Primary cutaneous lymphomas
Mycosis fungoides: diagnostic considerations
P.M. Jansen1 R. Willemze2 Departments of 1Pathology and 2Dermatology, Leiden University Medical Centre, The Netherlands. Correspondence: Patty M. Jansen and Rein Willemze E-mail :
[email protected] [email protected]
Hematology Education: the education program for the annual congress of the European Hematology Association
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Primary cutaneous lymphomas (PCL) represent a group of lymphoproliferative disorders of neoplastic lymphocytes presenting in the skin with no evidence of extracutaneous disease at the time of diagnosis. Whereas most lymphomas arise in lymph nodes, a considerable proportion primarily involve extranodal sites. After the gastrointestinal tract, the skin is the second most common site of extranodal non-Hodgkin lymphoma, with an estimated annual incidence of 1:100,000. In contrast to nodal non-Hodgkin lymphoma, most of which are B-cell derived, about 75% of PCL are of T-cell origin. Primary cutaneous T-cell lymphomas (CTCL) is a heterogeneous group of diseases which are classified according to the 2008 World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissue. In this review, the diagnostic and clinic-pathological features of the most common type of CTCL, mycosis fungoides, will be discussed. Learning goals
At the conclusion of this activity, participants should know about: - the clinical and histological characteristics of the different stages of mycosis fungoides (MF) and Sézary syndrome (SS); - the clinico-pathological subtypes of classic MF; - the morphological challenges in the diagnosis of MF.
2015;9:297-302 Primary cutaneous lymphomas (PCL) are non-Hodgkin lymphomas (NHL), mostly derived from B or T cells, presenting in the skin without extracutaneous manifestation at the time of diagnosis. Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL) and represents nearly 50% of all PCL.1 It predominantly affects elderly adults (median age 55-60), but can be seen in any age group, including children. The male-to-female ratio is about 2:1. The etiology is still unclear, but genetic mutations and occupational exposure have been implied.2t In its classic form, MF is an indolent NHL with prolonged clinical course, presenting as erythematous scaly patches that evolve slowly into plaques and tumors in some patients. Less than one-third of patients show an advanced clinical course with involvement of lymph nodes and/or visceral organs, usually involving large cell transformation.3,4 Over the past decades, a variety of clinical, histological and immunohistochemical subtypes of MF have been described. Although most of these are considered to be minor variants of classic MF, few are recognized as separate subtypes according to the World Health Organization (WHO) classification system of tumors of hematopoietic and lymphoid tissues.5
Introduction
Classic MF is traditionally divided into three stages (patch, plaque and tumor), but not all patients develop all stages or go through them in a linear fashion. The prognosis of patients with MF largely depends on the type and extent of skin lesions, as reflected by the revised tumor-nodes-metastasis-blood (TNMB) classification of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization (EORTC) (Tables 1 and 2).6 In previous studies, 10-year disease-specific survival rate was 97% for patients with limited patch/plaque disease (MF IA), 83% for generalized patch/plaque disease (MF IB), 42% for tumor stage MF (IIB), and less than 20% for histologically proven lymph node or visceral involvement (MF IVA and IVB).3,4,7
Clinical and histological features
The clinical presentation of patch-stage MF consists of asymmetric, irregularly shaped, scaly and erythematous macules and patches. They commonly affect the sun-protected skin areas such as the buttocks, lower trunk, breasts and legs (Figure 1). Histology of skin biopsies from patch stage MF demonstrate an epidermotropic neoplastic lymphoid infiltrate which is composed predominantly of small- to medium-sized atypical lymphocytes with hyperchromatic, cerebriform nuclei and clear cytoplasm. The atypical lymphocytes usually colonize the basal layers of the epidermis singly or in a lin-
Patch stage
Hematology Education: the education program for the annual congress of the European Hematology Association | 2015; 9(1) | 297 |
20th Congress of the European Hematology Association
ear fashion. Pautrier microabscesses, which consist of small aggregates of atypical lymphocytes, can be helpful to make a diagnosis but are only seen in a minority of cases.8 In addition to clinical and pathological criteria, ancillary studies may help make a diagnosis of MF. The neoplastic T cells in MF are usually CD4+ cells that express T-cell receptor (TCR) b and variable pan-T-cell markers such as CD2, CD3, CD5, and CD7. Loss of T-cell associated antigen expression is common and most frequently observed for CD7, followed by CD5. Up to 20% of cases display a CD8+ phenotype, which has a similar clinical behavior as CD4+ MF.9,10 T-cell receptor gene rearrangements studies are not required for diagnosis and may even be misleading since clonal T cells are also frequently found in inflammatory
skin conditions. Alternatively, it has been suggested that the diagnostic value of T-cell clonality evaluation in MF can be enhanced when an identical clone is detected at two or more different skin sites.11 The early lesions and diagnosis of MF often pose a significant diagnostic challenge because the clinical and histopathological features may simulate a variety of inflammatory skin disorders. Furthermore, clinical presentation and pathological findings may be conflicting, and some of the classic histological features, such as lymphocyte atypia or epidermotropism can be absent.8,12 Not uncommonly, a repeat biopsy is recommended, especially in cases where there is clinical concern for MF but an absence of distinct diagnostic pathological features.
Table 1. Tumor-nodes-metastasis-blood (TNMB) classification of mycosis fungoides and Sézary syndrome, according to the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC).
Plaques are raised, scaly and sharply demarcated lesions that are usually reddish, purplish, or brownish in color. Plaques commonly occur in the same body regions as patches, and may coalesce and form arcuate or serpiginous borders (Figure 2). While some plaques arise from patches, others develop on their own, and patches and plaques can occur simultaneously in one patient. Histologically, the atypical T cells in plaques often display irregularly convoluted nuclear membranes and hyperchromatic nuclei and
Plaque stage
T1 T2 T3 T4 N0 N1 N2 N3 M0 M1 B0 B1 B2
T (skin) Limited patch/plaque (involving
