An Algorithmic Approach to the Diagnosis of Cutaneous Lymphoid Infiltrates
Northwestern University School of Medicine
The evaluation of cutaneous lymphoid infiltrates is particularly challenging for the pathologist.
Often the answer to the diagnostic dilemma goes beyond the microscope requiring a thoughtful
clinico-pathological assessment. This is a unique scenario for the pathologist, which contrasts with
other situations like melanocytic lesions or epithelial tumors in which a diagnosis can be rendered in
most cases without interaction with the clinician.
Knowing the origin of most cutaneous lymphomas will help us understand this diagnostic dilemma.
The vast majority of cutaneous lymphomas arise from primed and matured lymphocytes. These lymphoid
infiltrates may respond to antigenic stimuli in similar manner than an inflammatory skin condition.
Hence, early cutaneous lymphomas may closely mimic pathologically and clinically an inflammatory
dermatosis. In addition, the malignant lymphoid population may elicit an intense lymphoid reaction which
is often clonotypic that may further obfuscate the malignant process. Besides the clinical information,
a proper diagnosis often requires the procurement of fresh tissue for flow cytometry, gene rearrangement
studies and even full staging with bone marrow biopsy and imaging studies.
There are four main issues that the pathologist needs to address when dealing with a dense
cutaneous lymphocytic infiltrate:
- Neoplastic vs. dysplastic vs. inflammatory (reactive lymphoid hyperplasia)
- B-cell vs. T-cell process vs. other
- Subtype of lymphoma.
- Primary cutaneous vs. secondary lymphoma
Reactive Lymphoid Hyperplasia
Reactive Lymphoid Hyperplasia (RLH) is an inflammatory reaction composed primarily by lymphocytes to
a known or unknown triggering stimulus. RLH may have architectural and cytological features that closely
simulate a lymphoma. The term "pseudolymphoma" is often used for such cases. However, this term is
misleading and confusing and its use is not recommended.
RLH, B-cell type: Patients are often young presenting with a solitary lesion often in the head and
trunk with a predilection for sites like the forehead, ear, nose, nipple, and scrotum. The lesions are
red non-ulcerated nodules covered by smooth skin. The treatment of choice is surgical excision, which at
the same time will provide the pathologist with adequate material for a thorough evaluation.
There are a number of distinct conditions that can present with a RLH, B-cell pattern. In order to
reach the correct diagnosis, pertinent clinical history may be needed. Some of the conditions to be
considered with this pattern are:
| Kimura's disease|
| Arthropod bite reaction (tick bite)|
| Lupus erythematosus / Jessner's|
| Ruptured cyst/ pseudolymphomatous folliculitis|
| Reaction to foreign body (tattoo, vaccine, acupuncture, surgical site etc)|
| Others (herpes, halo nevus, cancer, etc.)|
RLH, B-cell type, or lymphocytoma cutis, maybe difficult to differentiate from a primary cutaneous
follicular lymphoma. Both conditions display a follicular pattern at low magnification. RLH has sharply
demarcated germinal centers with a distinct mantle zone, tingible body macrophages and a high mitotic
activity. Some other clues favoring RLH include:
| Polymorphous infiltrate (eosinophils, plasma cells, histiocytes)|
| Paucity of intermediate cells|
| Prominent endothelial cells, margination, edema and/or fibrosis|
| Lack of light chain restriction (Kappa:Lambda between 4:1 and 1:2)|
| Granulomatous changes|
| Lack of adnexal destruction or "crush artifact"|
In reality, the distinction between lymphocytoma and lymphoma is often difficult if not impossible.
Furthermore, marginal zone lymphomas may have reactive germinal centers and conversely RLH with distorted
dermal mesenchymal tissue may present with a diffuse pattern.
RLH, T-cells type: There are numerous dermatoses that can present with a dense infiltrate composed
of reactive intermediate to large lymphocytes that can closely resemble a large cell T-cell lymphoma.
Other dermatoses characterized by chronic epidermotropic reactive T-cells may resemble mycosis fungoides.
Interestingly many of this entities display a CD8 T-cells phenotype, which is unusual for MF. Furthermore
the large cell variants of RLH often express CD30. Once again, knowledge of the clinical presentation is
of utmost importance.
|T-cell lymphoma (large cell type) mimics|
| ||VZV reaction|
| ||Molluscum contagiosum|
| ||Nodular scabies|
| ||Some "pagetoid reticulosis"|
|Mycosis fungoides mimics:|
| ||Actinic reticuloid|
| ||HIV photodermatitis|
| ||Drug hypersensitivity reaction (psycotropic drugs, antiepileptics, ACE-inhibitors, etc)|
| ||Others: lichenoid keratosis, lupus erythematosus and other interface dermatitis, contact dermatitis, erythema annulare centrifigum|
Cutaneous lymphoid dysplasias (CLD )
In the last few years, we have also witnessed numerous studies reporting T-cell clonality (TCC) in a
myriad of cutaneous conditions traditionally classified as benign dermatoses. This confusing trend has
elicited some debate about the relevance of TCC in cutaneous infiltrates and the lack of specificity of
TCC in the diagnosis of CTCL. However the detection of TCC in certain inflammatory dermatoses is
probably a real event that should not be blamed to over sensitivity of the PCR based tests.
In my opinion, there are a number of well-defined skin conditions characterized by persistent
cutaneous lymphoid infiltrates composed of a clonal population of T-cells with minimal cytologic atypia.
Furthermore all of these conditions can transform into bona fide CTCL and hence should be considered
precursor lesions. The defining criteria for CLD are:
- Chronic dermatitis recalcitrant to steroids
- Unknown triggering event
- Small/intermediate lymphocytes without nuclear atypia
- Potential for malignant transformation
The CLD encompasses various conditions with distinct clinical and pathological characteristics. The
following entities have been included in this group:
|Hypopigmented interface variant|
|Pigmented purpuric variant|
|Atypical lobular panniculitis|
|Syringolymphoid hyperplasia with alopecia|
|Idiopathic follicular mucinosis|
|Folliculotropic T-cell lymphocytosis|
|Pityriasis lichenoides chronica|
|Parapsoriasis en plaque|
|Idiopathic erythroderma (Pre-Sézary)|
Most of these conditions are primarily T-cell processes, but there are reports of RLH, B-cell type
with a known triggering stimulus including tick bites and tattoo reactions, which over time have
transformed into B-cell lymphomas. Hence some cases of RLH B-cell type may have similar characteristics
and malignant potential.
Cutaneous T-cell lymphomas
Mycosis fungoides is the prototype of CTCL. There are approximately 0.3 new cases per 100,000 people
diagnosed yearly with an estimated US prevalence of 18,000 to 20,000 cases. The majority of patients are
40 to 70 years of age with slight male and black predominance. MF is characterized by:
|Low grade lymphomas|
|Cutaneous homing features (CLA+)|
|T helper cells (CD4)|
|Mature & primed T-cells (CD45R0+)|
|TH2 cytokine profile|
The challenge in the diagnosis of CTCL is in the heterogeneity of clinical pathological presentation
as well as the slow evolution of the disease. The classic histopathological features include:
- Upper dermal band-like lymphocytic infiltrate with variable adnexal involvement.
- Variable epidermal changes, often with parakeratosis.
- Halo perinuclear effect with minimal spongiosis.
- Epidermotropism (basal, Pautrier microabscesses, duplets/triplets).
- Dermal fibroplasia (reticulated or laminar).
- Nuclear atypia (small cerebriform cells--intermediate--large cells). Intraepidermal lymphocytic atypia.
- Some eosinophils and plasma cells are frequently seen in advanced MF
Mycosis fungoides histological variants: Follicular MF (+/-Follicular mucinosis). Syringotropic MF,
Granulomatous MF (+\- elastolysis), Pustular MF, Ulcerative MF, Bullous MF, Hemorrhagic MF, Hypopigmented
MF, Hyperpigmented MF, D'Emblee MF, Eczematoid MF, Lichenoid MF, Ichthyosiform MF, etc.
Early on, the infiltrate in mycosis fungoides is rich in tumor-infiltrating lymphocytes (mostly CD-8
positive cells with clonotypic MHC-restricted cytotoxicity), Langerhans cells, dermal dendrocytes, and NK
cells. With disease progression, the reactive T-cell and NK cell population is depleted with a
concomitant increase of the malignant cells. Early on, the clonal T-cells tend to be localized in the
intra-epidermal compartment. With tumor progression, epidermotropism is lost, and there is a switch to a
predominantly TH-2 pro- immune-suppressive cytokine profile. Consequently, the patients often develop
anergy, hypergammaglobulinemia, hypereosinophilia, and loss of epidermotropism. This immune-suppressive
state favors the growth of the T-cell clone by depleting the cell-mediated immune system.
Immunohistochemical evaluation of epidermotropic infiltrates with CD4 and CD8 on paraffin embedded
tissue can be very useful. MF-mimics tend to have a predominance of CD8 cells in the intraepidermal
compartment. There are two exceptions of rare CTCL variants with intraepidermal CD8+ cells.
"Epidermotropic aggressive CD8 CTCL" first reported by Berti, which is an aggressive and often lethal
disease characterized by diffuse necrotic lesions with confluent necrotic keratinocytes and active
cytotoxic features. The juxtaepidermal variant is a recently described variant seen in young patients
often of African ancestry. The course is indolent responds relatively well to topical therapies.
Epidermotropic infiltrates composed of large T-cells without tumor lesions are unusual in mycosis
fungoides. Patch lesions of MF with large cells are not associated with a poor prognosis. Pagetoid
reticulosis is also characterized by epidermotropic large cells. This rare and obscure entity has a
typical presentation with verrucous lesions in an acral distribution. The epidermotropic infiltrate is
more often CD8+ than CD4+ and CD30 is commonly expressed. Many cases lack T-cell clonality.
Cutaneous T-cell lymphoma, large cell type
Diffuse, dense (superficial and deep) and mostly non-epidermotropic mononuclear cell infiltrate.
When a patient with a history of mycosis fungoides develops new tumor lesions the differential
|Tumor progression commonly associated with large cell transformation (CD30 + or -)|
|CD30 Lymphomas/lymphomatoid papulosis|
|Other tumors: Patients with MF are prone to develop other malignancies including B-cell lymphoma and Hodgkin's disease.|
|Pseudotumors (nodules without tumor cells) like picker's nodule (neurodermatitis) in follicular MF.|
Large cell transformation (LCT) of mycosis fungoides carries a poor prognosis with a 5-year survival
of 11 to 19% (Cerroni 1992, Diamandidou 1998). We must be careful not to confuse a primary cutaneous
CD30 lymphoproliferative disorder with MF with LCT. This is particularly important since both conditions
may coexist on the same patient and both entities can present with a dermal infiltrate composed of CD30+
Primary cutaneous CD-30+ lymphoma (Ki-1 lymphoma, anaplastic large cell
This condition can present at any age with one or multiples often ulcerated nodules. The prognosis
of tumors with limited skin involvement is excellent. However, some subsets of CD30+ LCL are
particularly aggressive. These presentations include involvement of multiple skin regions, extensive
single limb involvement, and associated pseudoepitheliomatous hyperplasia. The diagnosis of CD30+
lymphoma may also be difficult to differentiate from lymphomatoid papulosis (LyP). This is especially
true with the type C variant of LyP which is characterized by large nodules with cohesive sheets of CD30+
large cells. The defining criteria will depend on the clinical behavior. LyP type C should undergo
spontaneous regression which can take up to 8 weeks. A prudent approach by the clinician is to wait a
few weeks prior to therapeutical intervention. In CD30+ anaplastic large cell lymphoma, unlike MF with
LCT, the tumor cells show near-uniform expression of CD30 in more than 75% of the cells. The CD30 (Ki-1
antigen) is a marker of activated T and B cells and is not lineage specific. The antibody BER-H2 can be
used in paraffin embedded tissue. Large CD30+ reactive lymphocytes have been reported in a variety of
inflammatory conditions like arthropod bite or resolving ruptured cyst.
Medium and small cell variants of CD30+ anaplastic large cell lymphoma have been rarely described.
Patients with multiple cutaneous nodules, especially children, should be worked up for possible systemic
lymphoma with secondary skin involvement. Immune staining with ALK and EMA indicate a high likelihood of
a secondary CD30 lymphoma. With rare exceptions, cutaneous CD30 lymphoproliferative lesions are t(2;5)
Lymphomatoid papulosis is characterized by recurrent crops of papulonecrotic lesions that
histologically contain atypical lymphocytes. The term "Lymphomatoid" refers to the benign clinical
course usually encountered, although approximately 10% of the patients may subsequently develop lymphoma
(CTCL, CD30+ lymphomas). Histological features include: a superficial and deep perivascular and
interstitial mononuclear cell infiltrate with epidermotropism, and the presence of atypical lymphocytes
(Reed-Sternberg-like for Type A, small cerebriform for Type B). The vast majority of LyP cases are type
A with large atypical cells. A variable number of eosinophils and extravasated RBC's can be found.
Occasionally lymphocytic vasculitis is also noted. Most of the atypical large cells stain with T-cell
markers and CD-30 (Ki-1). Differential diagnosis includes CD-30 positive lymphoma, which shows less
non-specific inflammation and a more pure population of atypical cells. There are other entities that
can present with multiple papules with an atypical CD30+ large cell population. Such entities include
arthropod bite reactions (especially in children), dermal reactions associated with folliculitis, or
molluscum contagiosum. Post-transplant and methotrexate-induced lymphoproliferative disorders can
closely resemble LyP clinically and histopathologically.
Cutaneous B-Cell Lymphomas
The only trace of B-cells in normal skin is some secretory IgA cells present in eccrine and
sebaceous glands. A B-cell skin immune system is probably acquired with recruitment of B-cells after an
antigenic stimulus. This pool of reactive B-cells is probably the precursor of primary cutaneous B-cell
lymphoma (PCBL). Because of the great similarities with mucosal-associated lymphoid tissue (MALT)
lymphomas, PCBLs have also been called "SALT lymphomas".
Patients tend to present with a single or multiple red nodules or papules with smooth surface. The
lesions tend to localize in one anatomical area, most commonly head, neck or back. Extracutaneous spread
occurs in less than 10% of the cases, most commonly to the regional lymph node and rarely to the bone
marrow (especially follicular cell lymphomas). Mortality rate of primary cutaneous B-cell lymphomas is
low (4/133 patients). An uncommon subset of patients present with large tumor lesions on the legs.
These patients are often elderly females and this variant carries a poor prognosis.
Immunophenotyping of cutaneous B cell lymphomas is more reliable with flow cytometry than
immunohistochemistry. An adequate sample can be obtained by mincing a 4mm punch biopsy of fresh tumor
specimen and then filtering the sample to create a cell suspension. The panel of immunomarkers available
for flow cytometry is more comprehensive allowing for more precise tumor definition.
Initially, pan B-cell markers (CD79a, CD20) should be used. T-cell rich B-cell lymphomas and
lymphomatoid granulomatosis may show only focal clusters of B-cells with a dominant T-cell or in some
cases a histiocytic infiltrate. Conversely cases with a pure population of tumor B-cells with few
reactive T-cells are likely to be secondary cutaneous lymphomas with a primary nodal or other systemic
origin. Occasionally abnormal expression of CD43 and CD45RO has been reported in PCBL.
Infiltrates with a follicular pattern should be tested for bcl-2. Its expression is unusual on
primary cutaneous follicular center cell (FCC) lymphomas. Primary cutaneous B-cell lymphomas expressing
bcl-2 carries a poor prognosis even if a systemic lymphoma has not been detected (Grange Blood 2004).
Lymphomas composed of small/intermediate B-lymphocytes should be stained with CD5 and CD10. CD5
staining should alert us about a possible mantle cell lymphoma. Cyclin D1 can be used to confirm the
diagnosis. Occasionally SLL/CLL can present with skin infiltrates with or without large cell
transformation. CD23 can be used to identify this subtype. When the predominant cells are small cleaved
(centrocytes) with variable centroblasts in a diffuse or nodular pattern, the likely diagnosis is a
secondary FCC lymphoma. CD10 may be positive in this case. MUM-1 and Bcl-6 can be used for the
evaluation of large cell B-cell lymphomas. Besides the cytologic features showing a pure population of
intermediate to large cells with round nuclei, MUM-1 and strong bcl-2 expression will be helpful in the
diagnosis of leg-type lymphoma. Bcl-6 will support a FCC origin, but it may also be expressed in the
Surface immunoglobulins (sIG) cannot be detected in formalin fixed sections. Hence the role of
kappa and lambda is limited to cases suspicious for a plasmacytoma or a marginal zone lymphoma. mRNA in
situ hybridization may be helpful when cytoplasmic immunoglobulins cannot be detected. In approximately
25% of cases, light chain expression is absent. Cases with negative results may include early lymphomas
with many tumor-infiltrating lymphocytes, advanced large cells lymphomas that have lost their surface
immunoglobulins, and pre-B cell or null phenotype lymphomas. In addition, necrosis or linkage of plasma
proteins may lead to a loss of sIGs.
Follicular center cell lymphoma
This is the most common type of PCBL. Histologically it is characterized by an ill-defined
follicular pattern with centrocytes and centroblasts. The mantle zone is reduced or absent and there is
a confluence of the follicles, a lack of polarization and tingible bodies, and a low proliferative index.
Over time the infiltrate tends to become diffuse, often with large cell transformation. Large cell
transformation in primary cutaneous FCC lymphoma has no prognostic or therapeutic implications.
The phenotype is as follows: CD5 negative, CD10 often positive (negative on diffuse lesions), bcl-6
positive, MUM-1 usually negative. Bcl-2 is usually negative or weakly positive but occasionally positive
in primary skin lesions and especially in secondary skin tumors. In early FCC lymphomas, CD21 stains
dendritic reticulum cells (follicular dendritic cells) and outlines an irregular network pattern that
tends to disappear with time. The karyotype often includes t(14:18).
The distinction between a primary cutaneous and a secondary cutaneous lymphoma should be determined
on the clinical grounds. When a patient presents with multiple lesions in different anatomical areas, a
systemic lymphoma should be suspected. Rarely primary cutaneous FCC lymphomas can involve multiple
anatomical regions. The individual lesions are indistinguishable from PCBL. Approximately 5-10% of
advanced follicular lymphomas will involve the skin. Histopathological clues to suggest a systemic
lymphoma include a deep follicular or diffused infiltrate with a monomorphous infiltrate and relatively
few reactive cells. BCL-2 is often expressed.
Marginal zone lymphomas
Patients are often young adults with one or several deeply seated nodules in the extremities. The
prognosis is excellent prognosis with persistent lesions and high frequency of cutaneous recurrences.
The 5-year survival rate is 98%. Patients have no evidence of a paraproteinemia and are not at increased
risk of an autoimmune disorder. Rarely transformation into a large cell lymphoma can occur.
|Vertically oriented infiltrates often tracing adnexal structures.|
|Centrocyte-like/monocytoid cells with ample pale cytoplasm|
|"Monotypic" lymphoplasmacytoid/plasma cells at periphery in most cases|
|Occasionally with deep dermal reactive germinal centers which can be colonized by tumor cells.|
|Light chain restriction on plasmacytoid cells even on paraffin sections. CD5- and CD10-|
|Elderly patients ( average.76 y.o.) Women (M:F, 2:7)(M Vermeer et al., Arch Derm 1996)|
|Multiple or solitary nodules in the lower legs although it may occur in other areas.|
|Radiotherapy or chemotherapy; CR in 16/18 pts.|
|Relapse 9/18. 5 died of their lymphoma|
|Activated B-cell phenotype with MUM1 expression|
|Diffuse pattern with intermediate to large round cells (centroblasts/immunoblasts)|
|Necrotic areas, destructive pattern and minimal stromal reaction|
|Bcl-2 ++; staining is typically strong and in most neoplastic cells, Bcl-6: +/-, CD10: -/+|
Lymphoblastic lymphoma presenting in the skin
Extremely rare cutaneous presentation. Report of 6 patients with skin involvement (head/neck) at the
time of presentation. Frequently patients have bone marrow involvement and ALL.(C Sander et al., JAAD
|Uniform dermal infiltrate composed of small-medium size cells with blastic nuclear chromatin. Many mitosis and apoptotic cells.|
|CD10 (CALLA) +/-, CD20 +/-, TdT+, cytoplasmic Ig+, sIg-|
|Most cases reported, unlike mediastinal tumors, are pre-B-cell|
|Differential diagnosis: Burkitt's, small non-cleaved MZL|
|This is a high grade lymphoma that often responds to chemotherapy|
Primary (very rare) or spread from bone (multiple myeloma). Extraosseous lesions more common in IgD
secreting tumors (63%). Monomorphous infiltrate composed of plasma cells. Suspect myeloma if there is
nuclear atypia or multinucleated cells, mitosis and/or cytoplasmic IgD. Differential diagnosis:
Immunocytoma/marginal zone lymphoma (less maturity with more plasmacytoid cells).
Intravascular large B-cell lymphoma (malignant angioendotheliomatosis)
Elderly patients (F>M) present with CNS changes, dementia, fever, skin changes, etc.
|Indurated hemorrhagic plaques (>50% pts.). Rarely confined to skin only|
|Large B-cells in blood vessels with fibrin|
|Differential diagnosis: "inflammatory carcinoma" and reactive angioendotheliomatosis|
|MUM-1+ , Bcl-2+, CD10-/+, CD5-|
Subcutaneous panniculitis-like T-cell lymphoma
SPTL is characterized by the presence of primarily subcutaneous infiltrates of small, medium or
large pleomorphic T-cells with many histiocytes, predominantly involving the legs. Necrosis,
karyorrhexis and cytophagocytosis are common findings. Recent studies suggest that at least two groups
of SPTL with different histologies, phenotypes and prognosis can be distinguished. Cases with
α/β+ T-cell phenotype are usually CD8-positive, are restricted to the subcutaneous tissue with
minimal dermal or epidermal involvement, and often run an indolent clinical course. In contrast, SPTL
with γ/δ T-cell phenotype, are typically CD4-, CD8-, and often co-express CD56. The neoplastic
infiltrates are not confined to the subcutaneous tissue, but may involve the epidermis and/or dermis as
well. This subtype invariably has a very poor prognosis.
The disease may be complicated by a hemophagocytic syndrome, which is generally associated with a
rapidly progressive course. However, the hemophagocytic syndrome is probably less common than in
cutaneous γ/δ+ T-cell lymphomas with panniculitis-like lesions. Dissemination to
extracutaneous sites is rare. SPTCL may be preceded for years or decades by a more indolent
panniculitis. In the early stages the neoplastic infiltrates may lack significant atypia and a heavy
inflammatory infiltrate may predominate. EBV is absent.
Extranodal NK/T-cell lymphoma, nasal type
After the nasal cavity/nasopharynx, the skin is the second most common site of involvement of
extranodal NK/T-cell lymphoma; skin involvement may be a primary or secondary manifestation of the
disease. Patients are predominantly adult males. This lymphoma is more common in Asia, Central America
and South America. Patients generally present with multiple hemorrhagic and ulcerated plaques or tumors
and sometimes with central facial destructive features also designated lethal midlinegranuloma.
The infiltrate often involves dermis and often extends to the subcutis. Prominent angiocentricity
and angiodestruction are often accompanied by extensive necrosis. In most cases the infiltrate is mostly
composed of medium sized cells with a spectrum from small to large lymphocytes. The cells may have
irregular hyperchromatic nuclei with scant pale cytoplasm. In some cases a heavy inflammatory infiltrate
of small lymphocytes, histiocytes, plasma cells and eosinophils can complicate the diagnosis. The
neoplastic cells express CD2, CD56, cytoplasmic CD3ε and cytotoxic proteins (TIA-1, granzyme B,
perforin), but lack surface CD3. In rare cases CD56 is negative and detection of EBV by in-situ
hybridization and expression of cytotoxic proteins are required for diagnosis. LMP-1 is inconsistently
expressed.Hydroa vacciniforme-like CTCL is a rare type of EBV-associated lymphoma of CD8+ cytotoxic
T-cells which affects children almost exclusively in Latin America and Asia. In my opinion, this variant
is very closely related to nasal type, NK lymphoma.
Primary cutaneous aggressive epidermotropic CD8-positive cytotoxic T-cell lymphoma
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 clinical features are very similar to those observed in patients with a cutaneous
γ/δ T-cell lymphoma and cases described as generalized pagetoid reticulosis (Ketron-Goodman
type) in the past. These lymphomas may disseminate to other visceral sites (lung, testis, central
nervous system, oral mucosa), but lymph nodes are often spared.
The epidermis shows a pagetoid infiltrate of atypical lymphocytes with prominent necrotic changes.
Invasion and destruction of adnexal skin structures are commonly seen. Angiocentricity and angioinvasion
may be present. Tumor cells are small-medium-large with pleomorphic or blastic nuclei. The phenotype is
as follows: CD3+, CD8+, TIA-1+, CD45RA+, CD2-, CD4-, CD5-, EBV-.
Cutaneous gamma/delta T-cell lymphoma can present with a similar manner with extensive cutaneous and
even mucosal necrosis. The prognosis is also poor.
CD4+/CD56+ Hematodermic neoplasm (formally Blastic type, NK lymphoma)
The blastic cytological appearance and CD56 expression initially suggested an NK-precursor origin
of these lymphomas. More recent studies suggest derivation from a plasmacytoid dendritic cell precursor.
CD4+/CD56+ hematodermic neoplasm commonly presents in the skin with multiple nodules or tumors with or
without concurrent extracutaneous localizations. Most patients presenting with only skin lesions rapidly
develop involvement of bone marrow, peripheral blood, lymph nodes and extranodal sites. Only about half
of the patients have nodal or bone marrow involvement at presentation. The prognosis is poor. Some of
these cases may have been diagnosed in the past as "aleukemic leukemia cutis". The infiltrate is
non-epidermotropic, monotonous and is composed of medium-sized cells with finely dispersed chromatin and
absent or indistinct nucleoli resembling lymphoblasts or myeloblasts. There is a high mitotic index and
often some hemorrhage. The phenotype is as follows: CD4+, CD56+, CD3-, CD8-, myeloperoxidase-, CD45RA+,
CD123+, germline TCR, EBV-
Proposed WHO/EORTC classification of primary cutaneous lymphomas
Cutaneous T-cell and NK-cell lymphomas
|Mycosis fungoides variants and subtypeso Folliculotropic MF|
| || Pagetoid reticulosis|
| || Granulomatous slack skin|
|Adult T-cell leukemia/lymphoma|
|Primary cutaneous CD30-positive lymphoproliferative disorders|
|Primary cutaneous anaplastic large cell lymphoma|
|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-positive 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|
|Primary cutaneous intravascular large B-cell lymphoma|
Precursor hematologic neoplasm
| CD4+/CD56+ hematodermic neoplasm (formerly blastic NK cell lymphoma)|
| WHO-EORTC Classification ||Number ||Frequency (%) ||Disease-specific5-year survival (%)|
|CUTANEOUS T-CELL LYMPHOMAS|
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 LYMPHOMAS|
Indolent clinical behavior
|Primary cutaneous marginal zone B-cell lymphoma ||127 ||7 ||95|
|Primary cutaneous follicle center lymphoma ||207 ||11 ||99|
|Intermediate clinical behavior || |
|Primary cutaneous diffuse large B-cell lymphoma, leg type ||78 ||4 ||55|
|Primary cutaneous diffuse large B-cell lymphoma, other ||11 ||<1 ||50|
|Primary cutaneous intravascular large B-cell lymphoma ||6 ||<1 ||65|