The Pathology of Cutaneous T-Cell Lymphoma
The Pathology of Cutaneous T-Cell Lymphoma
The diagnosis of cutaneous T-cell lymphoma (CTCL) requires accurate histopathology, including immunocytochemistry, as well as careful clinical appraisal and analysis for T-cell clonality. This paper reviews the key histologic features of mycosis fungoides (MF) and its variants, and of lymphomatoid papulosis (LyP). Mycosis fungoides is an epidermotropic CTCL that evolves through distinct disease stages of patch, plaque, and tumor, often leading to transformation in the final stages. Disease staging is made clinically, and diagnosis may be difficult during the early stages because several common dermatologic conditions share features with MF. Therefore, clinical appraisal plus the presence of characteristic histopathologic features are needed to ensure accurate diagnosis. Clinical information is particularly important in the diagnosis of LyP, as the disease appears malignant histologically, but has a benign clinical course. Several other T-cell lymphomas were defined in a recent classification of these cutaneous lymphomas, and some key features of these disorders are also briefly reviewed.
There is a tendency in medicine for practitioners to consider histopathologic evidence as definitive. However, in cutaneous T-cell lymphoma (CTCL), successful diagnosis requires not only accurate histopathology, including immunocytochemistry, but also good clinical appraisal and analysis for T-cell clonality. Without due attention to each of these three parameters, there is a real danger of misdiagnosis and, therefore, inappropriate treatment of patients. This brief review will outline the principal histologic features of mycosis fungoides (MF), the most common CTCL, and lymphomatoid papulosis (LyP), with a few select comments on some lesser known T-cell lymphomas on which data are beginning to emerge.
Classification of T-Cell Lymphomas
In 2005, an updated World Health Organization/European Organisation for Research and Treatment of Cancer classification of cutaneous lymphomas was published, which aimed to resolve some of the shortcomings of earlier classifications (Table 1). Mycosis fungoides is the most common of the T-cell lymphomas, and folliculotropic MF (formerly follicular mucinosis), pagetoid reticulosis (the solitary form-Woringer-Kolopp), and granulomatous slack skin (GSS) are regarded as variants of MF. Sézary syndrome and adult T-cell leukemia/lymphoma are also included in this classification, but will not be discussed further in this review.
There is then the umbrella term primary cutaneous CD30+ lymphoproliferative disorders, which includes primary cutaneous anaplastic large-cell lymphoma (ALCL) and LyP. The classification also includes subcutaneous panniculitis-like T-cell lymphoma (SPTCL), for which there has been emerging evidence that the αβ variant has a better prognosis and is distinct from the γδ form. The latter is now included within the provisional category of cutaneous γδT-cell lymphoma, whereas SPTCL is reserved for the αβ variant. Three provisional groups are included in the updated classification: primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (Berti's lymphoma), cutaneous γδT-cell lymphoma, and primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma. The provisional status of these entities reflects the paucity of data on their clinical, pathologic and prognostic importance.
There remains a heterogeneous group of T-cell lymphomas that do not fit into any of the previous categories; for these, the term "peripheral T-cell lymphoma, unspecified," is reserved.
Mycosis fungoides, which accounts for almost 50% of all primary cutaneous lymphomas, is an epidermotropic CTCL that is characterized by a proliferation of small- to medium-sized T lymphocytes with cerebriform nuclei. The disease evolves through well-defined stages of patch, plaque, and tumor, often culminating in "transformation" in the final stages of the disease. Staging is a clinical judgement and should not be guessed histopathologically, although undoubtedly the histopathology does broadly reflect the disease stage.
Patch Mycosis Fungoides
Patch MF is difficult to diagnose because it has several differential diagnoses, most of which are more common, and the histopathologic differences are subtle. The differential diagnoses may include spongiotic dermatitis (most commonly eczema), lichenoid dermatitis, chronic superficial scaly dermatitis and pigmented purpuric dermatoses. Moreover, pigmented purpuric dermatosis can evolve into MF over some years, and longitudinal biopsy data have demonstrated the same clones in biopsies of the pigmented purpuric dermatosis and subsequent MF; thus, there is an uncertain relationship between these two conditions. Another differential diagnosis is that of isolated regressing lesions, which can mimic MF. This is not usually significant in practice, however, as the presence of only a single lesion seldom favors a diagnosis of MF.
Useful diagnostic features for MF include the following: the perinuclear halo, which is a clear space around the nuclei of lymphocytes and, while not absolutely pathognomonic, is a useful characteristic feature of early MF; Indian filing, or lining up of lymphocytes, in the basal epidermal layer; and a relative lack of spongiosis for the amount of infiltrate present. In lichenoid examples of MF, the lymphocytes produce little or no basal epidermal damage but appear simply to colonize the epidermis. This is in contrast to autoimmune lichenoid dermatoses, in which there is destruction of the stratum basalis and often colloid body formation. In addition, in the early stages of disease the lymphocytes are generally not very atypical; cytologic pleomorphism develops pari passu disease progression. Pautrier's microabscesses may be seen in patch MF, but are a more characteristic feature of plaque-stage disease.
Plaque Mycosis Fungoides
Essentially, this stage of MF tends to display the epidermal features of patch-stage disease, but simply in more florid form. Pautrier's microabscesses are, however, more numerous; these denote the presence of collections of neoplastic lymphocytes within a nonspongiotic epidermis. The dermal infiltrate is also more pronounced, and cytologic atypia of the lymphocytes more readily appreciated.
Tumor Mycosis Fungoides
In tumor MF, the epidermal component of the earlier disease stages is lost. Most of the disease is centered in the dermis, although there is often some residual epidermal disease. This stage is characterized by a large population of lymphocytes, usually markedly atypical, in the dermis. A diagnosis of tumor MF requires clinical evidence of patch- and plaque-stage disease, otherwise a different type of lymphoma is most likely. Although there are reports in the literature of MF tumor d'emblée, or de novo onset of tumor-stage MF, many of these cases were described before the availability of immunocytochemistry so they may well represent unidentified CD30+ anaplastic lymphoma. If MF tumor d'emblée occurs at all, it is exceptionally rare.
Transformed Mycosis Fungoides
In transformed MF, the infiltrating cells appear very high grade cytologically, are atypical, and constitute at least 25% of the population in cohesive expansile clusters. Formerly the diagnosis required that these cells express the CD30 surface antigen, but it is now predicated on high-grade cytology alone. The differential diagnosis at this stage includes other lymphomas, LyP (which may show some similar histologic features), and some infections such as herpesvirus, which can give a very florid inflammatory response with atypia. As ever, good clinical appraisal is required for diagnostic accuracy.