cutaneous lymphoproliferative disorders

CUTANEOUS LYMPHOPROLIFERATIVE

DISORDERS By- Dr. Kanwalpreet Kaur Moderator- Dr. Karuna Gupta

PRIMARY LYMPHOMAS- that present in the skin with no evidence of extracutaneous disease at the time of diagnosis

SECONDARY LYMPHOMAS- systemic lymphomas that secondarily involve the skin.

T and B cell infiltration patterns

Differences in adhesive ligands between T and B cells

Differential affinity for different compartments• Benign and malignant T cells migrate to

epidermis and its adnexa.• This phenomena is known as EXOCYTOSIS in BENIGN CONDITIONS; EPIDERMOTROPISM in MALIGNANT CONDITIONS.• This pattern may be blunted as tumour

evolves into more aggressive and poorly differentiated state.

• B cells spare epidermis and papillary dermis

• Sparing of papillary dermis produces grenz zone

• innate proclivity of B cells to aggregate into follicular structures, B-cell infiltrates in the skin often (but not invariably) show a nodular architecture

PATTERNS OF T AND B CELL INFILTRATION

T CELL PATTERN B CELL PATTERN- GRENZ ZONE AND GERMINAL CENTRE FORMATION

DISTINCTION FROM INFLAMMATION

In both T- and B-cell responses in skin

circulating lymphocytes initially adhere to activated endothelium lining dermal postcapillary venules. PERIVASCULAR/ANGIOCENTRIC DERMATITIS

Further migration may be Stunted e.g. erythema chornium migrans

Migration away from the vessel wall is presumably swift enough that in the case of T cells

papillary dermal accumulation and epidermotropism, in addition to a persistent angiocentric pattern

IMMUNOLOGICALLY ACTIVE T CELLS1.Produce cytokines and growth factors so T cell exocytosis is associated with epithelial spongiosis, acanthosis or apoptosis2. seen in contact hypersensitivity, psoriasis, cytotoxic dermatitis

MALIGNANT EPIDERMOTROPIC T CELL INFILTRATE1.Epidermis is passive2.No reactive epithelial alteration3.No spongiosis or apoptosis4.However, epidermal injury in the form of mucinous degeneration may occur.5.The epidermis becomes more extensively infiltrated, impaired maturation often manifests as clinical abnormalities in scale production

A: Abnormal epidermotropism into a “passive” epidermis. B: Scaling patches and plaques as a consequence of altered epidermal maturation associated with T-cell epidermotropism (MF).

REACTIVE B CELLS 1) perivascular accumulation of cells2) No significant involvement of papillary dermis or epidermis3) Grenz zone of papillary sparing 4) Preservation of archietecture

MALIGNANT B CELLS1) Destructive relationship

to pre-exsisting structures

2) Infiltatre in interstitial pattern causing

3) Splaying of collagen bundles and mesenchymal cells within reticular dermis

4) This progressive dermal infiltration+ epidermal sparing red to plum colored nodules covered by nonkeratotic epidermis

Normal and abnormal trafficking patterns. A: B-cell pattern showing nondestructive infiltration of superficial and deep dermis. B: B-cell lymphomas showing vascular invasion , replacement of subcutis , and diffuse interstitial pattern . C: Plum-colored nodule covered by thinned, glistening epidermis due to B-cell dermal infiltration.

CUTANEOUS LYMPHOID HYPERPLASIA (LYMPHOCYTOMA CUTIS, PSEDOLYMPHOMA)

Heterogenous spectrum of lymphoid infiltrates that can be similar histologically to malignant lymphomas but do not have clinical presentation or biological outcome of lymphoma.

Inflammatory infiltrate is band like, nodular or diffuse and composed of lymphocytes predominantly, but other inflammatory cells are also present.

Depending on the predominant cell type in the infiltrate, they are divided into T and B cell types.

WHO/EORTC CLASSIFICATIONCUTANEOUS T- cell and NK- cell Lymphomas1. MYCOSIS FUNGOIDES (MF)2. MYCOSIS FUNGOIDES VARIANTS AND SUBTYPES: a) Folliculotropic MF b) Pagetoid reticulois c) Granulomatous slack skin

3. SEAZARY SYNDROME4. ADULT T- cell LYMPHOMA5. PRIMARY CUTANEOUS CD30+ LYMPHOPROLIFERATIVE DISORDERS a) Primary cutaneous anaplastic large cell lymphoma (cALCL) b) Lymphomatoid papulosis

6. SUBCUTANEOUS PANNICULITIS LIKE T CELL LYMPHOMA7. EXTRANODAL NK/T- cell LYMPHOMA, NASAL TYPE8. PRIMARY CUTANEOUS PERIPHERAL T- cell LYMPHOMA, UNSPECIFIED a) Primary Cutaneous Aggressive Epidermotropic CD8+ T- Cell Lymphoma b) Cutaneous γ/ δ T- Cell Lymphoma c) Primary Cutaneous CD4+ Small/Medium Sized Pleomorphic T- Cell Lymphoma

CUTANEOUS B-cell LYMPHOMAS1. Primary cutaneous follicle centre lymphoma

2. Primary cutaneous marginal zone B-cell lymphoma

3. Primary cutaneous diffuse large B-cell lymphoma, leg type

4. Primary cutaneous diffuse large B-cell lymphoma , other

5. Intravascular large B-cell lymphoma

PRECURSOR HEMATOLOGIC NEOPLASMCD4+/CD56+ hematodermic neoplasm (blastic NK cell lymphoma)

MYCOSIS FUNGOIDES Low grade epidermotropic T-cell lymphoma Mycosis fungoides is relatively rare, accounting for less than

1% of non-Hodgkin lymphomas. However, of lymphomas that arise primarily in skin, it is the most common

Peak age 55-60 Male: female 2:1

CLINICAL FEATURES Typically begins as slowly progressive dermatitis-like patches

and plaques on non sun-exposed skin, and when untreated evolves to nodules and eventual systemic dissemination

Lesions initially -erythematous scaling patches and plaques that typically are resistant to antiinflammatory therapy;Large with polygonal or arcuate configurations;

Plaques and nodules of advanced disease which may eventually ulcerate

Extracutaneous spread• When extracutaneous spread eventuates, lymph nodes, spleen, liver, and

lungs are often involved, in addition to the peripheral blood.

• Bone marrow involvement is rare

• Lymph node enlargement at such advanced stages must be differentiated from nodal hyperplasia resulting from chronic drainage of involved sites (dermatopathic lymphadenopathy)

•  Progression to Extracutaneous disease correlates with extent of skin disease • A) Limited patch or plaque- very rare • B) Generalized plaque- 8 % • C) Tumorous or generalized erythroderma-30-40% Hence, extracutaneous is

more commonly seen in Sezary syndrome.

MICROSCOPIC FEATURES

Atypical SMALL to MEDIUM sized mononuclear neoplastic T cells with cerebriform nuclei infiltrating the upper dermis among epidermal keratinocytes (epidermotropism) forming intra epidermal aggregates (Pautrier microabscesses), or arranged in linear fashion just above the basement membrane.

Pautriers abscesses – pathognomonic but present only in 38 % cases of MF

Minimal epidermal spongiosis typically present Lymphocytes aligned within the basal layer

MICROSCOPIC FEATURES

 1.Patch stage: superficial band-like or lichenoid infiltrate, mainly lymphocytes and histiocytes, but also a few atypical cells (small/medium-sized, cerebriform nuclei, halo) usually confined to the epidermis (basal layer)= EPIDERMOTROPISM

2.Plaque stage: more pronounced epidermotropism with occasional characteristic intraepidermal collections of atypical cells (Pautrier microabscesses)

3. Tumor stage: more dense nodular or diffuse dermal infiltrate, may lose epidermotropism, more size and shape variability of tumor cells, histologic transformation to large cell phenotype may occur (>25% large lymphoid cells in the dermal infiltrate)

Papillary dermal interstitialinfiltrate associated with linear aggregation of neoplastic lymphocytes along the dermal-epidermal junction

CD4 Staining emphasizing this linear pattern of early epidermotropism

Plaque stage

Plaque-stage disease -prominent clusters of atypical lymphocytes within the epidermis (Pautrier microabscesses)

IMMUNOPHENOTYPING

CD2+, CD 3+ , CD 5+, CD4+, CD8-, CD 7- and usually CD 30-

CD 4 STAINING CD 8 STAINING

MOLECULAR GENETICS Clonal T-cell receptor( TCR) gene rearrangements

have been detected (mostly alpha/beta, rarely gamma/delta receptors)

Increased rate of aberrations involving multiple chromosomes 1,6,11,8,17,15,13, and 9 in advanced stage disease

DIFFERENTIAL DIAGNOSIS OF MYCOSIS FUNGOIDES AND DERMATITIC MIMICKS

ALGORITHM FOR DIAGNOSIS OF EARLY MF

 ISCL/EORTC Diagnostic algorithm : Point based system

A total of 4 points is required for the diagnosis of MF based on any combination of points from the clinical, histopathologic, molecular biological, and immunopathologic criteria.

CRITERIA MAJOR(2points)

MINOR(1 point)

CLINICALPersistent and/or progressive patches and plaques plus

Any2 Any 1

a) Non sun exposed areasb)size/shape variationc)PoikilodermaHISTOPATHOLOGICSuperficial lymphoid infiltrate plus Both Eithera)Epidermotropism without spongiosisb) Lymphoid atypiaMOLECULAR BIOLOGICAL: clonal TCR gene rearrangement

present

IMMUNOPATHOLOGIC:a) CD 2,3,5 < 50% of T cells Any oneb) CD7< 10% T cellsc) Epidermal discordance from expression of CD2,3,5 or CD 7 on dermal T cells

TNM STAGINGSKINT1- limited patches, plaques and /or plaques covering < 10% of skin surfaceT2- patches, papules or plaques covering 10% or more skin surfaceT3- one or more tumours (>1cm)T4- confluence of erythema covering 80% or more of body surface area

NODEN0- no clinically abnormal peripheral lymph nodes N1- clinically abnormal peripheral lymph nodes; histopathologically Dutch grade 1 or NC1 LN0-2N2- clinically abnormal peripheral lymph nodes; histopathologically Dutch grade 1 or NC1 LN0-2

N3- clinically abnormal peripheral lymph nodes histopathology dutch grades 3-4

VISCERALM0- no visceral organ involvementM1- visceral involvement

PERIPHERAL BLOOD INVOLVEMENTB0- absence of significant blood involvement:5% or less of peripheral blood lymphocytes are atypicalB1- low blood tumour burden:>5% of peripheral blood lymphocytes are atypicalB2- high blood tumour burden: 1000/microl sezary cells

FOLLICULOTROPIC MYCOSIS FUNGOIDES

It is characterised by – usual type of cells seen in epidermotropic forms of mycosis fungoides but is confined to hair follicles and is associated with follicular mucinosis.

CLINICAL FEATURES- slowly enlarging follicular patches or plaques on head and neck ; may be associated with alopecia

WORSE PROGNOSIS compared to other variants and require aggressive therapy

MICROSCOPIC FEATURES

Folliculocentric infiltrate with mucinous expansion of the follicle.Infiltrate is usually monomorphic containing cerebriform CD4+ Lymphocytes

PAGETOID RETICULOSIS(WORINGER-KOLOPP DISEASE)

Rare and peculiar form of mycosis fungoides

CLINICAL FEATURES- solitary acral lesion in the form of verrucous plaque that does not progress clinically

If multiple lesions are present / widely disseminated in skin- KETRON-GOODMAN type should not be considered pagetoid reticulosis but primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma

MICROSCOPIC FEATURES

-exclusively epidermal infiltration

-INFILTRATE- mononuclear convoluted T cells

-pagetoid pattern with or without intraepidermal nests

- Epidermal hyperplasia

- hyerkeratosis

Mixed infiltrate of non neoplastic lymphocytes and histiocytes may be seen in superficial dermis

IMMUNOPHENOTYPING

CD3+, CD4+, CD8- or CD3+, CD4-, CD8+

MOLECULAR GENETICS Clonal TCR gene rearrangements

GRANULOMATOUS SLACK SKIN

Extremely rare subtype CLINICAL FEATURES- slowly developing zones

of lax skin in the axillae and inguinal regions; occurs predominantly in men

Good prognosis

MICROSCOPIC FEATURES

Diffuse mononuclear infiltrate+ macrophages+multinucleate giant cells+ T cells with convoluted nucleus. Elastolysis seen in dermis.

SEZARY SYNDROME Potentially aggressive form

These malignant T cells have phenotypic and antigenic overlap with those of mycosis fungoides, Sezary syndrome is sometimes regarded as a mycosis fungoides variant. However, important clinical and histopathologic differences exist between classical mycosis fungoides and Sezary syndrome

Generalized redness and scaling of the skin (erythroderma) +lymphadenopathy + presence of malignant convoluted T cells (sezary cells) in the skin, lymph nodes and peripheral blood

CLINICAL FEATURES Diffuse skin erythema and lymphadenopathy. There may also be itching,

hair loss, nail dystrophy, and hyperkeratosis affecting the skin of palms and soles

In addition to lymph node, skin, and blood involvement, malignant T cells may also infiltrate viscera in late stages, although bone marrow is often spared

MICROSCOPIC FEATURES

band-like papillary dermal lymphoid infiltrate;Lack epidermotropism:More monomorphic cells

MICROSCOPIC FEATURES

dense perivascular and superficial dermal atypical lymphoid infiltrate with minimal focal epidermotropism.

LYMPH NODES- effacement of their architecture by atypical cells infiltrates

PERIPHERAL BLOOD-atypical lymphocytes with cerebriform nuclear contours, with smaller versions referred to as Lutzner cells, and larger ones as classical Sezary cells.

Diagnosis of Sezary syndrome requires at least 1,000 such cells per square millimeter with positive clones

A mixed population of small and large tumor lymphocytes with cerebriform nuclear morphology are noted (arrow on typical Sèzary cell).

Eosinophilia (top cell) is also frequently present in Sezary Syndrome and may contribute to the pruritus and atopy.

DIAGNOSIS * Diagnosis is made when there is a clonal rearrangement of the T-

cell receptor (TCR) in the blood (identified by PCR or southern blot analysis) plus

*either an absolute Sezary cell count of at least 1000 cells/microL *or one of the following two criteria 1) Increased CD4+ or CD3+ cells with a CD4 to CD8 ratio of 10

or more. 2) Increased CD4+ cells with an abnormal phenotype (such as a

CD4+ to CD7- ratio ≥40 percent or a CD4+ to CD26- ratio ≥30 percent)

DIFFERENTIAL DIAGNOSIS

1)Other causes of erythroderma: atopic dermatitis, seborrheic dermatitis, pityriasis rubra piliaris, psoriasis

2) Advanced mycosis fungoides

3) Adult T cell lymphoma/leukemia

PRIMARY CUTANEOUS CD30+ LYMPHOPROLIFERATIVE DISORDERS

Spectrum of related, relatively low-grade disorders that primarily affect skin and develop from an activated or transformed large T cell that expresses the CD30 antigen.

CD30 antigen is a cytokine receptor belonging to the tumor necrosis factor receptor superfamily

Second most common form of cutaneous T-cell lymphomas

It includes: a)primary cutaneous anaplastic large cell lymphoma (cALCL), b)lymphomatoid papulosis and c)borderline cases

Primary cutaneous anaplastic large cell lymphoma (cALCL)

CLINICAL FEATURES – solitary or localised tumours or nodules, large > 2cm, often ulcerated, red brown tumours.

Age- 60 yrs M:F- 2-3:1 Partial regression is common

MICROSCOPIC FEATURES

Nodular or diffuse dermal infiltrate sheets of cohesive CD30+ atypical cells; may also involve superficial cutis

A non neoplastic mixed inflammatory infiltrate of small reactive lymphocytes, macrophages, eosinophils is present

MICROSCOPIC FEATURES

ATYPICAL CELLS- large rounded or irregular vesicular nuclei; prominent centrally placed nucleoli; ample clear to amphophilic cytoplasm

IMMUNOPHENOTYPING

CD 30 IMMUNOSTAINING : strong cytoplasmic membrane staining of tumor cells

According to the WHO-EORTC system, cALCL is classified by the expression of CD30 in more than 75% of large atypical cells

Cells may also be CD4+; LOSS OF PAN-T MARKERS (CD2,CD3,CD5) may occur

EMA and ALK are notexpressed in C-ALCL, but these two markers are positivein systemic (nodal) anaplastic large cell lymphoma(ALCL).

MOLECULAR GENETICS

Clonal rearrangement of TCR genes is detected in 90% of cases

Translocation (t2;5) (p23;q35) charateristic of systemic ALCL is rarely, if ever, found in primary cALCL

Lymphomatoid papulosis CLINICAL FEATURES- presence of a

self-healing skin eruption of erythematous papules and nodules that may become haemorrhagic, necrotic, and/or ulcerative

While individual lesions take weeks to several months to resolve, the disease may recur for decades and is highly variable

Patients should be monitored lifelong since 2-25% of patients develop second lymphoma such as Hodgkin lymphoma or anaplastic large cell lymphoma

MICROSCOPIC FEATURES

Type A lymphomatoid papulosis

Borderline cases Borderline cases- those in which a difference between the clinical

and histologic appearance exists. Include cases with the clinical presentation of a CD30+ CALCL

but histologic features suggestive of LyP, and, conversely, cases with a recurrent, self-healing skin eruption that shows histologic features characteristic of a CD30+ CALCL.

The distinction between LyP and CD30+ CALCL is not always possible based on histologic criteria.

LyP type C has been described as a borderline lesion of CD30+ CALCL.

Thus, the clinical appearance and the clinical course over time are used as decisive criteria for the definitive diagnosis and choice of treatment.

PRIMARY CUTANEOUS AGGRESSIVE EPIDERMOTROPIC CD8+ CYTOTOXIC

T-CELL LYMPHOMA Provisional category in WHO-EORTC clasification Characterised by CD8+ cytotoxic epidermotropic T cell

infiltrates CLINICAL FEATURES- mean age- 53 yrs ulcerated and necrotic eruptive papules, nodules, and

tumors with frequent dissemination to other visceral sites- lungs,testis,CNS,oral mucosa

Lymph nodes – typically spared

Aggressive course. Mean survival – 32 months

MICROSCOPIC FEATURES- Medium to large pleomorphic cells; pronounced epidermotropism.

Epidermis often ulcerated + necrotic keratinocytes+ spongiosis

IMMUNOPHENOTYPICALLY- βF1+, CD3+, CD8+, granzyme B+, perforin+,TIA-1+ and CD4-.

MOLECULAR GENETICS-clonal TCR gene rearrangements are present in most of cases

PRIMARY CUTANEOUS CD4+ SMALL AND MEDIUM SIZED PLEOMORPHIC

T-CELL LYMPHOMA

Provisional category

Small to medium sized pleomorphic CD4+ CTCL without a history of classic patches and plaques of MF and a favorable clinical course

CLINICAL FEATURES-mean age- 69 yrs solitary nodule on the face, upper arms, or trunk is common. Patients may also present with multiple papules or nodules, but lack patches or plaques.

MICROSCOPIC FEATURES- diffuse growth pattern in dermis or subcutis; epidermotropism focal and inconspicous; neoplastic infiltrate is accompanied by mixed inflammatory infiltrate.

IMMUNOPHENOTYPICALLY- CD4+ CD8- Loss of CD2, CD3, CD5. CD30-

SUBCUTANEOUS PANNICULITIS –LIKE T-CELL LYMPHOMA( α β TYPE) Subcutaneous panniculitis-like T-cell lymphoma

(SPTCL) is defined as a rare lymphoma that (a) primarily infiltrates subcutaneous tissue; (b) shows high-grade cytologic features; (c) is composed of T cells with a cytotoxic phenotype

It only consists of cases with α β + T cell phenotype; cases with γδ T cell phenotype are included in separate category

CLINICAL FEATURES- subcutaneous nodules and plaques, usually on the legs or trunk. Systemic symptoms and signs, when present, may relate to

hemophagocytic syndrome with pancytopenia, fever, and hepatosplenomegaly usually in the absence of lymphadenopathy

MICROSCOPIC FEATURES

diffuse, variably cellular infiltrate involving both septae and lobules within the subcutis; sparing of dermis; INFILTRATE- smaller lymphocytes with visible cytoplasm admixed with larger transformed cells with hyperchromatic nuclei

Rimming of individual adipocytes by neoplastic T cells -characteristic, but not specific, feature

IMMUNOPHENOTYPING

CD3+, CD4-, CD8+,CD5+,TIA+,granzyme B +

MOLECULAR GENETICS- clonal TCR rearrangement in 50% cases

TIA-1 immunohistochemistry showing characteristic rimming about individual adipocytes.

CUTANEOUS γ/δ T-CELL LYMPHOMA

Provisional category CLINICAL FEATURES- eroded to ulcerated patches,

deep tumours located on extremities of adults. Constitutional symptoms usually present Mucosal and extranodal sites frequently involved Bone marrow, lymph nodes, and spleen are spared Highly aggressive course

MICROSCOPIC FEATURES-can be predominantly epidermotropic, dermal, or subcutaneous.

Subcutaneous infiltrates show rimming of neoplastic cells around individual adipocytes, similar to subcutaneous panniculitis–like T-cell lymphoma, but dermis and/or epidermis also are involved

IMMUNOPHENOTYPE CD3+, CD56+, granzymeB+, TIA-1+, CD4 −, CD8−, CD5−, and βF1−

MOLECULAR GENETICS- Clonal rearrangement of the TCR-γ gene occurs

ADULT T-CELL LEUKEMIA/LYMPHOMA

Develops in a small minority individuals with prolonged infection with human T-cell leukemia virus type 1 (HTLV-1)

MICROSCOPIC FEATURES-a superficial or diffuse infiltrate of pleomorphic multinucleate T lymphocytes with prominent epidermotropism is seen.

Lesion may be indistinguishable from mycosis fungoides

IMMUNOPHENOTYPE- CD3+,CD4+,CD8-, CD25+ MOLECULAR GENETICS- Clonal rearrangement of

the TCR genes and clonal integration of HTLV-1 occur

EXTRANODAL NATURAL KILLER/T-CELL LYMPHOMA,NASAL TYPE

Rare variant Neoplastic cells are NK cell phenotype, can be cytotoxic T cell derived

and are always EBV positive. CLINICAL FEATURES-multiple ulcerated plaques and nodules

typically distributed on the trunk or extremities. Accompanying systemic symptoms are common.

MICROSCOPIC FEATURES-Medium-sized pleomorphic lymphocytic infiltrates are present in the dermis and subcutis and show prominent localization and destruction of blood vessels. Apoptosis and necrosis are conspicuous.

IMMUNOPHENOTYPE-CD2+, CD56+, surfaceCD3−, TIA-1+, granzyme B+, perforin+, and EBV+

CUTANEOUS B CELL LYMPHOMA

WHO/EORTC CLASSIFICATIONCUTANEOUS T- cell and NK- cell Lymphomas1. MYCOSIS FUNGOIDES (MF)2. MYCOSIS FUNGOIDES VARIANTS AND SUBTYPES: a) Folliculotropic MF b) Pagetoid reticulois c) Granulomatous slack skin

3. SEAZARY SYNDROME4. ADULT T- cell LYMPHOMA5. PRIMARY CUTANEOUS CD30+ LYMPHOPROLIFERATIVE DISORDERS a) Primary cutaneous anaplastic large cell lymphoma (cALCL) b) Lymphomatoid papulosis

6. SUBCUTANEOUS PANNICULITIS LIKE T CELL LYMPHOMA7. EXTRANODAL NK/T- cell LYMPHOMA, NASAL TYPE8. PRIMARY CUTANEOUS PERIPHERAL T- cell LYMPHOMA, UNSPECIFIED a) Primary Cutaneous Aggressive Epidermotropic CD8+ T- Cell Lymphoma b) Cutaneous γ/ δ T- Cell Lymphoma c) Primary Cutaneous CD4+ Small/Medium Sized Pleomorphic T- Cell Lymphoma

CUTANEOUS B-cell LYMPHOMAS1. Primary cutaneous follicle centre lymphoma

2. Primary cutaneous marginal zone B-cell lymphoma

3. Primary cutaneous diffuse large B-cell lymphoma, leg type

4. Primary cutaneous diffuse large B-cell lymphoma , other

5. Intravascular large B-cell lymphoma

PRECURSOR HEMATOLOGIC NEOPLASMCD4+/CD56+ hematodermic neoplasm (blastic NK cell lymphoma)

PRIMARY CUTANEOUS FOLLICLE CENTRE CELL LYMPHOMA

Neoplasm derived from follicular centre B cells including centrocytes (cleaved follicular centre cells) and centroblasts (non cleaved follicular centre cells) Most common typeCLINICAL FEATURES – middle age men

one to several red- to plum-colored plaques, nodules or tumours;Head and neck or upper trunk;

MICROSCOPIC FEATURES

cutaneous infiltrates are nodular or diffuse, usually sparing the epidermis.

nodules are similar to germinal centers of lymph nodes; monomorphic neoplastic cells; devoid of mantle zone; no tingible body macrophages are present

Early lesions are mostly centrocytic, containing cells with small to large cleaved nuclei, with fewercentroblastic cells, which are large and contain prominent nucleoli

IMMUNOPHENOTYPING- CD20, CD79a, bcl-6

CD 20 STAINING BCL-6 STAINING NEGATIVE FOR MUM-1

Weak heterogeneous expression of Bcl-2 CD 21 highlighting FOLLICULAR DENDRITIC CELLS meshwork

PRIMARY CUTANEOUS DIFFUSE LARGE B CELL LYMPHOMA,LEG TYPE Predominance of centroblasts and immunoblasts. CLINICAL FEATURES- usually women of 70 years Red to blue nodules on leg Has poor prognosis

MICROSCOPIC FEATURES

Diffuse dense non epidermotropic monotonous infiltrates of predominantly medium to large cells with round nuclei, prominent nucleoli and frequent mitosis resembling centroblasts, large centrocytes, immunoblasts.

IMMUNOHISTOCHEMISTRY

CD 20 STAINING IRF4/MUM1 STAINING + BCL2 STAINING +

These are in contrast to follicular centre cell lymphoma of head and neck

PRIMARY CUTANEOUS MARGINAL ZONE B CELL LYMPHOMA

Lymphoma of small lymphoplasmacytoid cells, small lymphocytes, and plasma cells with monotypic cytoplasmic Ig.

In 2008 WHO classification, marginal zone lymphomas of skin are grouped into broader category of extranodal marginal zone lymphoma of mucosa associated lymphoid tissues(MALT lymphomas)

CLINICAL FEATURES- solitary or multiple cutaneous or subcutaneous tumors on the trunk and extremities

MICROSCOPIC FEATURES

nodular or diffuse infiltrates of small lymphoplasmacytoid cells, small lymphocytes, and plasma cells are present that can be associated with centrocytes and centroblasts.

Cell of origin – post germinal centre marginal zone B cell

MICROSCOPIC FEATURES

Reactive B cells follicles

Neoplastic cells infiltration in marginal zone distribution

MICROSCOPIC FEATURES

Atypical neoplastic cells have irregular nuclear contours and slightly dispersed chromatin

Some proliferations are composed of cells with abundant clear cytoplasm imparting a monocytoid appearance

IMMUNOHISTOCHEMISTRY

CD 20+ BCL 2+

NEGATIVE FOR CD5, CD 10 and BCL 6

INTRAVASCULAR LARGE B CELL LYMPHOMA

Intravascular B-cell lymphoma with a relatively poor survival rate at 5 years, especially if sites other than skin are involved.

CLINICAL FEATURES-violet patches and plaques on the legs and trunk, often thought to be subcutaneous

MICROSCOPIC FEATURES-dermal and subcutaneous blood vessels are dilated and stuffed with tumor cells that are somewhat pleomorphic

IMMUNOPHENOTYPICALLY-cells are CD20+ and CD79a+, with monotypic surface Ig

SECONDARY B CELL LYMPHOPROLIFERATIVE DISORDERS AFFECTING SKIN

PRECURSOR B CELL LYMPHOBLASTIC LYMPHOMA

Lymphoblastic lymphomas may be of either B or T cell lineageAlthough majority of systemic lymphoblastic lymphomas are of T cell lineage, but its B cell lineage lymphomas which show tendency for cutaneous involvement

CLINICAL FEATURES- <35 years head and neck

MICROSCOPIC FEATURES

Nodular or diffuse dermal infiltrate; mitotically active lymphoblasts with convoluted nuclei containing finely stippled chromatin and inconspicious nucleoli

IMMUNOHISTOCHEMISTRY

Precursor B cell Neoplastic cells lack surface immnoglobulin expression May harbour cytoplasmic μ chain + TdT, CD79a, CD19, CD 10 MOLECULAR GENETICS Favorable prognosis: hyperdiploidy >50 chromosomes Unfavorable prognosis: hypodiploidy, t(9;22), t(4;11)

t(1;19)

CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA

Most common mature B cell neoplasm to secondarily involve skin- leukaemia cutis

CLINICAL FEATURES- older adults; M:F- 2:1 Leukaemia cutis occurs in patients with established

CLL/SLL May produce localized or disseminated erythematous

plaques, papules or nodules

MICROSCOPIC FEATURES

May be angiocentric pattern, interstitial pattern and mixed nodular/diffuse pattern

Epidermis and papillary dermis uninvolved- typical grenz zone seen

Diffuse, cellular infiltrate composed of uniform populationsof small lymphocytes containing rounded, hyperchromatic nucleiwith inconspicuous nucleoli.

IMMUNOHISTOCHEMISTRY

+ ve CD 19, CD5, CD79a, CD23, CD43 -ve CD 10 , cyclin D1

NODAL FOLLICULAR LYMPHOMA

Low grade neoplasm of centrocytes and centroblasts (follicular centre cells)

CLINICAL FEATURES- >59 years head and neck

MICROSCOPIC FEATURES

The dermis is replaced by nodules of neoplastic cells that resemble germinal centers but lack mantle zones.

IMMUNOHISTOCHEMISTRY

Cell of origin – germinal B cell + surface immunoglobulin, BCL2 , CD 10, CD 19,

CD 20, CD22 -ve CD5 , CD43 MOLECULAR GENETICS- t(14;18)

MANTLE CELL LYMPHOMAB cell neoplasm of uniform populations of small to medium sized lymphocytes – resemble centrocytes

CLINICAL FEATURES- middle aged to older Disease is usually advanced at time of detection (stage III or

IV) and generally affects lymph nodes, spleen, bone marrow with or without peripheral blood involvement, and gastrointestinal tract

Involvement of skin – rare Cutaneous MCL more aggressive than PCFCL or

plasmacytoid B-CLL/SLL . Median survival – 3-5 years

MICROSCOPIC FEATURES

vaguely nodular to diffuse infiltrate composed of small- to medium-sized lymphocytes.

IMMUNOHISTOCHEMISTRY

Peripheral B cell of inner mantle zone

CD 20 +

+VE CD5, CD43, BCL2, Cyclin D1-ve CD 10 , CD23

MOLECULAR GENETICS-t(11;14) involving cyclin D1 gene and immunoglobulin heavy chain locus

DIFFUSE LARGE B CELL LYMPHOMA,NODAL TYPE

Aggressive lymphoma Diffuse tissue infiltration by monotonous populations of

large histiocytoid malignant lymphocytes Associated with EBV CLINICAL FEATURES- median age 70 years occasionally children also affected red to purpuric nodules

MICROSCOPIC FEATURES

Dermis is diffusely effaced by a destructive infiltrate causing effacement of pre-existing structures

Infiltrate is composed of large neoplastic lymphocytes resembling centroblasts

IMMUNOHISTOCHEMISTRY Peripheral germinal centre or post germinal

centre B cell CD19, CD20, CD22, CD79a

INTRAVASCULAR LARGE B CELL LYMPHOMA

Considered rare subtype of DLBCL Intraluminal aggregates of large malignant B cells

within vessels of involved tissues CLINICAL FEATURES- adults Widely disseminated with involvement of extranodal

tissues including skin red plaques and nodules

MICROSCOPIC FEATURES

Superficial dermal vessels are partially occluded by hyperchromatic malignant cells.

malignant-appearing lymphocytespartially adherent to the endothelial surface of involved vessels.

IMMUNOHISTOCHEMISTRY

Peripheral germinal centre or post germinal centre origindefective homing receptors CD11a/ CD18 impaired diapedesis intravascular accumulation

+ve CD20, CD5, CD10

PRECURSOR: CD4+/CD56+ HEMATODERMIC NEOPLASM

(BLASTIC NK CELL LYMPHOMA)

Rare aggressive neoplasm Once thought to have an NK cell origin, but now it

is believed to be derived from plasmacytoid dendritic cells.The neoplastic cells characteristically coexpress CD4 and CD56 without B-, T-, and NK-cell or myeloid lineage-specific markers

CLINICAL FEATURES-cutaneous lesions that typically are solitary or localized nodules or tumors in elderly men.

MICROSCOPIC FEATURES dermal infiltrate of monotonous medium-sized cells

with blastoid morphology is present regular nuclear contours, dispersed chromatin, and small, distinct nucleoli

Mitoses are frequent, but angiodestruction and necrosis are not seen

IMMUNOPHENOTYPING

CD 4+ CD 56 + CD 123 +

MPO –ve Also –ve for CD3, CD33

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