Hong Kong J. Dermatol. Venereol. (2010) 18, 190-201

Review Article

Cutaneous lymphoproliferative disorders

NJ Trendell-Smith

Cutaneous lymphoproliferative disorders (CLD) include reactive lymphoid hyperplasias, so calledcutaneous "pseudolymphomas", prelymphomatous conditions and definite malignant lymphomasof low and high grade malignancy. Reactive benign lymphoid proliferations in the skin, eitherlocalized or disseminated, mimicking primary lymphoma have been termed pseudolymphomas(PSL). These either resolve spontaneously or after elimination of the causative factor (e.g. drugs).Cutaneous prelymphomatous ("abortive") disorders (PLD) include a variety of idiopathic chronicdermatoses often unresponsive to topical therapy with persistent T-cell clones that should berecognized by dermatologists. Careful characterization and follow-up of these cases is essentialto ensure accurate diagnosis and to evaluate the potential progression to frank lymphoma. TheWHO-EORTC is the most current and widely used classification of primary cutaneous lymphomasbased on clinical, histological, immunohistochemical, molecular and cytogenetic features.Although these tumours have some morphological features in common with nodal lymphomas,some differ in their behaviour, prognosis and treatment requirements. This article summarizesthe features of cutaneous lymphoproliferative disorders and provides a few case studies asexamples of the major categories of disease.

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WHO-EORTC

Keywords: Cutaneous lymphoma, cutaneous pseudolymphoma, mycosis fungoides, WHO/EORTCclassification of cutaneous lymphomas

WHO-EORTC

Department of Pathology, Queen Mary Hospital,Hong Kong

NJ Trendell-Smith, MBBS, FRCPath

Correspondence to: Dr. NJ Trendell-Smith

Department of Pathology, Queen Mary Hospital, 102Pokfulam Road, Hong Kong

Cutaneous pseudolymphomas (PSL) are benignreactive polyclonal lymphoproliferative processesin the skin that may mimic the appearances oflymphoma clinically and/or histologically. PSL arean heterogeneous group of disorders that providea significant diagnostic challenge for both

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dermatologist and pathologist. Depending onthe predominant cell type PSL are broadlycharacterized as T-cell, B-cell and CD30 positivePSL. PSL may resolve spontaneously, aftercessation of the causative factor (e.g. drugs) orafter non-aggressive treatment.

Although strictly speaking PSL are idiopathic,T-PSL includes conditions such as actinic reticuloid(chronic actinic dermatitis), lymphomatoid drugeruption and lichenoid pigmented purpuricdermatosis. B-PSL includes conditions such aslymphocytoma cutis sometimes associated withBorrelia species, post vaccination or tattoo lesionsand pseudolymphomatous folliculitis etc. CD30-PSL often includes viral infections and infestationssuch as orf-milker’s nodule, molluscumcontagiosum, herpes simplex, EBV, HIV, arthropodbites and nodular scabies etc. Some patterns oflobular panniculitis, particularly lupus profundusmay mimic subcutaneous panniculitis-like T-celllymphoma.1

The diagnosis of primary cutaneous T-celllymphomas, especially mycosis fungoides, maytake many years to become clearly established.Rarely patients experience a variety of distinct pre-lymphomatous conditions (cutaneous T-celllymphoid dyscrasias). This is an evolving conceptwith the more widespread use of T-cell receptorgene rearrangement technology. Such cases mayinclude persistent atypical forms of pigmentedpurpuric dermatoses, follicular mucinosis,pityriasis lichenoides, parapsoriasis, clonalerythroderma, hypopigmented T-cell dyscrasia,atypical lobular panniculitis and syringolymphoidhyperplasia with alopecia in which a morerestricted oligoclonal to monoclonal T-cellrepertoire is demonstrable. These conditionsshould be followed carefully for the possibleprogression to frank, albeit usually low grade,lymphoma.2

Cutaneous B-cell lymphoid dyscrasias are lessclearly described although there may be a linkbetween the presence of certain inciting antigenslike Borrelia species in the progression of B-cell

lymphomagenesis from the benign counterpart oflymphocytoma cutis to primary cutaneous(extranodal) marginal zone B-cell lymphoma.3

T h e d i a g n o s i s a n d c l a s s i f i c a t i o n o fcutaneous lymphoproliferative disordershas undergone major change since the earlydays of pure morphology. The applicationof immunohistochemistry and polymerase chainreaction (PCR) detection of immunoglobulin (IgH)and T-cell receptor (TCR) gene rearrangements inconjunction with detailed clinicopathologicalcorrelation and long term multi-centre follow-upcontinues to finely tune diagnostic criteria.4,5

The skin is the second most common site ofex t ranoda l l ymphomas , fo l low ing thegastrointestinal tract. Some skin lymphomas differfrom their nodal counterparts in a number of waysas illustrated in the WHO/EORTC classificationof cutaneous lymphoma (2005)(Table 1).6

T-cell lymphomas e.g. mycosis fungoides are morecommon than B-cell lymphomas in the skin. Theclassical Alibert type of mycosis fungoides (MF) isnot uncommon, the histological variants ofmycosis fungoides are however rare, difficult todiagnose and include folliculotropic (pilotropic)and syringotropic MF, pagetoid reticulosis andgranulomatous slack skin.7

Cutaneous CD30 positive lymphoproliferativedisorders are a spectrum of disease from waxingand waning lymphomatoid papulosis to persistentALK negative primary cutaneous anaplastic largecell lymphoma.8

Recent studies show clinical, histological andimmunophenotypic di f ferences betweensubcutaneous panniculitis-like T-cell lymphoma(SPTL) with an alpha-beta to those with a gamma-delta T-cell phenotype suggesting they representdifferent entities. Whereas SPTL with an alpha-beta T-cell phenotype are homogenous with arather indolent clinical behaviour, SPTL with agamma-delta T-cell phenotype overlap with thegamma-delta T/NK cell lymphomas and

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invariably run a very aggressive clinical course.SPTL is now restricted to those lymphomas withan alpha-beta T-cell phenotype.9

Some disorders can be separated out asprovisional entities from the broader group ofperipheral T-cell lymphoma, unspecified (PTL,unspecified) in the WHO classification. Theseinclude the aggressive epidermotropic CD8positive T-cell lymphoma, cutaneous gamma-deltaT-cell lymphoma (including cases formerlydiagnosed as SPTL with a gamma-deltaphenotype) and primary cutaneous small/mediumsized pleomorphic T-cell lymphoma.6

In contrast to nodal follicular lymphoma primarycutaneous follicle centre lymphomas (PCFCL) donot generally express bcl-2 and are not typicallyassociated with the t(14;18) translocation. Mostpatients present with localized skin lesions on thehead and neck or trunk and, regardless of thehistological growth pattern or number of blasts,are highly responsive to radiotherapy and havean excellent prognosis.10

Primary cutaneous diffuse large B-cell lymphoma,leg type (PCLBCL, leg type) affects mostly elderlypeople and has a higher relapse rate and a moreunfavourable prognosis than PCFCL with a diffuse

large B-cell morphology. PCLBCL, leg type has apredominance of centroblasts and immunoblastsrather than large centrocytes, and consistentlystrongly expresses bcl-2 protein and Mum-1/IRF4.11

Clinical cases

Case 1 − Drug associated T-cell pseudolymphoma(T-PSL) (Atypical pigmented purpuric dermatosisassociated with use of both beta-blocker andcalcium channel inhibitor). Male 61, cayennepepper discoloration of lower legs associated withplaque on dorsum of left foot (Figure 1).Photomicrographs showing capillaritis and apattern simulating mycosis fungoides (H&E x 200)(Figure 2). Graph of PCR T-cell receptor gammagene (Figure 3) showing a "reactive" polyclonalpattern.

Case 2 − Cutaneous T-cell lymphoid dyscrasia(Primary idiopathic follicular mucinosis). Female32, solitary tumid erythematous plaque over lefteyebrow with some hair loss (Figure 4) andphotomicrographs showing follicular mucinosiswith mucin highlighted by alcian blue at pH2.5(H&E x 200). Graph of PCR T-cell receptor gammagene (Figure 5) showing a monoclonal patternindicative of persistent T-cell clonality.

Table 1. WHO-EORTC consensus classification of primary cutaneous lymphomas (2005)

Cutaneous T & NKCutaneous T & NKCutaneous T & NKCutaneous T & NKCutaneous T & NK-----cell lymphomascell lymphomascell lymphomascell lymphomascell lymphomas• Mycosis fungoides − Alibert-Bazin, folliculocentric, pagetoid reticulosis, granulomatous slack skin.• Sezary syndrome• Primary Cutaneous CD30+ lymphoproliferative disorders − primary cutaneous anaplastic large cell lymphoma

− lymphomatoid papulosis spectrum.• Subcutaneous panniculitis-like T-cell lymphoma• Extranodal NK/T-cell lymphoma, nasal type• Primary cutaneous peripheral T-cell lymphoma, unspecified − aggressive epidermotropic CD8+ T-cell

lymphoma, cutaneous gamma-delta T-cell lymphoma & CD4+ small/medium sized pleomorphic T-celllymphoma (all provisional entities).

Cutaneous BCutaneous BCutaneous BCutaneous BCutaneous B-----cell lymphomascell lymphomascell lymphomascell lymphomascell lymphomas• Marginal zone B-cell lymphoma• Follicle centre cell lymphoma• Diffuse large B-cell lymphoma, leg type• Diffuse large B-cell lymphoma, other − e.g. intravascular B-cell lymphoma.

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Figure 1. Case 1. Cayenne pepper discoloration oflower legs associated with plaque on dorsum of leftfoot. Figure 2. Case 1. Photomicrographs showing

capillaritis and a pattern simulating mycosis fungoides(H&E x 200).

Figure 3. Case 1. Graph of PCR T-cell receptor gamma gene showing a "reactive" polyclonal pattern.

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Figure 4. Case 2. Solitary tumid erythematous plaque over left eyebrow with somehair loss and photomicrographs showing follicular mucinosis with mucin highlightedby alcian blue at pH2.5 (H&E x 200).

Figure 5. Case 2. Graph of PCR T-cell receptor gamma gene showing a monoclonal pattern indicative ofpersistent T-cell clonality.

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Figure 6. Case 3. Leonine facies with infiltrative'boggy' plaques, eyebrow hair loss and weeping.

Figure 7. Case 3. Photomicrographs showing follicular mucinosis and features of mycosisfungoides with Pautrier microabscesses (H&E x 200).

Case 3 − Mycosis fungoides, folliculotropic variant.Female 44, leonine facies (Figure 6) with infiltrative'boggy' plaques, eyebrow hair loss and weeping.Photomicrographs (Figure 7) showing follicularmucinosis and features of mycosis fungoides withPautrier microabscesses (H&E x 200). Graph ofPCR T-cell receptor gamma gene (Figure 8)showing a monoclonal pattern confirminglymphoma.

Case 4 − Cu t aneou s CD30 po s i t i v elymphoproliferative disorder (primary cutaneousanaplastic large cell lymphoma). Female, age 32with persistent violaceous plaque graduallyincreasing in size over left elbow (Figure 9).Photomicrograph showing diffuse infiltrate ofhighly atypical large mononuclear cells (H&E x200) (Figure 10). Immunohistochemistry (Figure11) showing the tumour cells to be CD30+ andALK -. CD30 positive lymphoproliferative disorders− a spectrum from lymphomatoid papulosis toanaplastic large cell lymphoma (Figure 12).

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Figure 8. Case 3. Graph of PCR T-cell receptor gamma gene showing a monoclonal pattern confirminglymphoma.

Figure 9. Case 4. Persistent violaceous plaquegradually increasing in size over left elbow.

Figure 10. Case 4. Photomicrograph showing diffuseinfiltrate of highly atypical large mononuclear cells(H&E x 200).

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Figure 12. Case 4. CD30 positive lymphoproliferative disorders − a spectrum from lymphomatoidpapulosis to anaplastic large cell lymphoma.

Figure 11. Case 4. Immunohistochemistry showing the tumour cells are CD30+ and ALK-.

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Figure 13. Case 5. Painful deep seatedred nodules over arms, lower legs,thighs and neck & photomicrographsshowing a lymphocy t ic lobularpanniculitis (H&E x 100).

Figure 14. Case 5. Prominent rimming of fat cells by lymphocytes (H&E x200) & immunohistochemistry showing CD8>CD4, TIA-1+, bF1+ (alpha-beta T-cell phenotype), Ki67 5%.

Case 5 − Subcutaneous panniculitis-like T-celllymphoma. Female 26 with low grade fever, nightsweats and 10 lbs weight loss, painful deep seatedred nodules over arms, lower legs, thighs and neck& photomicrographs (Figure 13) showing alymphocytic lobular panniculitis (H&E x 100),

Prominent rimming of fat cells by lymphocytes(H&E x 200) & immunohistochemistry showingCD8>CD4, TIA-1+, bF1+ (alpha-beta T-cellphenotype), Ki67 5% (Figure 14). Graph of PCRof T-cell receptor gamma gene (Figure 15) showinga monoclonal pattern confirming lymphoma.

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Figure 17. Case 6. Photomicrographs showing diffusesheets of monocytoid and centrocyte-like cells in thedermis (H&E x 100 & x 200).

Figure 15. Case 5. Graph of PCR of T-cell receptor gamma gene showing a monoclonal patternconfirming lymphoma.

Figure 16. Case 6. Red to violaceous nodules overleft arm.

Case 6 − Primary cutaneous marginal-zoneB-cell lymphoma. Female 57, red to violaceousnodules over left arm (Figure 16) with nightsweats. Photomicrographs showing diffusesheets of monocytoid and centrocyte-like cells in

the dermis (H&E x 100 & x 200) (Figure 17).Immunohistochemistry (Figure 18) showingtumour cells to be CD20+, CD43+, CD10- &bcl-6-.

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Figure 18. Case 6. Immunohistochemistry showing tumour cells to be CD20+,CD43+, CD10- & bcl-6-.

Figure 19. Case 7. Large persistent nodule on right knee, photomicrographwith a diffuse dermal infiltrate of centroblasts and immunoblasts (H&E x 200).Immunohistochemistry showing tumour cells to be CD20+ (B-cell) & bcl-2+.

Case 7 − Primary cutaneous diffuse largeB - ce l l l ymphoma, l eg t ype . Ma le 59Large pers is tent nodule on r ight knee,photomicrograph with a di f fuse dermal

infiltrate of centroblasts and immunoblasts(H&E x 200). Immunohistochemistry showingtumour cells to be CD20+ (B-cell) & bcl-2+(Figure 19).

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Acknowlegements

I would like to thank dermatology colleagues atQueen Mary Hospital − Drs. Henry Chan and CKYeung for the clinical input & photos; and Dr. LPChung Molecular Pathology, Queen MaryHospital, the University of Hong Kong for generearrangment studies.

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