DEFINITIONCutaneous pseudolymphoma is defined by theWHO as a reactive polyclonal benignlymphoproliferative disease, predominantlycomposed of either B-cells or T-cells, localisedor disseminated.
CLINICAL ASPECTS Clinical manifestations are frequently not diagnostic and overlap with lymphoma.Two main problems exist:1. Lesional regression is common in cutaneous lymphoma and accordingly, regression does not necessarily indicate that the lesion is pseudolymphoma.2. Occasional cases of initial cutaneous pseudolymphoma can evolve into lymphoma (so- called ‘pseudo-pseudolymphoma’)
In general, pseudolymphoma is rare on the scalp and never displays clinical poikiloderma. In addition, lesions showing variability in size, shape and colour and occuring in non- exposed skin (such as buttocks) should be regarded as cutaneous T-cell lymphoma (CTCL) until proved otherwise.
SPECIFIC DISEASES THAT CAN MIMIC CUTANEOUS LYMPHOMA
EPITHELIAL NEOPLASMS:Tumours such as neuroendocrine carcinoma(Merkel cell tumour), neuroblastoma andprimitive neuro-ectodermal tumour can mimiccutaneous lymphoma.Epidermal involvement in Merkel cell tumourcan result in intra-epithelial collections ofcells that mimic Pautrier micro-abscesses inCTCL
LYMPHOCYTE-RICH EPITHELIAL NEOPLASMSClassically these include eccrinespiradenoma and lympho-epithelioma-likecarcinoma of the skin.A more recent entity is cutaneous lymph-adenoma, although increasingly this isregarded as a trichoblastoma withadamantinoid features
CUTANEOUS LYMPHADENOMAThere is outer palisading of cells, focally with clear-cellchange, within a loose fibrous stroma. There is also focal pigmentand a possible papillary mesenchymal body (lower left edge).Numerous intraepithelial lymphocytes are present, characteristic ofthis lesion.
IMMUNE RESPONSE TO EPITHELIAL DYSPLASIA OR MALIGNANCY AND OTHER NEOPLASMSCutaneous neoplasms such as basal cellcarcinoma, malignant melanoma anddermatofibroma can elicit extremelystrong lymphocytic stromal responses, inwhich the underlying neoplasm can bedifficult to identify.Lymphomatoid variants of actinickeratosis and benign lichenoid keratosis(lichen planus-like keratosis) exist.
DISEASES SEENUNCOMMONLY IN THE SKIN Include Extramedullary haemopoiesis, Malakoplakia, Whipple’s disease Ectopic thymus Rosai-Dorfman disease Inflammatory pseudotumour, Castleman’s disease and Kikuchi’s disease.
ROSAI-DORFMAN DISEASE: Can herald, co-exist with or follow nodal or systemic disease Its histologic appearance is usefully remembered by the alternative term of histiocytic lymphophagocytic panniculitis. S100 positive Moderate number of plasma cells present and stroma appears sclerotic or storiform.
CUTANEOUS ROSAI-DORFMAN DISEASE displaying large atypical histiocytes
INFLAMMATORY PSEUDOTUMOURS: A spectrum of disease that incorporates plasma cell granuloma and inflammatory myofibroblastic tumour. Former can display germinal centres, plasma cells and fibrosis. The latter displays myofibroblastic proliferation and 2p23 re-arrangement
CASTLEMAN’S DISEASE: especially the plasma cell variant, can present in the skin and in particular the vulva. The identification of human herpes virus type 8 can be helpful.
KIKUCHI’S DISEASE: Display the characteristic features of necrosis, karyorrhexis, apoptosis, immu noblasts and plasma cells. Exclude possibility of lupus erythematosus.
CLASSICAL DERMATOSES Many classic dermatoses mimic lymphoma and this is particularly frequent with autoimmune and connective tissue disorders.1. Lupus erythematosus2. Lichen sclerosus3. Pigmented purpuric dermatosis and lichen aureus4. Lymphomatoid dermatitis/eczema5. Lymphotoid folliculitis6. Acne rosacea
7. Angiolymphoid hyperplasia and Kimura’s disease8. Chronic photodermatoses9. Perniosis (chilblains)10. Annular erythemas11. Traumatic ulcerative granuloma (eosinophilic ulcer/granuloma of the tongue)12. Jessner and Kanof’s lymphocytic infiltration of the skin
LUPUS ERYTHEMATOSUS: (lupus erythematosus panniculitis) Characteristic features include epidermal involvement, germinal centre formation, plasma cells and hyaline necrosis. Cases may be extremely difficult to distinguish from subcutaneous panniculitis-like T-cell lymphoma.
This has resulted in some acceptance of an intermediary entity described as indeterminate lymphocytic lobular panniculitis or atypical lymphocytic lobular panniculitis Lupus erythematosus display localisation on hair follicles mimicking the folliculotropic variant of mycosis fungoides.
LICHEN SCLEROSUS: The interface dermatosis present in lichen sclerosus can closely mimic cutaneous CTCL in early stages. Can display florid, small-to-medium blood vessel lymphocytic vasculitis which closely resembles angiocentric variants of cutaneous lymphoma
PIGMENTED PURPURIC DERMATOSIS AND LICHEN AUREUS Suspicionraised in cases which are persistent or contain atypical cells. Inthese cases, consideration should be given a possible drug-related aetiology.
LYMPHOMATOID DERMATITIS/ECZEMA Described in association with external sensitization, it is now recognised to occur in occasional cases of atopic dermatitis and in particular, those with high IgE levels
LYMPHOMATOID FOLLICULITIS Predominantly in patients under 50 years of age Immunohistochemistry reveals mixed populations of B- and T-cells. Most characteristic diagnostic feature is the presence of moderate numbers of perifollicular antigen-presenting cells which are CD1a and S100 positive. Another feature is the tendency towards spontaneous regression.
ACNE ROSACEA Characterised by follicular interface changes which, together with a paucity of granulomas, can mimic early stages of follicular CTCL.
ANGIOLYMPHOID HYPERPLASIA AND KIMURA’S DISEASE Characterised by large numbers of lymphocytes and / or eosinophilis. Prominent hob-nail endothelial cells with vacuoles in small-to medium sized vessels, and germinal centres are the main diagnostic clues to angiolymphoid hyerplasia Kimura’sdisease can mimic human T-cell lymphotropic lymphoma.
CHRONIC PHOTODERMATOSES Chronic actinic dermatitis (including actinic reticuloid) and polymorphous light eruption are classical mimics of cutaneous lymphoma. Histological clues in chronic actinic dermatitis include dermal fibrosis and multinucleate stromal giant cells Polymorphous light eruption is often associated with edema of papillary dermis
Actinicprurigo recently added to this group and cause diagnostic problems by a high density of B-cells Photodermatoses can display increases in CD8 T-cells but this phenotype can also be present in some variants of CTCL.
PERNIOSIS (CHILBLAINS) An abnormal inflammatory response to cold, seen most frequently in acral locations, but it can occur on the thighs of horse-riders. Mimicked by variants of lupus erythematosus termed chilblain lupus. Both perniosis and chilblain lupus can resemble lymphoma because of dense perivascular collections of lymphocytes.
ANNULAR ERYTHEMAS Especiallyerythema annulare centrifugum can mimic lymphoma with dense perivascular collection of lymphocytes.
TRAUMATIC ULCERATIVE GRANULOMA (EOSINOPHILIC ULCER/GRANULOMA OF THE TONGUE) Located on the tongue, this entity can contain eosinophils and blast cells mimicking lymphoma.
JESSNER AND KANOF’S LYMPHOCYTIC INFILTRATION OF THE SKIN Lesions are usually on the face and discoid in nature. Papules expand peripherally but clear in centre and give rise to a circinate appearance. Spontaneous remission can occur but remission in weeks, months, or longer.
Histologically, mild perivascular and peri- adnexal lymphocytic infiltrate. There should be no involvement of the epidermis and oedema of papillary dermis appears frequent. Immunohistologysuggested increased dermal CD8 lymphocytes but no HLA-DR expression. This contrasts with lupus erythematosus which has fewer CD8 lymphocytes and greater HLA-DR expression.
Some studies highlighted the presence of so- called plasmatoid monocytes. The entity may overlap with polymorphous light eruption or lupus erythematosus. The entity has been described in HIV positive patients and occasionally, as a drug reaction.
ACRAL PSEUDOLYMPHOMATUS ANGIOKERATOMA OF CHILDREN (APACHE) First described in children on the extremities of arms and legs and often multiple and unilateral. Histologically, it is characterised by prominent postcapillary venules and a moderately dense lymphocytic infiltrate.
The cellular infiltrate may show interface changes with the epidermis and immunohistochemistry reveals mixed populations of B- and T-cells There appears to be overlap with the entity of papular angiolymphoid proliferation with epithelioid features (PALEFACE).
SOLITARY PSEUDO T-CELL LYMPHOMA Characterised by mixed populations of B- and T- cells, an increase in CD8 T-cells and the presence of histiocytes. Thereappears to be some overlap wit lymphomatoid benign lichenoid keratosis.
PSEUDOLYMPHOMA OF HAEMOTOLOGICAL DISEASESyn: insect-bite like reaction or eosinophilic eruption of haematological disease Initially recognized that mosquito bites in patients with chronic lymphocytic leukemia could be associated with florid cutaneous responses. This was followed by reports of insect bite like reaction in patients with CLL but no apparent history of insect bite.
More recently, this pseudolymphotamous reaction has been reported in patients with mantle zone lymphoma and in association with HIV infection. The entity is generally considered to have an association with altered immunity.
EXOGENOUSCAUSES OF CUTANEOUSPSEUDOLYMPHOMATUS REACTION
DRUGS List of drugs causing pseudolymphomatous reactions is extensive and can be usefully remembered by the prefix (anti-). Anti depressants, anticonvulsants, antihypertensives, anti biotics, anti-inflammatory and antihistamines. To this can be added calcium-channel blockers, lipid lowering drugs, colony stimulating factors, interleukins and inhibitors against tyrosinase and tumour necrosis factors.
VIRAL INFECTIONS In association with molluscum contagiosum, herpes simplex and varicella-zoster virus, parapox, cowpox, Epstein-Barr virus, human T-cell lymphotropic virus and HIV.
Molluscum contagiosum and herpes viruses appear to show a specific tendency for follicular reactions. HIV can manifest with a pseudolymphomatous interface dermatosis which is CD8 prominent
BACTERIAL INFECTIONS Associated with infections by spirochaetes including Borrelia burgdorferi and Treponema pallidum The cutaneous reaction to borrelia is specifically termed borrelia lymphocytoma and occurs in young patients with frequent involvement of earlobes, nipple or genitals.
Histological reaction has a pronounched B- cell component, which can mimic marginal zone or follicular centre lymphoma. Germinal centres can appear enlarged, irregular and have no mantle zone. Blast–cell numbers can be increased significantly Histiocytes and granulomas can be present and infiltrate can be of so-called ‘bottom- heavy’ distribution.
PARASITES AND OTHER EXTERNAL ORGANISMS Includes scabies and bites from many organisms, including scorpions, spiders and leeches. Initiate a reaction which is eosinophil rich with both B and T-cell.
ANTIGEN INJECTIONS Occurs frequently with vaccinations containing aluminium hydroxide Histiocytes display a characteristic purple-grey cytoplasm and particulate aluminium can be identified in some cells at high power magnification. Histochemical stains for aluminium are positive and aluminium can be identified on X-ray micro-analysis
Histological appearance can be variable and display patterns mimicking marginal zone lymphoma, granuloma annulare, lupus erythematosus or fat necrosis. Pseudolymophomatous reactions have been reported following desensitising procedures for pollen, dust and house mites.
METALS AND PIGMENT Reported most commonly against metal- based pigment in tattoos and the metals in earrings and acupuncture.
ETHNIC SCARIFICATION/FEMALE GENTIAL MUTILATION Cutaneous pseudolymphomatus reactions can follow this procedure.
SILICONE Associated with entry of silicone into soft tissue and skin Describedfollowing silicone injection for both breast and genital enlargement.
OTHER CELL TYPES THAT CAN MIMIC CUTANEOUS LYMPHOMA
PLASMA CELLS Prominent in certain infective and autoimmune /connective tissue disorders, to mimic cutaneous lymphoma. Applied particularly to spirochaete and Leishmania spp.infections and connective tissue disorders such as lupus erythematosus, morphoea and necrobiosis lipoidica.
Prominent in cutaneous manifestations of Castleman’s disease and represent a significant cellular component in stromal response to epidermal dysplasia and malignancy. Cutaneous plasmacytosis and cutaneous angioplasmocellular hyperplasia are 2 examples of reactive plasma cell proliferation. Distinction from neoplastic proliferation depends largely on the absence of a monoclone on immunohistochemistry and also genotypic analysis.
HISTIOCYTES Interstitial granulomatous disease is characterized by the presence of palisaded neutrophilic and granulomatous infiltrates with focal collagen degeneration. Can present as either a drug eruption or in association with autoimmune /connective tissue diseases, such as rheumatoid arthritis or lupus erythematosus.
ANTIGEN-PRESENTING CELLS Reactive Langerhans’ cells can show prominence in numerous classical dermatoses. For example, they can become prominent within the epidermis in eczema/dermatitis and mimic Pautrier abscesses as in CTCL. Inaddition, intra-epidermal Langerhans’ cells can become so prominent in CTCL that they can mimic Langerhans cell histiocytosis .
HISTOLOGICAL PATTERNS OF CUTANEOUS PSEUDOLYMPHOMATOSUS REACTIONS
Patterns can be divided into: Morphological, Cellular and cytological type Based on immunohistochemistry
MORPHOLOGICAL PATTERNS The main types described are those involving the epidermis (epidermotrophic), dermis (non- epidermotropic), follicular (with or without follicular mucinosis), subcutaneous and vascular. In general, an epidermotrophic infiltrate will have a significant T-cell component, whereas other patterns can be of T-cell, B-cell or mixed type. The pattern focused on blood vessels is specifically termed a lymphomatoid vascular reaction and is particularly associated with drug reactions, lupus erythematosus and varicella-zoster virus reaction.
CELLULAR AND CYTOLOGICAL PATTERNS LYMPHOMATOID: when cellular density and or nuclear atypia is pronounched or when features of mycosis fungoides are present. Entities include lymphomatoid dermatitis and lymphomatoid actinic and benign lichenoid keratosis.
PSEUDO-PAUTRIER ABSCESSES: represent situations where the number of antigen-presenting cells is substantially in excess of lymphocytes present. Also known as Langerhans’ cell microgranulomas. Seen in common dermatoses. ADIPOCYTE RIMMING: The rimming of adipocytes by lymphocytes in subcutaneous fat is observed in subcutaneous panniculitis-like T-cell lymphoma, lymphocytic lobular panniculitis and especially lupus erythematosus panniculitis.
IMMUNOPHENOTYPIC PROFILES Panor subset T-cell antigen loss can be a feature of CTCL but can be seen in reactive T-cell disorders. CD56 is used to identify CD56-positive natural killer/T-cell lymphomas. The CD15 antigen was initially associated with the descriptions of Hodgkin’s lymphoma. However treatment with agents like colony stimulating factors can be associated with a cutaneous pseudolymphomatus reaction with CD15 positivity.
CD30 – POSITIVE PSEUDOLYMPHOMA CD30 was associated with early immunophenotypic developments in Hodgkin’s lymphoma. This was quickly extended into the area of cutaneous CD30-positive T-cell lymphoproliferative disorders including lymphomatoid papulosis and anaplastic large cell lymphoma. CD30 positivity can be associated with activation of other cell types like those of B-cell, natural killer cell and myeloid lineage and additional natural tissue such as decidua and some non-lymphoid mesenchymal and epithelial tumour
Reactive CD30-positive T-cells can occur in drug eruptions, viral infections, tuberculosis and scabies. CD30-positive cells can be large, atypical & clustered and represent over 75% of cell population in some viral infections and scabies. CD30-positiveT-cells should be regarded as potentially occuring in any cutaneous inflammatory condition and their final interpretation based on overall histologic appearance & clinical setting.
CD30-positive decidua can mimic CD30- positive anaplastic large cell lymphoma. CD30-positive cells amongst neutrophils, as in ruptured follicular cysts and hidradentitis suppurativa, can mimic the neutrophil-rich variant of CD30- positive anaplastic large cell lymphomas.
CD30-positive lymphocytes in a cutaneous drug eruption
THE EVOLUTION OF HISTORICALCUTANEOUS PSEUDOLYMPHOMA INTO LYMPHOMA OR LYMPHOID HYPERPLASIA
HISTORICAL PERSPECTIVE OFCUTANEOUS PSEUDOLYMPHOMA Kaposi and Spiegler published independently on cutaneous lymphoid infiltrates Their descriptions were those of either single or multiple sarcomatous-like skin lesions, referred to as sarcoids. Some cases regressed and were associated with a good prognosis, whereas others spread and cause death. Credit for these observations was given by Darier.
Although Kaposi and Spiegler described both fatal and non-fatal cases, authors over the next 70 years focussed on the latter. Although meaning the same disease, this resulted in copious different terminology, including: Lymphocytoma Lymphadenosis benigna cutis Cutaneous lymphoplasia Cutaneous lymphoid hyperplasia Large-cell lymphocytoma Reactive pseudolymphoma The term ‘pseudolymphoma of Spielger-fendt’ advocated by Lever, erroneously applied the rubber stamp of benign to this group of disorders..
THE ADVENT OF CUTANEOUS MARGINAL ZONE LYMPHOMA Primary cutaneous marginal zone and follicular centre lymphoma now recognized in international lymphoma classification. Advances facilitating the recognition of primary cutaneous marginal zone lymphoma included immunohistochemistry which identified lymphocyte subtypes, immunohistochemical and genotypic methods to assess clonality and finally the recognition of MALT lymphoma in GIT.
Thiswas followed by recognition that MALT lymphoma also existed in skin and some cases could be linked to antigen presentation. Finally, developments in lymphoma classification saw the term MALT lymphoma replaced by marginal zone lymphoma.
CUTANEOUS LYMPHOID HYPERPLASIA Preferred term for reactive/benign lymphoproliferative disorders where no etiological agent is apparent. Based on the presence or absence of epidermal involvement and the phenotypic cell content, they are referred to as either cutaneous T-cell or B-cell predominant lymphoid hyperplasia.
Cutaneous B-cell predominant lymphoid hyperplasia is difficult to distinguish from cutaneous lymphoma because reactive germinal centres and tingible body macrophages can also be seen in primary cutaneous marginal zone lymphoma. In both reactive and neoplastic conditions, lymphoid follicles and germinal centres show similar morphological changes including increased size, asymmetry, loss of polarity, confluence, increased blast-cell numbers and increased mitotic activity.
As morphological appearances are unhelpful, detailed immunohistochemistry should be always undertaken. Significant help and attention should be paid to B-cell distribution, nuclear proliferation ratee and bcl-2 bcl-6 and CD10 status.
CLONAL DERMATITIS AND CLONAL CUTANEOUS LYMPHOID HYPERPLASIA Studies into CTCL, using TCR gene re- arrangement analysis, identified a small number of cases of eczema/dermatitis, in the control population, with T-cell monoclones. This observation formed the basis of a new disease entity called clonal dermatitis. Similar findings were then made in some cases of cutaneous lymphoid hyperplasia and this led to the equivalent term of clonal cutaneous lymphoid hyperplasia.
Clonal dermatitis/clonal cutaneous lymphoid hyperplasia has a low but significant risk of transformation into lymphoma and requires multidisciplinary team discussion, possible staging and follow up with re-biopsy if necessary.
CONCLUSION In the future, molecular abnormalities specific to the diagnosis of primary cutaneous lymphoma may be identified and new methodologies, such as gene expression profiling, will be useful in this extremely difficult area. At the moment, the co-existence of genotypic and cytogenetic abnormalities should heighten the degree of suspicion for lymphoma, as should the presence of monoclones that are persistent, reproducible and of significant size.