marker to lose expression in CTCL. However, it should be noted that loss of CD7 can occur in benign processes as well. Loss of other markers can also occur in CTCL. In erythroderma associated with Sezary syndrome, loss of CD26 is frequently seen.
Basic immunophenotypic schematic for primary cutaneous T-cell and B-cell lymphomas
In addition to the qualitative evaluation of CD marker expression (positive, decreased, negative), a quantitative assessment is made regarding the CD4:CD8 ratio, which has a normal value of 2:1.7
An increased CD4:CD8 ratio is typically found in classic patch stage mycosis fungoides (MF)/CTCL, which decreases in more advanced stages of the disease. Nonetheless, there are unusual CTCL variants with a decreased CD4:CD8 ratio.6
In Sezary syndrome, the CD4:CD8 ratio is typically greater than 10.8
In addition to immunophenotyping, T-cell receptor gene rearrangement analysis can also assist in the diagnosis of CTCL.
The location of the T-cell proliferation infiltrate can also influence how CD markers are used. If the T-cell proliferation localizes to the epidermis and/or dermis, staining for CD30 is traditionally used. This divides T-cell lymphomas into a CD30-negative group that includes classic mycosis fungoides and variants of CTCL that typically have an increased CD4:CD8 ratio and a CD30-positive group that includes cutaneous anaplastic large cell lymphoma (C-ALCL), lymphomatoid papulosis (LyP), and the C-ALCL-LyP spectrum ().
Immunophenotypic algorithm for primary cutaneous T-cell lymphomas with predominant epidermal and dermal involvement
In contrast, if the T-cell infiltrate centers toward the lower dermis and into the subcutaneous tissue, the specimen may be stained for CD56 (), a marker found on natural killer (NK) cells, a subset of T-cells, and often found to be positive in panniculitis-like T-cell lymphomas.6
Further testing to identify the tumor's immunophenotype can then be used. In subcutaneous panniculitis-like-T-cell lymphoma (SPTL), there are two major T-cell phenotypic variants: α/β+ and γ/δ+. The majority of SPTL is of the γ/δ+ T-cell receptor (TCR) type, which is CD3+, CD4-, and CD8+ and rarely expresses CD56 and CD30. In contrast, the γ/δ phenotype is CD3+, CD4-, CD8- with common expression of CD56 and occasional expression of CD30. These phenotypical differences are important as the α/β+ type runs an indolent clinical course while the γ/δ+ type exhibits aggressive clinical behavior. Furthermore, in the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification system, only the γ/δ+ type is classified as a SPTL. The α/β+ variant is considered a type of cutaneous γ/δ+ T-cell lymphoma.9,10
Extranodal NK-T-cell lymphoma-nasal type usually expresses CD2, CD56, cytoplasmic CD3ε and granzyme B, T-cell intracellular antigen-1 (TIA-1), and perforin and lacks surface CD3.6,11
Immunophenotypic algorithm for primary cutaneous T-cell lymphomas with predominant subcutis involvement