—  SYMPOSIUM #07  —

Cutaneous Lymphomas: Pathology, Biology, and Clinical Correlations
Moderators: Elaine S. Jaffe and Christopher Meijer

Section 1 - WHO-EORTC Classification for Cutaneous Lymphoma

Christopher Meijer
Dept of Pathology, Vrije Universiteit Medical Center
Amsterdam. The Netherlands

R.Willemze
Dept of Dermatology Leyden University Medical Center
Leyden, The Netherlands


The WHO-EORTC classification for cutaneous lymphomas recognizes disease entities rather than histologic subgroups. It is based on a combination of clinical, histological, phenotypical and molecular characteristics. It was the result of extensive discussions between dermatologists and pathologists during consensus meetings in Lyon in September 2003 and Zurich in Jan 2004 . It combines the view of the European dermatologists and pathologists that primary cutaneous lymphomas are separate disease entities with their own clinical histopathological and molecular characteristics (EORTC classification for primary cutaneous lymphomas) and the experience of haematologists and haematopathologists derived from classifying lymphomas of haematopoietic and lymphoid tissues (WHO classification of tumors. Pathology and genetics of haematopoietic and lymphoid tissues). This classification is a major achievement since more than 95% of all the cutaneous lymphomas can be classified. The WHO-EORTC classification is given in Table 1. Even more important : several studies have shown that this classification is clinically relevant and as such is important for the management and treatment of patients with cutaneous lymphomas.

Table 1. WHO-EORTC classification of cutaneous lymphomas with primary cutaneous manifestations

Cutaneous T-cell and NK-cell lymphomas
Mycosis fungoides
MF variants and subtypes
Folliculotropic MF
Pagetoid reticulosis
Granulomatous slack skin
Sézary syndrome
Adult T-cell leukemia/lymphoma
Primary cutaneous CD30+ lymphoproliferative disorders
Primary cutaneous anaplastic large cell lymphoma
Lymphomatoid papulosis
Subcutaneous panniculitis-like T-cell lymphoma*
Extranodal NK/T-cell lymphoma, nasal type
Primary cutaneous peripheral T-cell lymphoma, unspecified
Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional)
Cutaneous γ/δ T-cell lymphoma (provisional)
Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)
Cutaneous B-cell lymphomas
Primary cutaneous marginal zone B-cell lymphoma
Primary cutaneous follicle center lymphoma
Primary cutaneous diffuse large B-cell lymphoma, leg type
Primary cutaneous diffuse large B-cell lymphoma, other Intravascular large B-cell lymphoma
Precursor hematologic neoplasm
CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma)†

Table 2 gives the disease specific 5 years survival of these lymphomas based on the data from the Austrian and Dutch Cutaneous lymphoma registries

Table 2. Relative frequency and disease-specific 5-year survival of 1905 primary cutaneous lymphomas classified according to the WHO-EORTC classification

WHO-EORTC classification No. Frequency, %* Disease-specific
5-year survival, %
Cutaneous T-cell lymphoma
Indolent clinical behavior
Mycosis fungoides 800 44 88
Folliculotropic MF 86 4 80
Pagetoid reticulosis 14 < 1 100
Granulomatous slack skin 4 < 1 100
Primary cutaneous anaplastic large cell lymphoma 146 8 95
Lymphomatoid papulosis 236 12 100
Subcutaneous panniculitis-like T-cell lymphoma 18 1 82
Primary cutaneous CD4+ small/medium pleomorphic T-cell lymphoma† 39 2 75
Aggressive clinical behavior
Sézary syndrome 52 3 24
Primary cutaneous NK/T-cell lymphoma, nasal-type 7 < 1 NR
Primary cutaneous aggressive CD8+ T-cell lymphoma† 14 < 1 18
Primary cutaneous γ/δ T-cell lymphoma † 13 < 1 NR
Primary cutaneous peripheral T-cell lymphoma, unspecified ‡ 47 2 16
Cutaneous B-cell lymphoma
Indolent clinical behavior
Primary cutaneous marginal zone B-cell lymphoma 127 7 99
Primary cutaneous follicle center lymphoma 207 11 95
Intermediate clinical behavior
Primary cutaneous diffuse large B-cell lymphoma, leg type 85 4 55
Primary cutaneous diffuse large B-cell lymphoma, other 4 < 1 50
Primary cutaneous intravascular large B-cell lymphoma 6 < 1 65

NR indicates not reached. * Data are based on 1905 patients with a primary cutaneous lymphoma registered at the Dutch and Austrian Cutaneous Lymphoma Group between 1986 and 2002

†Primary cutaneous peripheral T-cell lymphoma, unspecified excluding the three provisional entities indicated with a double dagger ‡

The aim of this handout is not to fully describe the different entities but rather to discuss difficulties in correctly classifying these lymphomas.

Cutaneous T-cell Lymphomas (CTCL)

Mycosis Fungoides (MF)
MF, the most prevalent primary CTCL, is a commonly epidermotropic CTCL characterised by a proliferation of small to medium sized T lymphocytes with cerebriform nuclei. A characteristic localisation of these cerebriform cells in the basal layers of the epidermis either as single haloed cells or in a linear configuration (soldiers in a row) is diagnostic. During the clinical evaluation from plaques to tumors the skin infiltrates show less epidermotropism and become more diffuse. The atypical cells may vary in size from small- to medium sized to blast cells and may loose their characteristic indentations.

Phenotype : CD2+,CD3+,CD4+,CD5-/+,CD8-. Sometimes: CD8+ and CD 4-Note that later stages of MF may have a cytotoxic phenotype (TIA-1+, granzyme B pos) and may be CD30+..Remarks: Prognosis of MF is dependent of stage of disease and extent of skin lesion and is independent from the phenotype observed

Important
1. From the variants of MF (see table1) folliculotropic MF is the most important. Histopathologically involvement of perivascular and periadnexal localisation of dermal infiltrates with variable infiltration of the follicular epithelium by medium sized or large hyperchromatic often CD30 pos blast cells with cerebriform nuclei and. and sparing of the epidermis. Mucinous degeneration (alcian blue pos) , eo's and plasmacells are presenting most cases. To make the diagnosis a hair follicle should be present in the epidermis Prognosis is comparable with tumor stage MF (5years survival 70-80%), but worse than classical plaque stage MF.

Histologically these CD30 pos blast cells might erroneously point to C-ALCL . Very helpful in the diagnosis of folliculotropic MF is the presence of remnants of hair follicles, easily demonstrated by keratin staining, infiltrated by atypical (cerebriform) cells in the neighbourhood of CD30 pos blast cells. Making additional sections to show the hair follicles in the slides and additional clinical information will further facilitate the diagnosis.

2. Pagetoid reticulosis is a variant of MF characterized by the presence of localized Patches or plaques with an intradermal proliferation of neoplastic T cells with a CD3+,CD4+,CD8- or CD3+,CD4-,CD8+ phenotype . Although the neoplastic cells, which have medium-sized or large , sometimes hyperchromatic and cerebriform nuclei express CD30, the exclusive localization of these CD30 pos cells with typical morphology in the epidermis is so characteristic that it usually does not pose diagnostic problems.

3. Histologically tumor stage MF in which CD30 pos blast cells my be present should be differentiated from cutaneous anaplastic large cell lymphoma.(c-ALCL)

Sezary Syndrome is characterised by the triaderythroderma, generalised lymphadenopathy and atypical cells with indented ,cerebriform nuclei (Sezary cells) in the epidermis, lymphnode and peripheral blood. However at the moment there is no concensus about the exact criteria: number of atypical cells in the blood (1000 cells per mm 3), the CD4+/CD8+ ratio of the expanded abnormal cells in the blood ( ratio =10?), or the demonstration of an abnormal clone by cytogenetics or molecular methods in the blood.

The histological picture of SS may be the same as that of MF, but the cellular infiltrates are more monotonous and epidermotropism may be absent. Early stage histology may be non-specific.

Phenotype CD3+, CD4+, CD8-, and sometimes CD3+,CD4-,CD8+. In this last case the differential diagnosis of actinic reticuloid should be excluded.

Prognosis
The stricter the criteria the worse the prognosis.In general median survival is poor 2-4 year.

Primary Cutaneous CD30+ Lymphoproliferative Disorders
This is the second most common group of CTCL (about 30%).c-ALCL and Lymphomatoid Papulosis (LyP) form the ends of the spectrum of disease.

C-ALCL affects mainly adults with a male to female ratio of 2-3:1. Most patients present with solitary or locali­zed nodules or tumors, and sometimes papules, and often show ulceration. Multifocal lesions are seen in about 20% of the patients. The skin lesions may show partial or complete spon­taneous regression, as in LyP. These lymphomas frequently relapse in the skin. Extracutaneous dissemination occurs in approximately 10% of the patients, and mainly involves the regional lymph nodes.

LyP is characterized by the presence of papular, papulonecrotic and/or nodular skin lesions at different stages of development, predominantly on the trunk and limbs. Individual skin lesions disappear within 3 to 12 weeks, and may leave behind superficial scars. The duration of the disease may vary from several months to more than 40 years. In up to 20% of patients LyP may be preceded by, associated with or followed by another type of malignant (cutaneous) lymphoma, generally MF, a (C-)ALCL or Hodgkin's lymphoma

Histologically c-ALCL is characterised by diffuse non epidermotropic , sheets of CD30+ tumor cells. Most commonly the tumor cells have anaplastic cell morphology, but they may have an immunoblastic or pleomorphic appearance. Prognosis is independent of cell type.

Reactive lymphocytes are often present at the border of the tumor sheets. Eo's may be present. Ulcerating lesions may show a LyP-like histology with an abundant inflamma­tory infiltrate of reactive T-cells, histiocytes, eosinophils, neu­trophils, and relati­vely few CD30-positive cells. In such cases epidermal hyperplasia may be prominentThe histologic picture of LyP is extreme­ly varia­ble, and in part corre­lates with the age of the biopsied skin lesion. Three histologic subtypes of LyP (types A, B and C) have been described, which represent a spectrum with overlapping features. In LyP type A lesions, scatte­red or small clusters of large, someti­mes multinuclea­ted or Reed-Sternberg-like, CD30-positive cells are intermingled with numerous inflamma­tory cells, such as histio­cytes, small lympho­cytes, neu­trophils and/or eosinophils. LyP, type C lesions demonstrate a monotonous population or large clusters of large CD30-positive T-cells with relatively few admixed inflamma­tory cells. LyP, type B is uncommon (<10%) and is characterized by an epidermotropic infiltrate of small atypical cells with cerebriform nuclei similar to that observed in MF.

Immunophenotype
The neoplastic cells in C-ALCL generally show an activated CD4+ T-cell phenotype with variable loss of CD2, CD5 and/or CD3 and frequent expression of cytotoxic proteins (granzyme B, TIA-1, perforin). Some cases (<5%) have a CD8+ T-cell phe­notype. CD30 must be expressed by the majority (more than 75%) of the neoplastic T-cells. Unlike systemic CD30-positive lymphomas, most C-ALCL express the cutaneous lymphocyte antigen (CLA), but do not express EMA and ALK (anaplastic lymphoma kinase), indicative of the 2;5 chromosomal translocation or its variants. Unlike Hodgkin and Reed-Sternberg cells in Hodgkin's disease, staining for CD15 is generally negative. Co-expression of CD56 is observed in rare cases, but does not appear to be associated with an unfavorable prognosis.

The large atypical cells in the LyP type A and type C lesions have the same phenotype as the tumor cells in C-ALCL. The atypical cells with cerebriform nuclei in the LyP type B lesions have a CD3+, CD4+, CD8- phenotype and do not express CD30 antigen.

Genotype
Clonal rearranged T-cell receptor genes have been demonstrated in most C-ALCL and in 60-70% of LyP. The t(2;5)(p23;q35) and its variants are not or rarely found in C-ALCL. In LyP this translocation has not been demonstrated.

Prognosis
The prognosis of C-ALCL is usually favorable with a 10-year disease-related survival exceeding 90%.Patients presenting with multifocal skin lesions and patients with involvement of only regional lymph nodes have a similar prognosis to patients with only skin lesions. No difference in clinical presentation, clinical behavior or prognosis is found between cases with an anaplastic morphology and cases with a non-anaplastic (pleomorphic or immunoblastic) morphology.

LyP has an excellent prognosis. In a recent study of 118 LyP patients only five patients (4%) developed a systemic lymphoma, and only 2 patients (2%) died of systemic disease over a median follow-up period of 77 months. Risk factors for the development of a systemic lymphoma are unknown.

Differential Diagnosis on Histology of C-ALCL
  1. Histologic criteria alone are often insufficient to differentiate between C-ALCL and LyP -the two ends of the spectrum- and clinical appearance and course are used as decisive criteria for the definite diagnosis and choice of treatment.

  2. Systemic anaplastic large cell lymphoma: It is important to rule out secondary localisations of systemic ALCL, because they have a poorer prognosis Systemic ALCL are often ALK positive indicative of the t(2;5) or its variant translocations, lack the expression of cutaneous lymphocyte antigen (CLA) and show the expresson of EMA. Especially the last two features are important n the differentiation of ALK neg systemic AlCL, since their clinical course is worse than ALK pos systemic ALCL.

  3. An important differential diagnosis is Mycosis Fungoides with transformation in CD 30 pos blast cells. Recognition bears prognostic information because MF with transformation in this cell type is associated with a poor progosis.

  4. Folliculotropic MF For criteria : see above

  5. Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma. (Berti et al 1999)


The prognosis is poor. The cells often express CD30 and are mostly CD3+, CD8+, TIA-1+, granzyme B +, perforin +,. Differentiation from C-ALCL is based on the clinical presentation and clinical behavior. Helpful is immunophenotyping since the cells are CD45RA+ and CD45RO-, CD4-,CD2-, CD5-,CD7-/+. Histologically, besides ulceration, the invasion and destruction of adnexal skin structures is prominent in contrast to C-ALCL.

5.Reactive skinconditions such as viral infections (herpes, moluscum contagiosum, orf);scabies;Arthropod reactions; drug eruptions; atopic dermatitis

Subcutaneous Panniculitis Like T-cell Lymphomas
Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is defined as a cytotoxic T-cell lymphoma characterized by the presence of primarily subcutane­ous infiltrates of small, medium-sized or large pleomorphic T-cells and many macropha­ges, predominantly affecting the legs, and often complicated by a hemop­hagocytic syndrome. Recent studies demonstrate that SPTL with a γ/δ (CD56+) phenotype differ from SPTL with an α/β (CD8+) phenotype by: 1. Presence of dermal and epidermal involvement 2. Much poorer prognosis 3.Overlap with other (muco)cutaneous γ/δ T-cell lymphomas (Massone et al 2004)These studies have strengthened the view that SPTL with an α/β phenotype and SPTL with a γ/δ phenotype are different entities of which SPTL with a γ/δ phenotype have a poor prognosis and should therefore be placed in a the group of .primary cutaneous T-cell lymphomas , unspecified as a provisional entity primary cutaneous γ/δ T-cell lymphomas

Histopathology reveals subcutaneous infiltrates simulating a panniculitis showing small, medium-sized or sometimes large pleomorphic T cells with hyperchromatic nuclei and often many macrop­hages. The overlying epidermis and dermis are typically uninvolved. Rimming of individual fat cells by neoplastic T cells is a helpful, though not completely specific diagnostic feature. Necrosis, karyorrhexis and cytophagocytosis are com­mon findings.

In the early stages the neoplastic infiltrates may lack significant atypia and a heavy inflammatory infiltrate may predominate. These lymphomas show a α/β+, CD3+, CD4-, CD8+ T-cell phenotype, with expression of cytotoxic proteins. CD30 and CD56 are rarely, if ever, expressed.

Extranodal NK/T cel lymphoma, nasal type. This lymphoma is characterized by nearly always EBV pos small, medium or large cells with an NK-cell or more rarely a cytotoxic T-cell phenotype. The cells are CD56+,CD2+,CD3e+ , TIA-1+, perforin +, granzyme B+, and lack surface CD3. EBV in situ hybridisation with EBER is nearly always pos; Latent membrane protein 1 (LMP-1) is inconsistently expressed. The neoplastic cells often express CD30 as seen in C-ALCL. The presence of EBV in the neoplastic CD30+ cells, demonstration of LMP-1, and detection of CD56 help to make the differential diagnosis with C-ALCL. Moreover the neoplastic cell show prominent angiocentricity and angiodestruction often accompanied by extensive necrosis which is not seen n C-ALCL. T-cell receptor rearrangements are usually germline in contrast to C-ALCL

Although primary cutaneous NK/T cell lymphoma have been described , primary nasal cases of NK/T cell lymphoma with secondary skin involvement occur as frequent and asking for additional clinical information helps to reach the definite diagnosis.

Primary cutaneous T-cell lymphomas unspecified: The designation PTL, unspecified is maintained for cutaneous T-cell lymphomas that do not fit into any of the better defined subtypes of CTCL as presented in the WHO-EORTC classification of cutaneous lymphoma In this group 3 provisional entities have bee recognized but more cases have to be studied to sort out whether they are real entities
  • Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma

  • Cutaneous γ/δ T-cell lymphoma

  • Primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma
Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma is separated in the WHO-EORTC classification of cutaneous lymphoma as a provisional entity in the group of primary cutaneous peripheral T-cell lymphoma, unspecified and characterized by a proliferation of epidermotropic CD8+ cytotoxic T-cells and an agressive behaviour. Clinically, these lymphomas are characterized by the presence of localized or disseminated eruptive papules, nodules and tumors showing central ulceration and necrosis or by superficial, hyperkeratotic patches and plaques. The prognosis is poor. The cells often express CD30 and are mostly CD3+, CD8+, TIA-1+, granzyme B +, perforin +,. Differentiation from C-ALCL is based on the clinical presentation and clinical behavior. Helpful is immunophenotyping since the cells are CD45RA+ and CD45RO-, CD4-,CD2-, CD5-, CD7-/+. Histologically, besides ulceration, the invasion and destruction of adnexal skin structures is prominent in contrast to C-ALCL

Cutaneous γ/δ T-cell Lymphoma is defined as a lymphoma composed of a clonal proliferation of mature γ/δ T-cells with a cytotoxic phenotype and is grouped together with related conditions of similar cells in mucosal sites.The histologic pattern of involvement by the skin infiltrates can be epidermal, dermal or subcutaneous or a combination of these patterns. The tumor cells are medium-sized to large cells with ccoarsely clumped chromatin. Apoptosis and angioinvasion seem common.In this group cases formerly classified as SPTL are present.

Primary Cutaneous CD4-pos Small/Medium-sized Pleomorphic T-cell Lymphoma
CTCL defined by a predominance of small to medium-sized CD4-positive pleomorphic T- cells without (a history of) patches and plaques typical of MF and in most cases a favorable clinical course.2 In contrast to the EORTC classification, in the WHO-EORTC classification the term small/medium-sized pleomorphic CTCL is restricted to cases with a CD4+ T-cell phenotype. Cases with a CD3+, CD4-, CD8+ phenotype usually have a more aggressive clinical course are included in the group of aggressive epidermotropic CD8-positive CTCL. Characteristically, these lymphomas present with a solitary plaque or tumor, generally on the face, the neck or the upper trunk. Less commonly, they present with one or several papules, nodules or tumors.

Note: From a practical point of view the best way to classify cutaneous T-cell lymphoma is the following algorithm;
  1. Is the proliferation in the skin mycosis fungoides or Sezary Syndrome

  2. If not is it a CD30 pos lymphoproliferative disease: c-ALCL or LyP dependent from the clinical pictures

  3. If CD30 negative is extra nodal NK/T-cell lymphoma nasal type: EBV and/or CD56 present

  4. Is SPTL excluded: Check CD56 , γ/δ and Cytotoxic phenotype

  5. If none of the foregoing: Primary cutaneous T-cell lymphomas unspecified
And exclude the provisional entity Primary cutaneous CD4-pos small/medium-sized pleomorphic T-cell lymphoma because of its good clinical behaviour and remember: ask your clinician for detailed information . It will help you!.

Cutaneous B-cell lymphomas
In the WHO-EORTC classification three main types of CBCL are recognized:
  • primary cutaneous marginal zone B-cell lymphoma , having an excellent prognosis

  • primary cutaneous follicle center lymphoma (PCFCL), having a excellent prognosis

  • primary cutaneous large B-cell lymphoma, leg type (PCLBCL, LT)with an intermediate lymphoma.. In addition, it contains a category PCLBCL, other for diffuse large B-cell lymphomas, which do not fit in the group of PCLBCL, LT or the group of PCFCL with a diffuse infiltration of large centrocytes.
PCMZL show nodular to diffuse infiltrates with sparing of the epidermis. The infiltrates are composed of small lymphocytes, marginal zone B-cells (centrocyte-like cells), lymphoplasmacytoid cells and plasma cells, admixed with small numbers of centroblast- or immunoblast-like cells and many reactive T cells. Reactive germinal centers are frequently observed. They may be surrounded by a population of small to medium-sized cells with irregular nuclei, inconspicuous nucleoli and abundant pale cytoplasm (marginal zone B-cells). Monotypic plasma cells are often located at the periphery of the infiltrates and in the superficial dermis beneath the epidermis. PAS-positive intranuclear or intracytoplasmic inclusions may be present in cases with a predominance of lymphoplasmacytoid cells. PCMZLs rarely show transformation into a diffuse large B cell lymphoma.

Immunophenotype
The marginal zone B-cells express CD20, CD79a and bcl-2, but are negative for CD5, CD10, and bcl-6, which may be useful in distinction from PCFCL. Reactive germinal centers are typically bcl-6+, CD10+ and bcl-2-. Plasmacells express CD138 and CD79a, but generally not CD20, and in most cases show monotypic cytoplasmic immunoglobulin light chain expression on paraffin sections. Plasmacells are bcl-2 pos

Genetic features
Immunoglobulin heavy chains (IgH) are clonally rearranged. Recent studies suggest the presence of the t(14;18)(q32;q21) involving the IGH gene on chromosome 14 and the MLT gene on chromosome 18 in a proportion of PCMZL. However, other translocations observed in gastric MALT lymphomas, such as t(11;18)(q21;q21) and t(1;14)(p22;q32) have not been found in PCMZL.45,144,145

PCFCL is defined as a tumor of neoplastic follicle center cells, which may show a follicular, a follicular and diffuse or diffuse growth pattern, and which is predominantly composed of generally large centrocytes (large cleaved cells). A clear-cut follicular growth pattern is more commonly observed in lesions arising on the scalp than those presenting on the trunk.150 Small and early lesions contain a mixture of centrocytes, relatively few centroblasts and many reactive T cells. Large centrocytes, often multilobated, are a common feature of PCFCL. The large neoplastic B-cells may have a fibroblast-like appearance.In small and/or early lesions a clear-cut follicular growth pattern or more often remnants of a follicular growth pattern may be observed. If present, the abnormal follicles are composed of malignant bcl-6+ follicle center cells enmeshed in a network of CD21+ or CD35+ follicular dendritic cells. The follicles are ill-defined, lack tingible body macrophages and generally have a reduced or absent mantle zone. With progression to tumorous lesions the neoplastic B-cells increase both in number and size, whereas the number of reactive T-cells steadily decreases. Follicular structures, if present before, are no longer visible except for occasional scattered CD21+ or CD35+ follicular dendritic cells. Tumorous skin lesions generally show a monotonous population of large follicle center cells, generally large centrocytes and multilobated cells and in rare cases spindle-shaped cells, with a variable admixture of centroblasts and immunoblasts. Usually, a prominent stromal component is present.

Immunophenotype
The neoplastic cells express the B-cell-associated antigens CD20 and CD79a.and consistently express bcl-6. CD10 expression is particularly observed in cases with a follicular growth pattern, but is uncommon in PCFCL with a diffuse growth pattern. Staining for CD5 is negative. Unlike nodal and secondary cutaneous follicular lymphomas, PCFCL do not express bcl-2 protein or show faint bcl-2 staining in a minority of neoplastic B-cells.. Staining for MUM-1/IRF4 is negative.46

PCLBCL, LT is defined by a predominance or confluent sheets of medium-sized to large B-cells with round nuclei resembling centroblasts and/or immunoblasts, which generally shows strong expression of Bcl-2 and MUM-1.Recently also FOX-P1 was shown to be present in these lymphomas.Admixture with reactive lymphocytes is rare



Differential Diagnosis (dd) of Cutaneous B-Cell Lymphomas
  1. In the dd of PCMZL and PCFCL use of bcl-2 and bcl-6 and CD10 is very helpful. PCFCL do show bcl-6 and are bcl-2 negative.

  2. Important is the dd between PCFCL and PCLBCL,LT because of the different prognosis and the consequences for treatment.The definitions given imply that differentiation between PCFCL and PCLBCL, LT is determined primarily by morphology (round versus cleaved cell predominance) and no longer by site (leg versus non-leg) as in the EORTC classification. This implies that tumors presenting on the leg showing a predominance of large cleaved cells are now classified as PCFCL, while tumors presenting on the head or trunk showing a predominance or confluent sheets of centroblasts and/or immunoblasts are included in the group of PCLBCL, LT. Thus a proportion of patients classified as Primary cutaneous follicle center cell lymphoma or primary cutaneous large B-cell lymphoma , leg in the EORTC classification will be assigned to another prognostic category, which may have important therapeutic consequences. Recent studies suggest that this concerns 10-15% of PCFCCL and PCLBCL, leg, but exact data are not yet available. These studies also illustrate that the definition of the group of PCLBCL, other leaves room for different interpretations, and that there is uncertainty how these patients should be treated.

    The use of the new WHO-EORTC classification suggest that it may contribute to better diagnosis and treatment of the B-cell lymphomas. Indeed the results of a previous European multicenter study and the results of the reclassification study of B-cell lymphoma of the registry of the Dutch cutaneous working group for cutaneous lymphoma indicate that reclassification of PCFCCL (EORTC) with a predominant round cell morphology as PCLBCL, LT proved clinically relevant, which implies that such cases should be treated primarily with multiagent chemotherapy. However, reclassification of PCLBCL, leg (EORTC) with a predominant cleaved cell morphology into the group of indolent PCFCL proved less fortunate, since these cases have a much worse prognosis than PCFCL not presenting on the leg and should not be treated routinely with radiotherapy . Consistent with the results of a previous European multicenter study, we suggest that in addition to the WHO-EORTC classification also site of presentation is taken into account to select the most appropriate treatment in patients with CBCL.

  3. dd PCLBCL, LT and PCLBCL, other


Comparison of Bcl-2 positive and Bcl-2 negative PCLBCL, LT showed no difference in 5-year DSS ( Kodama et al. 2005)Similarly, neither in the present study nor in the study of Kodama et al. significant differences in 5-year OS and DSS were found between PCLBCL, LT with or without expression of MUM-1 or FOXP1. These data indicate that expression of Bcl-2, MUM-1 or FOXP1 should not be used as markers to differentiate between PCLBCL, LT and PCLBCL, other, and that the term PCLBCL, other should only be used for the exceptional types of CBCL .

Summarizing:
  1. PCFCL localized on trunk and head have a good prognosis and can be treated with radiotherapy. However PCFCL localized on the leg have also an intermediate prognosis and in contrast to other PCFCL should also be treated with multiagent chemotherapy.

  2. PCLBCL,LT have an intermediate prognosis whether they are localized on the leg the trunk or the head and should be treated with multiagent chemotherapy.

  3. The term PCLBCL, other should only be used for the exceptional types of CBCL . These include rare cases of intravascular large B-cell lymphoma, T-cell/histiocyte-rich B-cell lymphoma or plasmablastic lymphoma with only skin lesions at first presentation.


Reference List


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