Cutaneous Lymphomas: Pathology, Biology, and Clinical Correlations
Moderators: Elaine S. Jaffe and Christopher Meijer
Section 1 -
WHO-EORTC Classification for Cutaneous Lymphoma
Dept of Pathology, Vrije Universiteit Medical Center
Amsterdam. The Netherlands
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
Table 2 gives the disease specific 5 years survival of these lymphomas based on the data from the
Austrian and Dutch Cutaneous lymphoma registries
| 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. Relative frequency and disease-specific 5-year
survival of 1905 primary cutaneous lymphomas classified according to the WHO-EORTC classification
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
| 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|
peripheral T-cell lymphoma, unspecified excluding the three provisional entities indicated with a double
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
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
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.
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
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
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.
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
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
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.
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
Differential Diagnosis on Histology of C-ALCL
- 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.
- 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.
- 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.
- Folliculotropic MF For criteria : see above
- 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
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
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
- Primary cutaneous aggressive
epidermotropic CD8+ cytotoxic T-cell lymphoma
- Cutaneous γ/δ T-cell
- Primary cutaneous CD4-positive
small/medium-sized pleomorphic T-cell lymphoma
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;
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!.
- Is the proliferation in the skin mycosis fungoides or Sezary Syndrome
- If not is it a CD30 pos lymphoproliferative disease: c-ALCL or LyP dependent from the clinical
- If CD30 negative is extra nodal NK/T-cell lymphoma nasal type: EBV
and/or CD56 present
- Is SPTL excluded: Check CD56 , γ/δ and Cytotoxic phenotype
- If none of the foregoing: Primary cutaneous T-cell lymphomas
Cutaneous B-cell lymphomas
In the WHO-EORTC classification three main types of CBCL are recognized:
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
- 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.
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
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.
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
- 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.
- 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.
- 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 .
- 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.
- 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.
- 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.
- Willemze , Jaffe ES, BurgG et al WHO-EORTC classification of cutaneous lymphoma. Blood 2005; 105 :3768-3785
- Bekkenk M, Geelen FAMJ, van Voorst Vader PC, et al. Primary and secondary cutaneous CD30-positive lymphoproliferative disorders: long term follow-up data of 219 patients and guidelines for diagnosis and treatment. A report from the Dutch Cutaneous Lymphoma Group. Blood. 2000; 95:3653-3661.
- Liu HL, Hoppe RT, Kohler S, Harvell JD, Reddy S, Kim YH. CD30+ cutaneous lymphoproliferative disorders: The Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol. 2003;49:1049-1058.
- Paulli M, Berti E, Rosso R, et al. CD30/Ki-1 positive lymphoproliferative disorders of the skin: clinicopathologic correlation and and statistical analysis of 86 cases. J Clin Oncol. 1995;13:1343-1354.
- Kaudewitz P, Stein H, Dallenbach F, et al. Primary and secondary cutaneous Ki-1+ (CD30+) anaplastic large cell lymphomas. Morphologic, immunohistologic, and clinical-characteristics. Am J Pathol. 1989;135:359-367.
- Kummer JA, Vermeer MH, Dukers DF, Meijer CJLM, Willemze R. Most primary cutaneous CD30-positive lymphoproliferative disorders have a CD4-positive cytotoxic T-cell phenotype. J Invest Dermatol. 1997;109:636-40.
- Beljaards RC, Meijer CJLM, Scheffer E, et al. Prognostic significance of CD30 (Ki-1/Ber-H2) expression in primary cutaneous large-cell lymphomas of T-cell origin. A clinicopathologic and immunohistochemical study in 20 patients. Am J Pathol. 1989;135:1169-1178.
- de Bruin PC, Beljaards RC, van Heerde P, et al. Differences in clinical behaviour and immunophenotype between primary cutaneous and primary nodal anaplastic large cell lymphoma of T- or null cell phenotype. Histopathol. 1993;23:127-135.
- DeCouteau JF, Butmarc JR, Kinney MC, Kadin ME. The t(2;5) chromosomal translocation is not a common feature of primary cutaneous CD30+ lymphoproliferative disorders: comparison with anaplastic large cell lymphoma of nodal origin. Blood. 1996;87:3437-3441.
- Natkunam Y, Warnke RA, Haghighi B et al. Co-expression of CD56 and CD30 in lymphomas with primary presentation in the skin: clinicopathologic, immunohistochemichal and molecular analyses of seven cases. J Cut Pathol. 2000; 27:392-399.
- Miyamoto T, Yoshino T, Takehisa T, Hagari Y, Mihara M. Cutaneous presentation of nasal/nasal type T/NK cell lymphoma: clinicopathological findings of four cases. Br J Dermatol. 1998;139:481-487.
- Cheung MMC, Chan JKC, Lau WH, et al. Primary non-Hodgkin lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients. J Clin Oncol. 1998; 16:70-77.
- Bekkenk MW, Jansen PM, Meijer CJLM, Willemze R. CD56+ hematological neoplasms presenting in the skin: a retrospective analysis of 23 new cases and 130 cases from the literature. Annals of Oncology. 2004;15:1097-1108.
- Jaffe ES, Krenacs L, Raffeld M. Classification of cytotoxic T-cell and natural killer cell lymphomas. Seminars in Hematology. 2003;40:175-184.
- Van Doorn R, Scheffer E, Willemze R. Follicular mycosis fungoides: a distinct disease entity with or without associated follicular mucinosis. Arch Dermatol 2001;138:191-198.
- Histopathology and genetics of cutaneous T-cell lymphoma.Hematol Oncol Clin North Am. 2003;17:1277-1311.
- Berti E, Tomasini D, Vermeer MH, Meijer CJLM, Alessi E, Willemze R. Primary cutaneous CD8-positive epidermotropic cytotoxic T-cell lymphoma: a distinct clinicopathologic entity with an aggressive clinical behaviour. Am J Pathol. 1999;155: 483-492
- Santucci M, Pimpinelli N, Massi D, et al. Cytotoxic/natural killer cell cutaneous lymphomas. Report of EORTC Cutaneous Lymphoma Task Force Workshop. Cancer. 2003;97:610-627.
- Bekkenk MW, Vermeer MH, Jansen PM, et al. Peripheral T-cell lymphomas unspecified presenting in the skin: analysis of prognostic factors in a group of 82 patients. Blood. 2003;102:2213-2219.
- Vermeer MH, Geelen FAMJ, Kummer JA, et al. Expression of cytotoxic proteins by neoplastic T-cells in mycosis fungoides is associated with progression from plaque stage to tumor stage disease. Am J Pathol 1999;154:1203-1210
- Burg et al WHO classification of cutaneous lymphomas 2005: histological and molecular aspects Recently the WHO-EORTC classification was extensively discussed in volume ; J.Cutan. Pathol.2005;33; 1-60
- Willemze R, Kerl H, Sterry W et al. EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood. 1997;90:354-371.
- Jaffe ES, Harris NL, Stein H, Vardiman JW. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Hematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001.
- Willemze R, Jaffe ES, Burg G et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105:3768-3785.
- Kodama K, Massone C, Chott A et al. Primary cutaneous large B-cell lymphomas: clinicopathologic features, classification, and prognostic factors in a large series of patients. Blood. 2005;106:2491-2497.
- Zinzani PL, Quaglino P, Pimpinelli N et al. Prognostic Factors in Primary Cutaneous B-Cell Lymphoma: The Italian Study Group for Cutaneous Lymphomas. J Clin Oncol. 2006.
- Hoefnagel JJ, Vermeer MH, Jansen PM et al. Bcl-2, Bcl-6 and CD10 expression in cutaneous B-cell lymphoma: further support for a follicle centre cell origin and differential diagnostic significance. Br J Dermatol. 2003;149:1183-1191.
- Hoefnagel JJ, Dijkman R, Basso K et al. Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling. Blood. 2005;105:3671-3678.
- Hans CP, Weisenburger DD, Greiner TC et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103:275-282.
- Muris JJ, Meijer CJ, Vos W et al. Immunohistochemical profiling based on Bcl-2, CD10 and MUM1 expression improves risk stratification in patients with primary nodal diffuse large B cell lymphoma. J Pathol. 2006;208:714-723.
- Barrans SL, Fenton JA, Banham A, Owen RG, Jack AS. Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome. Blood. 2004;104:2933-2935.
- de Leval L, Harris NL, Longtine J, Ferry JA, Duncan LM. Cutaneous b-cell lymphomas of follicular and marginal zone types: use of Bcl-6, CD10, Bcl-2, and CD21 in differential diagnosis and classification. Am J Surg Pathol. 2001;25:732-741.
- Hoefnagel JJ, Vermeer MH, Jansen PM et al. Primary cutaneous marginal zone B-cell lymphoma: clinical and therapeutic features in 50 cases. Arch Dermatol. 2005;141:1139-1145.
- Grange F, Bekkenk MW, Wechsler J et al. Prognostic factors in primary cutaneous large B-cell lymphomas: a European multicenter study. J Clin Oncol. 2001;19:3602-3610.