Cutaneous T-cell lymphomas
In contrast to nodal lymphomas, in which B-cell NHLs represent the vast majority of lymphoid neoplasms, CTCL accounts for 65% of primary CL.22 CTCL displays a broad spectrum of clinical manifestations with patches, plaques, papules and nodules.
Mycosis fungoides (MF) is the most common form of primary CL and makes up approximately 40% of all CL. In the WHO/EORTC and the WHO classification, the term MF is by definition restricted to classical cases with patches and plaques, or to variants showing a similar course. The so called d’emblée form of MF has been excluded and belongs to the group of primary cutaneous peripheral T-cell lymphoma, unspecified. Histologically, MF is characterized in its plaque stage by a dense, often band-like superficial infiltrate of small lymphocytes with atypical cerebriform nuclei, which is often accompanied by a variable number of eosinophils and occasionally by plasma cells. The epidermotropism of atypical lymphocytes with formation of Pautrier collections composed of atypical lymphocytes is the histological hallmark. In the early patch stage of MF, however, histological findings are subtle, with less prominent or even lacking atypia of lymphocytes, interface changes with vacuolization, and lining up of lymphocytes along the junctional zone. In early MF, epidermotropism with Pautrier collections is found in only 19% of biopsy specimens.23 MF is a neoplasm of lymphoid cells with a CD4+ T-helper phenotype and a TH2 cytokine pattern. Recently, various phenotypes of otherwise classic MF has been described including CD8+ MF, which often presents with hyper- or hypopigmented patches and plaques, CD56+ MF and CD4− CD8− double-negative MF.24,25 These phenotypes do not appear to be of prognostic impact.26 A T-cell clone is found in only half of biopsy specimens in early disease stages. Thus, neither molecular tests for T-cell clonality nor phenotypic markers are of significant diagnostic value in early MF.
MF displays a broad spectrum of variants and subtypes.24 Folliculotropic MF is of importance due to its prognostic impact, since it exhibits a worse prognosis, with 5-year survival rates of approximately 60–70%, and thus requires more intensive treatment. The previously used term MF-associated follicular mucinosis has been replaced by folliculotropic MF, after two larger studies showed that not all folliculotropic MF cases were associated with mucinous degeneration of the hair follicles.27,28 Similarly, the prognosis of granulomatous MF with a 5-year survival of 66% is worse than in classic MF and in granulomatous slack skin (GSS).29 Histologically, granulomatous MF presents with sarcoid-like or granuloma annulare-like infiltrates (Figure 1). Remarkably, epidermotropism of atypical lymphocytes is present in only half of cases.29 Since granulomatous MF and GSS exhibit overlapping and often identical histological features, the distinction between granulomatous MF and GSS is based on the clinical manifestation with occurrence of bulky skin folds in the intertriginous areas in GSS.29 Pagetoid reticulosis and GSS were listed as subtypes of MF mainly due to their distinct clinical features and excellent prognosis. Pagetoid reticulosis is by definition restricted to cases with a well-circumscribed erythematous and scaling, slowly growing solitary lesion. Histologically, there is prominent epidermotropism of small and medium-sized lymphocytes with cytoplasmic halo and variable phenotypes including CD4+, CD8+ and CD30+ forms.30 Recently, recommendations for the stage-adapted treatment of MF have been published.31 Ultraviolet-light therapy and retinoids are therapeutic cornerstones in patch and plaque stages of the disease.
Sézary syndrome (SS) is a rare form of CTCL, accounting for 3% of all CLs. The characteristic clinical presentation encompasses erythroderma, alopecia, palmoplantar hyperkeratosis and lymphadenopathies.32 Histologically specific features with epidermotropism of atypical lymphocytes are found in only 40% of biopsy specimens, which makes the histological assessment of SS challenging.33 In the remaining cases, a band-like infiltrate of small lymphocytes with or without nuclear atypia and lack of epidermotropism or only a subtle perivascular infiltrate are found.33–35 There is leukaemic spread of tumour cells with atypical enlarged lymphocytes, so called Sézary or Lutzner cells. In most definitions, >1000 cerebriform cells/ml peripheral blood are required for the diagnosis of SS, but consensus on the diagnostic criteria for SS has still to be found.36 The prognosis of SS is poor, with a median survival of 2–4 years.6
The primary cutaneous CD30+ lymphoproliferative disorders (LPD) are the second most common from of CTCL.37 This group represents a spectrum of diseases including lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (PCALCL) and borderline cases. LyP is characterized by multiple papulo-nodular lesions (Figure 2), which undergo spontaneous regression after a few weeks or months. The disease usually persists for years or even decades, but has an excellent prognosis.38 Aggressive treatment should thus be avoided. Nevertheless, patients suffering from LyP should be monitored life-long, since 5–25% of patients develop a second lymphoma like Hodgkin’s lymphoma, MF and primary cutaneous or nodal anaplastic large cell lymphoma (ALCL).38 The expression of fascin may represent a prognostic marker indicating increased risk for the development of second lymphomas in LyP patients.39 Histologically, LyP exhibits a spectrum ranging from scattered or grouped CD30+ large pleomorphic or anaplastic tumour cells in the background of neutrophils and eosinophils (type A) (Figure 3A,B) to an epidermotropic infiltrate of small lymphocytes (type B) or cohesive sheets of tumour cells with only a few admixed reactive cells (type C).40 The CD30+ cells in LyP express CD4 and commonly T-cell intracytoplasmic antigen-1 (TIA-1), but other phenotypes (CD8+ or CD56+) are also observed. Tumour necrosis factor receptor-associated factor-1 (TRAF-1) and MUM1 have recently been described as adjunctive markers for differentiating between LyP and PCALCL, but contradictory results on their diagnostic value have been reported.41–43 LyP, PCALCL and secondary infiltrates of systemic ALCL as well as tumour stage of MF and transformation in SS show overlapping histological and phenotypical features and may be impossible to distinguish on histological and phenotypic grounds alone. It exemplifies that differentiation can be achieved only by clinicopathological correlation and staging examinations.
Figure 3. Lymphomatoid papulosis. A, Large anaplastic tumour cells, small lymphocytes and eosinophils. B, Expression of CD30 by the tumour cells.
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In contrast to LyP, PCALCL presents with solitary or grouped, frequently ulcerated large tumours. Histologically, a nodular cohesive infiltrate of large pleomorphic, anaplastic or immunoblastic tumour cells with a high mitotic rate is found. Eosinophils may be admixed.44 By definition, >75% of the tumour cells have to express CD30.7,37 The tumour cells most commonly express CD4, but CD3 expression may be weak or absent. In contrast to systemic ALCL, which frequently shows expression of ALK due to underlying t(2;5) translocation, PCALCL lacks this transformation and expression of ALK in the vast majority of cases.45,46 The neutrophil-rich form of ALCL shows scattered tumour cells within dense infiltrates of neutrophils and may simulate pyoderma gangrenosum.47 The prognosis of PCALCL is favourable, with a 5-year survival rate of 95%, even in patients with involvement of regional lymph nodes.38 Excision and radiotherapy are first-line therapy in solitary tumours. Low-dose methotrexate is effective for grouped or multiple lesions of PCALCL. Multiagent chemotherapy should be restricted to cases with extracutaneous spread.38
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) accounts for 1% of all CL. In the WHO/EORTC classification and the WHO classification (4th edn, 2008), this term is by definition restricted to cases expressing a T-cell receptor (TCR) α/β phenotype.7,9 The demonstration of expression of β-F1 (TCR α/β) by immunohistochemistry is a pivotal diagnostic marker for this entity, which accounts for 75% of all subcutaneous forms of T-cell lymphomas. Histologically, lobular infiltrates of small to medium-sized lymphoid cells with pleomorphic nuclei are found. Karyorrhexis and cytophagocytosis may be present (Figure 4). There is rimming of adipocytes by tumour cells, but this is not an entirely disease-specific feature. It can also be seen in lupus panniculitis, which is one of the major differential diagnoses. Phenotypically, SPTCL expresses CD8 and cytotoxic proteins. SPTCL is associated with a good prognosis with a 5-year survival rate of 80%.48 Tumour spread to other tissues is rare. In contrast, tumour cells in subcutaneous lymphoma with a γ/δ TCR phenotype express CD56, CD2 and CD3, but are negative for CD4 and CD8. Immunohistochemically the γ/δ TCR phenotype can be demonstrated by expression of TCR δ-1 (TCR γ/δ) on fresh frozen tissue or indirectly by the lack of β-F1 expression on formalin-fixed paraffin-embedded biopsy specimens. Histologically, angiocentric growth may be found. Often additional involvement of the dermis and even an epidermotropic component of the infiltrate is seen. In contrast to the TCR α/β+ form, the γ/δ+ form has an unfavourable prognosis.48,49 Cases displaying a TCR γ/δ phenotype were therefore excluded from subcutaneous panniculitis-like T-cell lymphoma and reclassified as part of primary cutaneous γ/δ T-cell lymphoma.48 Whereas α/β+ SPTCL can be controlled by systemic steroids or even followed by a ‘wait and see’ strategy, γ/δ+ lymphoma with subcutaneous involvement requires multiagent chemotherapy, new targeted therapies or even allogeneic bone marrow stem cell transplantation.
Figure 4. Subcutaneous panniculitis-like T-cell lymphoma: infiltrates of small and medium-sized lymphoid cells with pleomorphic nuclei. Rimming of adipocytes by tumour cells, karyorrhexis and cytophagocytosis.
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All cases that do not belong to MF, SS, CD30+ LPD, SPTCL or extranodal NK/T-cell lymphoma are assigned to the group of peripheral T-cell lymphoma, unspecified (PTL, NOS) according to the WHO/EORTC and WHO classifications. This still poorly characterized entity most often presents with rapidly evolving multiple nodules without preceding patches and plaques as in MF.50 By definition, CD30 expression is absent or limited to only a minority of tumour cells. Among PTL, NOS, three subtypes with distinct clinical and pathological and prognostic features were delineated. Cutaneous γ/δ lymphomas have been listed a provisional entity in the WHO/EORTC classification and have been incorporated as a separate entity in the WHO classification (4th edn, 2008). This lymphoma is rare.49 Involvement of the subcutis and epidermotropic infiltrates and angiocentric and angiodestructive growth are frequently observed.51 The tumour cells express CD2, CD3, CD56 and cytotoxic proteins, but are negative for Epstein–Barr virus in most cases. Prognosis is poor independent of primary or secondary cutaneous involvement. Treatment with multiagent chemotherapy and bone marrow transplantation may be effective.
Primary cutaneous aggressive (epidermotropic) CD8+ T-cell lymphoma (CD8+ AETCL) represents another subtype of PTL, NOS, associated with a poor prognosis and a median survival time of <3 years.49,52 This lymphoma presents with disseminated, rapidly evolving erosive or ulcerating plaques and nodules. Histology shows an epidermotropic infiltrate of small to medium-sized lymphoid cells with pleomorphic nuclei and numerous necrotic keratinocytes, erosion and ulceration (Figure 5). The tumour cells express CD8, TIA-1 and other cytotoxic proteins and CD45RA. This subtype of PTL, NOS has to be distinguished from CD8+ MF, which also displays a band-like and epidermotropic infiltrate, but only very few or no necrotic keratinocytes. In contrast to CD8+ AETCL, CD8+ MF manifests clinically with hyper- or hypopigmented patches and plaques, but no erosions, necroses or ulcerations, and has the same favourable prognosis as classic MF.
Figure 5. Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma: epidermotropism of small to medium-sized tumour cells with atypical, chromatin dense nuclei. Note the numerous necrotic keratinocytes.
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The primary cutaneous CD4+ small/medium pleomorphic T-cell lymphoma (CD4+ SMPTL) is a provisional entity within the group of PTL, NOS. It presents in most cases with a solitary nodule in the absence of preceding patches and plaques (Figure 6).53 Histologically, nodular infiltrates of small or to a lesser extent medium-sized slightly pleomorphic lymphocytes and admixed eosinophils, plasma cells and histiocytes are found.54 Epidermotropism may focally be present. Distinction from nodular form of T-cell pseudolymphoma (PSL) is challenging. Nuclear pleomorphism and detection of a clonal T-cell population favour the diagnosis of CD4+ small/medium T-cell lymphoma. Recent studies indicate that this entity in fact represent a neoplastic proliferation of follicular T-helper cells based on the expression of CXCL-13 and PD-1.55 CD4+ SMPTL exhibits a favourable prognosis with 5-year survival rates of >90%,50 but recent data suggest that this CL entity may encompass a prognostically heterogeneous group of tumours.56
Cutaneous B-cell lymphomas
The classifications of CBCL has long been a matter of confusion and debate. It is therefore not surprising that the most significant changes in the WHO/EORTC classifications belonged to CBCL. The WHO classification (4th edn, 2008) has adopted the definitions and criteria of the WHO/EORTC classification (Table 1).
Primary cutaneous marginal zone B-cell lymphoma (PCMZL) is defined as an indolent B-cell lymphoma composed of small B cells, marginal zone cells, lymphoplasmacytoid cells and mature plasma cells.7,57 In the WHO classification (4th edn, 2008), PCMZL belongs to the group of extranodal marginal zone lymphoma of MALT lymphoma.58 Recent data suggest that most cases of PCMZL differ from other extranodal marginal zone lymphomas as regards the expression of class-switched immunoglobulins and CXCR3.59 As regards classification, histological and immunophenotypic similarities nevertheless justify including PCMZL in the larger group of extranodal MALT lymphomas. Histologically, nodular and confluent infiltrates of small lymphocytes, mostly lymphoplasmacytoid cells or more rarely monocytoid cells, are the major component of PCMZL (Figure 7). These cells express B-cell markers and Bcl-2, but are negative for Bcl-6. The infiltrates are separated from the overlying epidermis by a Grenz zone.60 Additionally, reactive germinal centres of varying number and size and numerous T cells as well as histiocytes are commonly found in PCMZL. Monotypic plasma cells are mostly located at the periphery of the infiltrates and are a major diagnostic criterion for MZL, but there is no consensus on the ratio of immunoglobulin light chains required to be monotypic. Differentiation from other B-cell infiltrates with follicular pattern can be challenging.
Figure 7. Primary cutaneous marginal zone B-cell lymphoma (MALT lymphoma): nodular and confluent infiltrates of small lymphocytes (darker areas) with remnants of germinal centres (pale zones).
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Absence of mantle zone and lack of polarization were identified as distinguishing features in PCFCL,61 but diagnosis can be achieved only by correlating clinical, histological, phenotypic features and clonality data. Recent data showed clusters of CD123+ plasmacytoid dendritic cells (PDC) in all cases of PCMZL, but not in other forms of CBCL. Thus, PDC may be a diagnostic marker for differentiation from other CBCLs, but they do not distinguish PCMZL from B-cell PSL.62 PCMZL has an excellent prognosis, with a 5-year survival rate of 98%, but recurrences are seen in half of patients.63,64 Extracutaneous spread occurs very rarely. Excision and radiotherapy are first-line therapies.65 Alternatively, intralesional interferon-alpha and intralesional or systemic rituximab are effective.66 The aetiopathogenesis of PCMZL has still to be elucidated. The similarities between PCMZL and B-cell PSL and the link with other extranodal MALT lymphomas suggest that PCMZL is a lymphoproliferation driven by infectious agent(s) or autoantigens. In a subset of cases, borrelia species and hepatitis C virus sequences could be found, but they may be only two out of several infectious agents linked to PCMZL.67,68 The findings of PDC and T cells in B-cell PSL and PCMZL indicate that these two diseases may represent different evolutionary steps of a lymphoproliferation composed of PDC, T cells and B cells driven by antigenic stimulation.69
Primary cutaneous follicle centre lymphoma (PCFCL) is defined as a tumour of neoplastic follicle centre cells with a mixture of small and large cleaved cells (centrocytes) and, to a lesser extent, large non-cleaved cells (centroblasts) with prominent nucleoli.7,8 In the WHO classification (4th edn, 2008), PCFCL is listed as a separate entity and not only as a variant of extranodal follicular lymphomas.9 Histologically, three growth patterns can be seen: a follicular, a follicular and diffuse, and a diffuse pattern. In all three patterns, the tumour is predominantly composed of centrocyte-like tumour cells with cleaved nuclei. In the follicular growth pattern, the tumour cells are arranged in large neoplastic follicles, which lack polarization and display a small or absent mantle zone.70 Tingible body macrophages are usually not present.61 The diffuse pattern is in fact the most common seen in PCFCL. No follicular structures can be discerned, but irregular networks of CD21+ follicular dendritic cells are found and may be an adjunctive maker for differentiation between this growth pattern of FCL and the diffuse infiltrates in DLBCL, leg type. The tumour cells in PCFCL express CD20 and Bcl-6. In contrast to nodal FCL, Bcl-2 expression and t(14;18) are found in only a small minority of PCFCL. PCFCL has an excellent prognosis, with a 5-year survival rate of >90%.6,64 Nevertheless, recurrences are seen in up to 40% of patients. Extracutaneous spread occurs very rarely. PCFCL arising at the legs and those cases with expression of FOX-P1 appear to have a worse prognosis and should probably be treated more aggressively, similar to DLBCL, leg type.71
In contrast to these low-malignant CBCL forms, primary cutaneous diffuse large B-cell lymphoma (PCDLBCL) is characterized by a dense nodular infiltrate of centroblast-like and immunoblast-like tumour cells with non-cleaved nuclei and prominent nucleoli, but without significant admixture of centrocyte-like cells (Figure 8). Among the group of PCDLBCL, the most common form is PCDLCBL, leg type, which frequently develops on the legs of elderly patients and exhibits an unfavourable prognosis.71,72 It may appear unusual to add the localization to the designation of this lymphoma entity. It is, however, paralleled by other extranodal lymphomas such as extranodal NK/T-cell lymphoma, nasal type. PCDLBCL, leg type displays a characteristic phenotype with strong expression of Bcl-2 and MUM1, but variable expression of Bcl-6 and absence of CD10.72 Apart from the leg type of PCDLBCL, the plasmablastic lymphoma and the T-cell-rich large B-cell lymphoma were included into the group of DLBL. The term PCDLBCL, other, was used to designate diffuse B-cell lymphomas that lack the typical clinical, histological and phenotypic features of PCDLBL, leg type, and do not conform to the definition of PCFCL. These very rare cases show an intermediate prognosis.73
Figure 8. Primary cutaneous diffuse large B-cell lymphoma, leg type: infiltrate composed predominantly of centroblast-like and immunoblast-like tumour cells with round, non-cleaved nuclei and prominent nucleoli. Admixture of a few centrocyte-like cells with cleaved nuclei.
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The blastic plasmacytoid dendritic cell neoplasm is rare, and has traditionally been included in lymphoma classifications. Its designations serve as an example of the evolution of the terms applied to this aggressive lymphoma. Originally considered as a blastic NK-cell lymphoma, expanding knowledge of dendritic cells and the immunophenotypic characterization of the tumour cells showed that the tumour cells belong to plasmacytoid dendritic cells.74 Thus, the designations of the same entity underwent changes from blastic NK-cell lymphoma to agranular CD4+ CD56+ haematodermic neoplasm (WHO/EORTC classification 2005)75 and finally blastic plasmacytoid dendritic cell neoplasm in the WHO classification.76 The disease presents with multiple contusiform plaques. Involvement of oral mucosa is common. Histologically, there is a diffuse monotonous infiltrate, which is band-like in the upper and mid dermis with column-like extensions into the deeper dermis and subcutis. The tumour cells resemble blasts with fine dispersed chromatin (Figure 9). Numerous extravasated erythrocytes are found between the tumour cells, which give the lesions their characteristic clinical contusiform appearance. This neoplasm displays a unique phenotype with expression of CD4, CD56, CD123, and TCL-1.74 In some patients, the disease develops in the context of myelodysplastic syndrome.77 Leukaemic spread occurs in the majority of patients (70%).74 This dendritic cell neoplasm is associated with a poor prognosis.74,76
Figure 9. Blastic plasmacytoid dendritic cell neoplasm: tumour cells display nuclei with fine dispersed chromatin. Note extravasated erythrocytes.
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