1. CUTANEOUS
PSEUDOLYMPHOMA
SHAHIN HAMEED

2. DEFINITION
Cutaneous pseudolymphoma is defined by the
WHO as a reactive polyclonal benign
lymphoproliferative disease, predominantly
composed of either B-cells or T-cells, localised
or disseminated.

3. 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’)

4.  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.

5. SPECIFIC DISEASES THAT CAN
MIMIC CUTANEOUS
LYMPHOMA

6. EPITHELIAL NEOPLASMS:
Tumours such as neuroendocrine carcinoma
(Merkel cell tumour), neuroblastoma and
primitive neuro-ectodermal tumour can mimic
cutaneous lymphoma.
Epidermal involvement in Merkel cell tumour
can result in intra-epithelial collections of
cells that mimic Pautrier micro-abscesses in
CTCL

7. LYMPHOCYTE-RICH
EPITHELIAL NEOPLASMS
Classically these include eccrine
spiradenoma and lympho-epithelioma-like
carcinoma of the skin.
A more recent entity is cutaneous lymph-
adenoma, although increasingly this is
regarded as a trichoblastoma with
adamantinoid features

8. CUTANEOUS LYMPHADENOMA
There is outer palisading of cells, focally with clear-cell
change, within a loose fibrous stroma. There is also focal pigment
and a possible papillary mesenchymal body (lower left edge).
Numerous intraepithelial lymphocytes are present, characteristic of
this lesion.

9. IMMUNE RESPONSE TO EPITHELIAL
DYSPLASIA OR MALIGNANCY AND
OTHER NEOPLASMS
Cutaneous neoplasms such as basal cell
carcinoma, malignant melanoma and
dermatofibroma can elicit extremely
strong lymphocytic stromal responses, in
which the underlying neoplasm can be
difficult to identify.
Lymphomatoid variants of actinic
keratosis and benign lichenoid keratosis
(lichen planus-like keratosis) exist.

10. DISEASES SEEN
UNCOMMONLY IN THE SKIN
 Include
 Extramedullary haemopoiesis,
 Malakoplakia,
 Whipple’s disease
 Ectopic thymus
 Rosai-Dorfman disease
 Inflammatory pseudotumour,
 Castleman’s disease and
 Kikuchi’s disease.

11.  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.

12. CUTANEOUS ROSAI-DORFMAN DISEASE
displaying large atypical histiocytes

13.  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

14.  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.

15.  KIKUCHI’S DISEASE:
 Display the characteristic features of
necrosis, karyorrhexis, apoptosis, immu
noblasts and plasma cells.
 Exclude possibility of lupus
erythematosus.

16. CLASSICAL DERMATOSES
Many classic dermatoses mimic lymphoma and
this is particularly frequent with autoimmune and
connective tissue disorders.
1. Lupus erythematosus
2. Lichen sclerosus
3. Pigmented purpuric dermatosis and lichen
aureus
4. Lymphomatoid dermatitis/eczema
5. Lymphotoid folliculitis
6. Acne rosacea

17. 7. Angiolymphoid hyperplasia and Kimura’s
disease
8. Chronic photodermatoses
9. Perniosis (chilblains)
10. Annular erythemas
11. Traumatic ulcerative granuloma
(eosinophilic ulcer/granuloma of the
tongue)
12. Jessner and Kanof’s lymphocytic
infiltration of the skin

18. 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.

19.  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.

20. 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

21. 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.

22. 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

23. 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.

24. ACNE ROSACEA
 Characterised by follicular interface
changes which, together with a paucity of
granulomas, can mimic early stages of
follicular CTCL.

25. 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.

26. 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

27.  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.

28. 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.

29. ANNULAR ERYTHEMAS
 Especiallyerythema annulare centrifugum
can mimic lymphoma with dense
perivascular collection of lymphocytes.

30. TRAUMATIC ULCERATIVE GRANULOMA
(EOSINOPHILIC ULCER/GRANULOMA OF THE
TONGUE)
 Located on the tongue, this entity can
contain eosinophils and blast cells
mimicking lymphoma.

31. 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.

32.  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.

33.  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.

34. SPECIFICALLY NAMED CUTANEOUS
PSEUDOLYMPHOMAS

35. 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.

36.  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).

37. 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.

38. PSEUDOLYMPHOMA OF
HAEMOTOLOGICAL DISEASE
Syn: 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.

39.  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.

40. EXOGENOUSCAUSES OF CUTANEOUS
PSEUDOLYMPHOMATUS REACTION

41. 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.

42. 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.

43.  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

44. 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.

45.  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.

46. 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.

47. INSECT-BITE REACTION DISPLAYING NUMEROUS
EOSINOPHILS

48. 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

49.  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.

50. METALS AND PIGMENT
 Reported most commonly against metal-
based pigment in tattoos and the metals
in earrings and acupuncture.

51. ETHNIC SCARIFICATION/FEMALE
GENTIAL MUTILATION
 Cutaneous pseudolymphomatus reactions
can follow this procedure.

52. SILICONE
 Associated with entry of silicone into
soft tissue and skin
 Describedfollowing silicone injection for
both breast and genital enlargement.

53. OTHER CELL TYPES THAT CAN MIMIC
CUTANEOUS LYMPHOMA

54. 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.

55.  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.

56. 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.

57. 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
.

58. HISTOLOGICAL PATTERNS OF CUTANEOUS
PSEUDOLYMPHOMATOSUS REACTIONS

59.  Patterns can be divided into:
 Morphological,
 Cellular and cytological type
 Based on immunohistochemistry

60. 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.

61. 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.

62.  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.

63. PSEUDO-PAUTRIER ABSCESS

64. 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.

65. 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

66.  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.

67.  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.

68. CD30-positive lymphocytes in a cutaneous drug eruption

69. THE EVOLUTION OF HISTORICAL
CUTANEOUS PSEUDOLYMPHOMA INTO
LYMPHOMA OR LYMPHOID
HYPERPLASIA

70. HISTORICAL PERSPECTIVE OF
CUTANEOUS 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.

71.  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..

72. 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.

73.  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.

74. 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.

75.  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.

76.  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.

77. 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.

78.  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.

79. 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.