WHO/EORTC Classification of Cutaneous Lymphomas 2005
Introduction
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Lymphoma in skin, in the past were considered to be manifestations of systemic processes.
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A variety of
T- and B-cell neoplasms can involve the skin, either
primarily or secondarily.
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After GI, skin
is the 2nd most common site of extranodal non-Hodgkin
lymphoma, annual incidence of 1:100,000.
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Primary cutaneous lymphomas, completely different clinical behavior
and prognosis from histologically similar systemic
lymphomas, which may involve the skin secondarily
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Treatment for
primary vs secondary is usually different.
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EORTC –
Classification 1997
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WHO –
Classification 2001
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Concensus meetings on
2003 and 2004 lead to the 2005 WHO/EORTC classification.
WHO/EORTC 2005 Classification
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Combines features
of both classifications.
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Takes into
account morphologic, molecular, and clinical features of each entity.
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Comprises
primary cutaneous
B, T, and NK lymphomas.
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Terminology is
compatible with that of systemic lymphomas (WHO), but reflects the organ specific
peculiarities of cutaneous lymphomas.
Cutaneous T-cell lymphomas
Mycosis Fungoides
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Mycosis fungoides - 44% CL
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MF initially
presents in the skin and shows a characteristic stepwise clinical progression
with potential extracutaneous involvement.
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Skin lesions
do not resolve.
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Patches→
thin plaques→ thick plaques, minority progress to systemic disease.
Histologic features of MF
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Pautrier microabscessess – 10%
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Psoriasiform – lichenoid pattern
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Lymphocytes
aligned in the basal layer (at tips of rete ridges)
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Epidermotrophism 95%
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Cerebbriform cells seen in
50% of cases
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Eosinophils, plasma
cells, and macrophages may be admixed.
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Immunohistochemistry is helpful but not necessary for dx.
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CD2 +, CD3 +, CD4+, CD5+ TCRbeta+
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CD8 -, Cd 30 –
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Rare cases may
be CD8 + or CD30+
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5yr survival
90%
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Tx Skin-targeted
therapies as photo (chemo)–therapy PUVA, topical nitrogen mustard or chlormustine (BCNU), or radiotherapy, including total skin
electron beam irradiation.
MF variants
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Folliculotrophic MF
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Pagetoid reticulosis
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Granulomatous slack skin (GSS)
Bulky skin lesions on major
skin folds
Band like infiltrate with
giant cells
Elastophagocytosis
and emperipolesis
T(H) phenotype
Giant cells are CD68 +
100 % 5 yr survival
Sezary Syndrome
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ISCL
(International society of cutaneous lymphoma
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Absolute sezary cell count of 1000 cells/mm
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Expanded CD4
population resulting in CD4/CD8 ratio of > 10
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Loss of any of
the T cell antigens (CD2, CD3, CD4, and CD5) or demonstration of T cell clonality by molecular studies.
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20% 5 yr
survival
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Tx Extracorporeal photopheresis
(ECP), either alone or in combination with other treatment modalities (
interferon alpha, methotrexate, campath)
CD 30 + T cell lymphoproliferative disorders of the skin
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Lymphomatoid papulosis/ Primary cutaneous anaplastic large cell lymphoma/
Hallmark is CD 30 +, however
both entities differ in clinical and histologic
presentations.
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Represent 30%
of cutaneous lymphomas
Lymphomatoid Papulosis
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Three histologic subtypes of LyP (types
A, B, and C) have been described, which represent a spectrum with overlapping
features
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LyP type A lesions,
scattered or small clusters of large, sometimes multinucleated or
Reed-Sternberg–like, CD30+ cells are intermingled with numerous inflammatory
cells, such as histiocytes, small lymphocytes, neutrophils, and/or eosinophils.
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LyP type C lesions
demonstrate a monotonous population or large clusters of large CD30+ T cells
with relatively few admixed inflammatory cells.
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LyP type B is
uncommon (less than 10%) and is characterized by an epidermotropic
infiltrate of small atypical cells with cerebriform
nuclei similar to that observed in MF.
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The large
atypical cells in the LyP type A and type C lesions
have the same phenotype as the tumor cells in C-ALCL.
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The atypical
cells with cerebriform nuclei in the LyP type B lesions have a CD3+, CD4+, CD8- phenotype and do
not express CD30 antigen.
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Clonally
rearranged T-cell receptor genes have been detected in approximately 60%-70% of
LyP lesions.
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Chronic
recurrent, self-healing papulonecrotic or papulonodular skin eruption with histologic
features of a malignant lymphoma.
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Histologically malignant but
clinically benign
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Considered a low-grade cutaneous T-cell lymphoma
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Adults, median
age 45, M:F 1.5, trunks and limbs
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Individual
lesion disappear within 3 to 12 weeks
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10-15% of the
cases may be followed by a cutaneous lymphoma,
usually MF
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4% develop
systemic lymphomas
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Px - 98% 5yr survival
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Tx – Long term follow
up without active tx
Primary Cutaneous Anaplastic Large
Cell Lymphoma
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Shares histologic and immunohistochemical
features with nodal type.
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Differs in age
of onset, genetic features, etiology, and prognosis.
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Presents
as single or multiple grouped nodules or tumors confined to one extremity of
body area.
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Large cells
with an anaplastic, pleomorphic,
or immunoblastic cytomorphology
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There is no
clinical evidence or history of LyP, MF, or another
type of CTCL
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CD30 antigen
by more than 75%of tumor cells.
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Activated T
cell phenotype, CD4+ , CD25, CD71, HLADR.
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Variable loss
of CD2, CD3, and CD5
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CLA +, EMA -, ALK-
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Lack translocation 2:5, 90% have clonal rearrangement of TCR.
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Px is excellent, 10 yr survival of over 90%
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Tx radiotherapy or
surgery
Subcutaneous panniculitis like T-cell lymphoma
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Adults and
children, no sex predilection
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Most often on
legs
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Systemic symptoms
such as fever, fatigue, and weight loss may be present.
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Can
be associated with hemophagocytic syndrome, rapidly
progressive course.
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Panniculitis like growth
of T cells with hyperchromatic nuclei and often many
macrophages.
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Overlying
epidermis and dermis are typically uninvolved.
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Rimming of
individual fat cells by neoplastic T cells
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Necrosis, karyorrhexis, and cytophagocytosis
are common findings
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Plasma cells
and reactive lymphoid follicles are generally absent, in contrast to lupus profundus, and other forms of lobular panniculitis.
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Cytotoxic T-cell
lymphoma, subcutaneous infiltrates of pleomorphic T
cells.
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α/β T cells, CD 2+, CD3+, CD5+, CD4-, CD8 +, CD43 +, TIA-1 + granzyme B +, perforin +
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Neoplastic T cells show clonal T-cell receptor (TCR) gene rearrangements
l 5-year survival of 80%
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Tx Doxorubicin-based
chemotherapy and radiotherapy
Primary cutaneous peripheral T-cell lymphoma, unspecified
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T-cell neoplasms that do not fit into any of the better defined
subtypes of T-cell lymphoma/leukemia .
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10% of CTLs
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Cutaneous gamma/delta
T-cell lymphoma
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Primary cutaneous aggressive epidermotropic
CD8+ cytotoxic T-cell lymphoma
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Primary cutaneous CD4+ small/medium-sized pleomorphic
T-cell lymphoma
Cutaneous gamma/delta T-cell lymphoma
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Clonal proliferation
of mature, activated γ/δ T cells
expressing a cytotoxic phenotype.
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Epidermotropic, dermal, and
subcutaneous.
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Dermal and
epidermal involvement often coexists with subcutaneous disease, in contrast to
SPTCL of α/β origin.
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Apoptosis and
necrosis are common, often with vascular invasion.
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CD3+, CD2+,
CD43+, CD45RO+,
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CD15-, CD30-,
CD20-, CD25-
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CD4-, CD8 –
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Positive for
TIA-1 and the cytotoxic proteins granzyme
B, granzyme M, and perforin.
Primary cutaneous aggressive epidermotropic
CD8+ cytotoxic T-cell lymphoma
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Clinically,
this form of CD8+ cutaneous lymphoma differs from the
slowly progressive CD8+ form similar to classic MF. It presents with erosive
plaques rather than patches. It exhibits an unfavorable prognosis with rapid
course .
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The tumor
cells have a CD3+, CD8+, granzyme B+, perforin+, TIA-1+, CD45RA+, CD45RO-, CD2-, CD4-, CD5-
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The neoplastic T cells show clonal
TCR gene rearrangements. Specific genetic abnormalities have not been
described.
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Median
survival of 32 months
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Patients are
generally treated with doxorubicin-based multiagent
chemotherapy.
Primary cutaneous CD4+ small/medium-sized pleomorphic
T-cell lymphoma
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This is a non-cytotoxic CTCL characterized by a predominance of small to
medium-sized CD4+ pleomorphic T cells with clinical
features not compatible with MF.
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Diffuse or
nodular lymphoid infiltrate, predominantly perivascular
and periadnexal and shows a tendency to extend to the
subcutaneous tissue.
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It consists of
small-to-medium-sized pleomorphic lymphoid cells with
irregular hyperchromatic nuclei and a pale scanty
cytoplasm
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Patients are
commonly adults, who present with solitary, localized, or more frequently
generalized nodules or tumors. No sites of predilection have been recorded
Cutaneous
B-cell lymphomas
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Cutaneous marginal zone
B cell lymphoma
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Primary cutaneous follicle center lymphoma
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Cutaneous large B cell
lymphoma, leg type
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Cutaneous large B cell
lymphoma, other
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Cutaneous intravascular
large B cell lymphoma
Cutaneous
marginal zone B-cell lymphoma (MZL)
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Adults trunk
or extremities, especially the arms
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The nodular or
diffuse infiltrate
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Small to medium-sized lymphocytes
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Irregular nuclei, dispersed chromatin,
inconspicuous nucleoli and an abundant pale cytoplasm
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Monocytoid appearance (reniform nuclei) or plasma cell differentiation.
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Typified by darker
centers surrounded by brighter zones of pale-staining cells.
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Dutcher bodies and intracytoplasmic
PAS+ globular inclusions may be seen
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immunophenotype: CD19+,
CD20+, CD22+, CD79a+, bcl-2+,CD5-, CD10-, CD23-, bcl-6-
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IgH genes are clonally
rearranged in >70% of cases
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MZL, the t(11;18) not seen in primary cutaneous MZL
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t(14;18)(q32;q21) translocation involving IGH
and MALT1 seen in 1/3 of cases.
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The prognosis
of CMZL is excellent with a 5-year survival close to 100%.
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Tx radiotherapy or surgical excision
Primary Cutaneous Follicle Center Lymphoma
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Solitary or
grouped plaques and tumors
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Scalp,
forehead, and trunk
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Synonyms, reticulohistiocytoma of back, or Crosti
lymphoma
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The
skin lesions gradually increase in size over years, but dissemination to extracutaneous sites is uncommon.
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Neoplasm of
follicle center cells (centrocytes and centroblasts)
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Follicular,
follicular and diffuse or a diffuse growth pattern
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Grading of
primary cutaneous FCL as in its nodal counterpart
based is not prognostically relevant.
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Few mitosis,
and no tingible body macrophages seen (present in pseudolymphoma)
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CD19+, CD20+,
CD22+, CD79a+, CD5-, CD43 -, bcl-2 -, bcl-6 +
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Bcl-2 gene
rearrangement and t(14;18) chromosomal translocation are absent in most
cases.
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5-year
survival of more than 95%
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Tx radiotherapy or
surgical excision
Cutaneous
diffuse large B-cell lymphoma (DLBCL)
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composed of
large B cells (centroblasts and immunoblasts)
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DLBCL,
leg-type and DLBCL, other
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DLBCL, leg
type, is the most common variant, occurs on the leg and less frequently at
other sites.
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DLCL other include;Tcell/histiocyte-rich DLBCL, plasmablastic
lymphoma and others that do not fulfill the criteria for a DLBCL, leg-type
Diffuse large B-cell lymphoma (DLBCL), leg-type
Histology
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Diffuse growth
pattern, monomorphous infiltrate, entire dermis
involvement, adnexal structures are usually destroyed
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The epidermis
is often spared, Grenz zone
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Centrocytes are absent
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Mitotic
figures can frequently be detected
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Nuclei are
round with coarsely clumped chromatin.
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Minimal
inflammatory component and little stromal reaction.
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CD19+, CD20+,
CD22+, and CD79a+ CD10-, Bcl-6 + in most cases.
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Combination +
Bcl-2, and + MUM-1/IRF4 is characteristic regardless of site and distinguish
from FCL diffuse type.
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The t(14;18) can
be detected in secondary cutaneous large B-cell lymphomas but not in primary cutaneous diffuse large B-cell lymphomas.
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The 5-year
survival 55%
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PCLBCLs on the leg
have an inferior prognosis compared to PCLBCLs
presenting at other
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Tx Radiotherapy and Rituximab
Diffuse large B-cell lymphoma, other
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Neoplastic large B-cells
that lack the typical features of DLBCL, leg-type and do not conform to the
definition of primary cutaneous FCL with diffuse
growth pattern.
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T cell rich, histiocyte rich, plasmablastic
(HIV) variants
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CD19+, CD22 +,
and CD79a+, with light-chain restriction, negative for CD15 and CD30, which
excludes Hodgkin lymphoma.
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5 yr survival
65%
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Tx Radiotherapy and Rituximab
Intravascular large B-cell lymphoma (IVL)
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Rare highly
malignant large-cell lymphoma with systemic spread
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Tumor cells in
the lumina of small vessels, particularly capillaries
and venules.
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Skin and the nervous system are preferential sites of primary
manifestation.
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The tumor
cells express B-cell markers in the vast majority of cases; rarely a T-cell
phenotype is found
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Patients with disease limited to the skin (cutaneous
variant) have a significantly better outcome than the other patients with IVL. 3-year overall survival: 56% versus 22%
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Tx Multiagent
chemotherapy
Blastic NK-cell
lymphoma or CD4+/CD56+ hematodermic neoplasm
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Cell of origin
is not yet completely elucidated
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Cytogenetically,
they are related to dendritic cells.
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Skin
involvement occurs in 87% of the patients and manifests with contusiform, brownish infiltrated plaques or nodules.
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The oral
mucosa is commonly involved.
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The cells
express CD4, CD56, CD123 and TCL-1 but are negative for other T-, B-, NK-cell,
or myeloid markers.
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median
survival, 14 months)
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Systemic
chemotherapy
Extranodal NK/T-cell lymphoma, nasal type
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Adults, males, Asia, Central America, and South America.
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plaques or tumors preferentially on the trunk and extremities, ulceration is
common.
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Dense
infiltrates in dermis and often the subcutis.
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Epidermotropism, prominent angiocentricity and angiodestruction
and extensive necrosis.
l Small to large cells with irregular or oval nuclei,
moderately dense chromatin, and pale cytoplasm,
histiocytes, plasma cells, and eosinophils can be seen.
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ExpressCD2,
CD56, cytoplasmic CD3 , and cytotoxic
proteins (TIA-1, granzyme B, perforin),
but lack surface CD3.
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In rare CD56-
cases detection of EBV by in situ hybridization and expression of cytotoxic proteins are required for diagnosis.
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EBV
is expressed almost in all cases, suggesting a pathogenetic
role of this virus
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Nearly allways EBV+ lymphoma of small, medium, or large cells
usually with an NK-cell, or more rarely a cytotoxic
T-cell, phenotype.
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The skin is
the second most common site of involvement after the nasal cavity/nasopharynx
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Skin
involvement may be a primary or secondary manifestation
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Since both
groups show an aggressive clinical behavior and require the same type of
treatment, distinction is not useful.
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median
survival of 27 months was reported, compared with 5 months for patients
presenting with cutaneous and extracutaneous
disease.
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Tx systemic hemotherapy
Conclusion
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The new
WHO/EORTC classification of cutaneous lymphomas,
employs a terminology compatible with systemic lymphomas but also reflects the
organ-specific pecularities of cutaneous
lymphomas.
References
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1)WHO-EORTC classification for cutaneous lymphomas Blood, 15 May 2005, Vol. 105, No. 10, pp. 3768-3785.
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2)WHO/EORTC classification of cutaneous
lymphomas 2005: histological and molecular classification Journal of Cutaneous
Pathology
Volume 32 Page 647 - November 2005