T cell lymphomatoid contact dermatitis: a challenging … · lation. A skin biopsy showed ... NR NR...

Contact Dermatitis • Review Article CODContact Dermatitis

T cell lymphomatoid contact dermatitis: a challenging case and reviewof the literatureThomas J. Knackstedt1 and Kathryn A. Zug1,2

1Section of Dermatology, Department of Surgery, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03766, USA and2Department of Surgery, Geisel School of Medicine, Dartmouth College, One Rope Ferry Road, Hanover, NH 03755, USA

doi:10.1111/cod.12294

Summary Lymphomatoid contact dermatitis is a pseudolymphoma with clinical and histologi-cal features of allergic contact dermatitis and cutaneous T cell lymphoma. Incorrectdiagnosis may lead to unnecessary testing, unnecessary treatment, or patient harm.The objective of this study is to present a case to demonstrate the diagnostic chal-lenge and overlap between allergic contact dermatitis and cutaneous T cell lymphomain a patient with lymphomatoid contact dermatitis caused by methylchoroisothiazoli-none/methylisothiazolinone and paraben mix, and to review the existing literaturein order to summarize the demographics, clinical features, allergens and treatmentsreported for lymphomatoid contact dermatitis. A search of major scientific databases wasconducted for English-language articles reporting cases of lymphomatoid contact der-matitis or additional synonymous search headings. Nineteen articles with a total of 23patients were analysed. Lymphomatoid contact dermatitis was more common in men,with an average age of 58.5 years. Fourteen unique allergens were identified and con-firmed by patch testing. However, no single test or study was diagnostic of lymphoma-toid contact dermatitis. Allergen avoidance was the most useful management tool, butselected patients required topical or systemic immunosuppression. In conclusion, with-out specific diagnostic features, evaluation for lymphomatoid contact dermatitis shouldinclude a thorough history and examination, patch testing, and biopsy with immunohis-tochemistry and clonality studies.

Key words: allergic contact dermatitis; allergic contact pseudolymphoma; cutaneousT cell lymphoma; lymphomatoid contact dermatitis; mycosis fungoides; patch testing.

Although allergic contact dermatitis and cutaneous Tcell lymphoma are straightforward to diagnose in theirtypical presentations, the features of early disease mayblur the lines between benign-reactive and malignantconditions. A subset of patients present with a benignpseudolymphomatous allergic contact dermatitis with

Correspondence: Kathryn A. Zug, Section of Dermatology, Department ofSurgery, Dartmouth Hitchcock Medical Center, One Medical Center Drive,Lebanon, NH 03756, USA. Tel: +1 603 650 3101; Fax: +1 603 727 7911.E-mail: [email protected]

Funding: None.Conflicts of interests: The authors declare no conflict of interests.

Accepted for publication 15 July 2014

clinical and histological features suggestive of cutaneousT cell lymphoma, but remain responsive to conservativetopical therapy and allergen avoidance. Patch testing,skin biopsies and molecular studies may either aid orhinder in making the correct diagnosis. An incorrectdiagnosis can result in unnecessary testing and treat-ment. We present a patient who shows the diagnosticchallenge and overlap between allergic contact dermati-tis, cutaneous T cell lymphoma, and lymphomatoidcontact dermatitis caused by methylchloroisothiazoli-none (MCI)/methylisothiazolinone (MI) and parabenmix, and review the literature on this topic.

Patient Presentation

A 58-year-old man presented to his local dermatologistwith a 1-year history of a pruritic dermatitis on the right

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons LtdContact Dermatitis, 72, 65–74 65

LYMPHOMATOID CONTACT DERMATITIS: CASE REPORT AND REVIEW • KNACKSTEDT AND ZUG

Fig. 1. Scaly, erythematous patches on the buttocks after the use ofwet wipes containing methylparaben and methylisothiazolinone.

buttock (Fig. 1). He was patch tested (TRUE Test®), andthis showed positive allergens with no apparent corre-lation. A skin biopsy showed an atypical intradermallymphoid infiltrate (CD8+

>CD4+), and clonal T cellreceptor gene rearrangements were identified by poly-merase chain reaction (Fig. 2). The patient was thenreferred to us and diagnosed with localized CD8+ cuta-neous T cell lymphoma stage 1A. Local radiation therapy(30 Gy) was administered with curative intent. Althoughthe lesions initially resolved, a scaly, erythematous patchrecurred in the previously treated site 5 months afterradiation therapy. A repeat biopsy showed a psoriasi-form, spongiotic and patchy lichenoid infiltrate withprominent epidermotropism of mixed CD4+ and CD8+

T cells (CD4+>CD8+) (Fig. 3). Because of a concern

about cutaneous lymphoma relapse and radiation ther-apy failure, T cell receptor gene rearrangement studieswere repeated, but showed no evidence of T cell clonality.Review of the patient’s prior patch testing report from thereferring physician showed the following results. On theD2 reading, paraben mix gave a 2+ reaction and MCI/MIcaused only slight erythema (?+). On the D4 reading,both allergens gave a 2+ reaction. Specific questioningby us revealed the habitual use of wet wipes after toilet-ing. The wipe ingredients included methylparaben and

Fig. 2. Inflammatory infiltrate of atypical lymphocytes in thesuperficial dermis with epidermotropism, first biopsy. (a)Haematoxylin and eosin, ×20. (b) Immunohistochemistryhighlighting CD8+ T cell predominance in the epidermis.

MI. The patient was educated to avoid moist wipes andthe identified positive preservative allergens. His rashsubsequently quickly resolved, and has not recurred.

Methods

In order to review lymphomatoid contact dermatitis, adatabase search for English-language full-text articleswas performed (Fig. 4). Searches were limited to head-ings containing ‘lymphoma or mycosis fungoides andcontact or allergic dermatitis,’ ‘lymphomatoid contactdermatitis’, and ‘allergic contact pseudolymphoma.’Databases used in the search included OVID MEDLINE(1946 to April 2013), CINAHL (1937 to April 2013),and PubMed. All study types and journals were consid-ered for inclusion. Specific data points were extractedand recorded, including: patient age, sex, rash distri-bution, identified allergens with patch test results andsource, potential occupational relationship, routinehistology, immunohistochemistry, T cell receptor gene

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd66 Contact Dermatitis, 72, 65–74


Fig. 3. Psoriasiform, spongiotic and patchy lichenoidinflammatory infiltrate of atypical lymphocytes in the superficialdermis with epidermotropism, second biopsy. (a) Haematoxylin andeosin, ×10. (b) Haematoxylin and eosin, ×20.

rearrangement, and treatment history. If the intensityof the patch test reactions was not identified as 1+, 2+,or 3+, the descriptions of the reactions were interpretedaccording to the grading recommended by the ICDRG (1).Studies with insufficient detail regarding patient age, sex,patch testing results or skin histology were not included.

Results

Ninety-one articles were identified from search head-ings of the database query. Nineteen publications, all incase report or case series format, met the study criteriaand are summarized in Table 1 (2–20). Twenty-threecases of lymphomatoid contact dermatitis were identifiedfrom the reports, dating from 1976 to 2013. Amongthe 23 patient cases, 14 unique allergens were identi-fied. In summary, 16 (69.6%) male and 7 (30.4%) femalepatients were identified, with an average age of 58.5 years(range 34–82 years). Rashes or lesions were localized tothe thighs in 9 (39.1%) cases or to the head and neck

area with equal frequency (39.1%). The buttocks andgroin were the third most common sites of involvement,with 5 (21.7%) cases. Many patients had more than onearea of involvement, or presented with a generalized rashwithout a distinct distribution. According to the ICDRGcriteria, over half (68.1%) had a strong (2+) or extremelystrong (3+) patch test reaction. The remaining patients(31.9%) had a weak (1+) reaction. Positive patch testresults were not described in detail for 2 cases. A clearlink to an occupational allergen exposure was evident inonly 5 (21.7%) cases. Biopsies were performed on everypatient, and the pathology reports described variabledegrees of lymphohistiocytic infiltration, spongiosis,epidermotropism, and cytological atypia. Immunohis-tochemical staining was performed in 10 cases, anddescribed in varying detail (Table 1). T cell receptor generearrangement studies were performed in 11 cases, andwere interpreted as negative, polyclonal, or inconclu-sive. Only 1 case had a positive gene rearrangement.Medical work-up was conservative in most cases, butat times included potassium hydroxide skin preparationexamination for dermatophytes, computed tomographyimaging, bone marrow biopsy, and urine/serum proteinelectrophoresis. Treatment was limited to topical steroidsand allergen avoidance in >80% of the cases. Never-theless, 4 (18.1%) patients received systemic therapies,including oral prednisone, radiation therapy, photother-apy (narrow-band ultraviolet B), or tumour necrosisfactor inhibitors.

Discussion

Pseudolymphoma is a broad term encompassing benignreactive T and B cell lymphoproliferative disorders thatclinically and histologically resemble true lymphomas(15). Lymphomatoid contact dermatitis, which consti-tutes a subset of pseudolymphomas, has been associatedwith contact allergen hypersensitivity, and clinicallyresembles mycosis fungoides. It was first described byOrbaneja et al. in 1976 in 4 patients with biopsies con-sistent with cutaneous T cell lymphoma and patch testspositive for phosphorus sesquisulfide from match box use(19). In 2007, lymphomatoid contact dermatitis receivedsignificant attention from the European dermatological,scientific and regulatory communities because of the ini-tially cryptic widespread outbreak of a severe dermatitisprimarily presenting on the hips, legs, and buttocks. Thissevere eruption primarily affected patients in the UnitedKingdom and Finland, and was termed ‘toxic sofa’ der-matitis; the contact allergen dimethyl fumarate, a mouldinhibitor contained in sachets in the leather furniture,was later identified as the culprit allergen (21). Unfortu-nately, a summary of these cases could not be included in



Fig. 4. Literature search and article selection process.

our analysis, because of insufficient details of the mycosisfungoides-like cases among the numerous initial reports.A number of patients exposed to the furniture developeda severe dermatitis, sometimes resembling mycosis fun-goides, and some patients required hospitalization (21).

Lymphomatoid contact dermatitis is a rare and prob-ably under-reported disease, with only 23 cases havingbeen described in the literature since the term was firstcoined in the 1970s. Among reported cases, lymphoma-toid contact dermatitis was seen more frequently in males,with an average age of 58 years. Interestingly, whereasallergic contact dermatitis is common to all age rangesand is more frequent in women, the age distribution of

lymphomatoid contact dermatitis models that of cuta-neous lymphoma as a disease of the elderly (average agesof 57–80 years), and has a male predominance (22, 23).The reason for this is unclear, but may be an altered andenhanced immune response with age or an increased sus-ceptibility to chronic inflammation. The clinical patternsof presentation of lymphomatoid contact dermatitis andcutaneous T cell lymphoma can also have similarities. Thedistribution of lymphomatoid contact dermatitis on thepelvis, upper legs and buttocks is considered to be classicfor the ‘bathing trunk’ distribution most common to earlymycosis fungoides. Why lymphomatoid contact dermati-tis and cutaneous T cell lymphoma present in this manneris unknown.



Tab

le1.

Lym

phom

atoi

dco

nta

ctde

rmat

itis

case

char

acte

rist

ics

Stud

yYe

ar

(No.

of

patie

nts)

age

in

year

sSe

xLo

catio

nA

llerg

enSo

urce

Patc

h

test

resu

lts∗

Occ

upat

iona

lH

isto

logy

IHC

Clo

nalit

y

stud

ies

Trea

tmen

tC

omm

ents

Orb

anej

a(1

9)19

76(4

)54,

39,4

2,64

MTh

igh,

face

Phos

phor

ous

sesq

uisu

lfide

Mat

chbo

xst

riker

+++

No

Den

sein

filtr

ate,

band

-like

hist

iocy

tes,

lym

phoc

ytes

,eo

sino

phils

,ex

ocyt

osis

,lim

ited

spon

gios

is

NR

NR

Topi

cals

tero

ids

–

Wal

l(2)

1982

44M

Eyel

ids,

thig

h,bu

ttoc

ks,

geni

talia

Ethy

lene

diam

ine

dihy

droc

hlor

ide

Ken

acom

b®

crea

m++

No

Patc

hypa

rake

rato

sis,

psor

iasi

form

acan

thos

is,m

od.

dens

ely

mph

ohis

tiocy

ticin

filtr

ate,

som

epl

asm

ace

lls,

periv

ascu

lar

epid

erm

otro

pism

,so

me

spon

gios

is,

irreg

ular

nucl

ei

NR

NR

Alle

rgen

avoi

danc

e,ny

stat

in,

tria

mci

nolo

ne,

neom

ycin

,gra

mic

idin

,be

tam

etha

sone

vale

rate

0.05

%

Elec

tron

mic

rosc

opy:

larg

eab

norm

ally

mph

ocyt

es,

larg

ece

rebr

iform

nucl

eiK

OH

-neg

ativ

e

Aya

la(3

)19

8762

MTh

igh,

face

Phos

phor

ous

sesq

uisu

lfide

0.5%

pet.

Mat

chbo

x+++

Yes

(far

mer

)M

oder

ate

derm

ally

mph

oid

infil

trat

ew

ithep

ider

mot

ropi

sm,

larg

ein

trae

pide

rmal

Paut

rier

absc

ess-

like

stru

ctur

es,m

arke

dnu

clea

rat

ypia

and

mito

ticfig

ures

NR

NR

Topi

cals

tero

ids

–

Alo

mar

(20)

1989

62M

Low

erle

gs,

gene

raliz

edA

zody

esTr

ouse

rcl

oth

++

No

NR

NR

NR

Pred

niso

ne–

Sche

na(4

)19

9549

MLo

wer

legs

,ge

nera

lized

Cob

alt

naph

then

ate

2%pe

t.M

arbl

efin

ishi

ng++

Yes

(mar

ble

wor

ker)

Diff

use

dens

ein

filtr

ate,

para

kera

tosi

s,so

me

spon

gios

is,f

eweo

sino

phils

,man

ysm

alll

ymph

sw

ithirr

egul

arnu

clei

,few

larg

ece

lls

CD

4+/C

D8+

4:1,

CD

30–

NR

NR

Neg

ativ

eto

coba

ltch

lorid

e1%

pet.

Dan

ese

(5)

1995

58M

Nos

eN

icke

lsul

fate

5%pe

t.G

lass

esw

ithm

etal

fram

e

‘Pos

itive

’N

oPa

rake

rato

sis,

som

esp

ongi

osis

,ly

mph

ocyt

icde

rmal

infil

trat

e

CD

3+,C

D4+

Neg

ativ

eA

llerg

enav

oida

nce,

topi

cals

tero

ids

–

Stra

nsky

(6)

1996

56M

Upp

erch

est,

gene

raliz

edN

icke

lsul

fate

5%pe

t.M

etal

chai

nne

ckla

ce‘P

ositi

ve’

No

NR

NR

NR

NR

NR



Tab

le1.

Con

tinu

ed

Stud

yYe

ar

(No.

of

patie

nts)

age

in

year

sSe

xLo

catio

nA

llerg

enSo

urce

Patc

h

test

resu

lts∗

Occ

upat

iona

lH

isto

logy

IHC

Clo

nalit

y

stud

ies

Trea

tmen

tC

omm

ents

Hou

ck(7

)19

9768

FSh

ould

er,c

hest

Nic

kels

ulfa

te2.

5%pe

t.G

old-

plat

edne

ckla

ce+

No

Supe

rfici

alba

nd-li

kein

filtr

ate,

exoc

ytos

is,

intr

aepi

derm

alm

icro

absc

esse

s,pl

eom

orph

ism

,he

tero

chro

mas

ia,r

are

mito

sis

inly

mph

ocyt

es

NR

NR

Tria

mci

nolo

neoi

ntm

ent

0.1%

Nor

mal

com

plet

ebl

ood

coun

tan

dco

mpl

ete

met

abol

icpa

nel

Flem

ing

(8)

1997

34F

Earlo

beG

old

sodi

umth

iosu

lfate

0.5%

pet.

Earr

ings

++

No

Prom

inen

tde

rmal

oede

ma,

derm

ally

mph

ohis

tiocy

ticin

filtr

ate,

som

epl

asm

ace

lls,f

orei

gnbo

dygi

ant

cells

NR

Neg

ativ

eA

llerg

enav

oida

nce

–

Mar

liere

(9)

1998

(2)8

2,58

1,M

2,F

Tem

ple

IPPD

Rubb

erch

ain

ongl

asse

s++

No

Lym

phoc

ytic

infil

trat

ein

the

uppe

rde

rmis

,so

me

spon

gios

is,

epid

erm

otro

pism

NR

1,PO

S2,

PCA

llerg

enav

oida

nce

–

Cal

zava

ra-P

into

n(1

0)20

0240

MA

xilla

ryfo

lds,

inne

rth

ighs

,scr

otum

,in

guin

alre

gion

p-Ph

enyl

ened

iam

ine

Oil

prod

uct,

blac

kcl

othi

ng

++

Yes

(oil

prod

uct

trad

er)

Para

kera

tosi

s,ac

anth

osis

,ap

opto

ticke

ratin

ocyt

es.

Mod

erat

ely

dens

ely

mph

oid

infil

trat

e,ep

ider

mot

ropi

sm,

lym

phoc

ytes

with

larg

e,hy

perc

hom

atic

and

conv

olut

ednu

clei

CD

2+,C

D3+

,C

D5+

,C

D7+

,C

D8+

>

CD

4+

PCA

llerg

enav

oida

nce,

topi

cala

ndor

alst

eroi

ds

Oil

prod

ucts

(ant

ioxi

dant

s)an

dbl

ack

clot

hes

(azo

dyes

),cr

oss-

reac

tion

Evan

s(1

1)20

0368

MTh

igh

PTBP

Blac

kle

athe

rgl

asse

sca

seca

rrie

din

pock

et

++

No

Flat

teni

ngof

epid

erm

is,

mild

hype

rker

atos

is,

supe

rfific

alin

filtr

ate

with

inte

rfac

ech

ange

,exo

cyto

sis,

cellu

lar

atyp

ia

CD

3+,C

D4+

Neg

ativ

eM

omet

ason

efu

roat

e0.

1%–

Con

de-T

abod

a(1

2)20

0761

FEa

rlobe

Gol

dso

dium

thio

sulfa

te1%

pet.

Earr

ings

+++

No

Der

mal

infil

trat

e,ly

mph

ocyt

es,

mul

tinuc

leat

edgi

ant

cells

with

bire

frin

gent

incl

usio

ns,e

pide

rmis

spar

ed

CD

45+

,CD

3+,

CD

20–

NR

NR

–

Ezze

dine

(13)

2007

58M

Butt

ocks

Teak

,Tec

tona

gran

dis

L.To

ilet

seat

++

No

Aca

ntho

sis,

para

kera

tosi

s,su

perfi

cial

infil

trat

ew

ithfo

cali

nter

face

chan

ges,

exoc

ytos

is,

mild

spon

gios

is,m

ildcy

tolo

gica

laty

pia

CD

3+,C

D4+

,C

D30

–,

CD

56–

Neg

ativ

eA

llerg

enav

oida

nce,

topi

cals

tero

ids

Did

not

reso

lve

with

alle

rgen

avoi

danc

e



Tab

le1.

Con

tinu

ed

Stud

yYe

ar

(No.

of

patie

nts)

age

in

year

sSe

xLo

catio

nA

llerg

enSo

urce

Patc

h

test

resu

lts∗

Occ

upat

iona

lH

isto

logy

IHC

Clo

nalit

y

stud

ies

Trea

tmen

tC

omm

ents

Mar

tinez

-Mor

an(1

4)20

0958

MH

ands

,for

earm

s,ne

ckIP

PDRu

bber

glov

esan

dau

tom

otiv

epe

dal

cabl

es

+++

Yes (m

achi

nist

)Ly

mph

oid

infil

trat

ew

ithm

arke

dep

ider

mot

ropi

sm,

disc

rete

spon

giot

icm

icro

vesi

cula

tion,

larg

e,hy

perc

hrom

atic

,co

nvol

uted

nucl

ei

CD

3+,C

D4+

,C

D8+

CD

4+>

CD

8C

D30

+,

CD

45RO

+,

CD

1a+

Neg

ativ

eA

llerg

enav

oida

nce,

topi

cals

tero

ids

Dev

elop

men

tof

lym

phom

atoi

dco

ntac

tde

rmat

itis

onth

eIP

PDpa

tch

area

Men

dese

(15)

2010

44F

Butt

ocks

,glu

teal

clef

t,gr

oin

Met

hylc

hlor

o-is

othi

azol

inon

e,qu

ater

nium

-15

Moi

stw

ipes

++

No

Chr

onic

derm

atiti

sw

ithpr

omin

ent

epid

erm

otro

pism

and

min

imal

spon

gios

isan

deo

sino

phils

NR

Neg

ativ

eTo

pica

lste

roid

s,et

aner

cept

,infl

ixim

abPr

ior

diag

nosi

sof

inve

rse

psor

iasi

s

Alv

arez

-Gar

rido

(16)

2010

81F

Dor

sum

ofha

nds,

spre

adin

gto

face

Benz

ydam

ine

hydr

ochl

orid

e1%

pet.

Gyn

aeco

logi

cal

clea

nsin

gso

lutio

n

++

No

Den

sein

ters

titia

land

periv

ascu

lar

lym

phoi

din

filtr

ate,

num

erou

ssm

allt

om

ediu

m-s

ized

cells

with

hype

rchr

omat

ican

dco

nvol

uted

nucl

ei

CD

4+/C

D8+

,5:

6N

egat

ive

Topi

cals

tero

ids

Nor

mal

SPEP

/UPE

P

Hes

sion

(17)

2010

68F

Thig

h,bu

ttoc

ks,

geni

tals

Reac

tive

Blac

k5,

Reac

tive

Blue

238,

Reac

tive

Red

238,

carb

am

ix,d

iphe

nyl-

guan

idin

e

Und

erga

rmen

tel

astic

band

+N

oSu

perfi

cial

and

deep

periv

ascu

lar

lym

phoi

din

filtr

ate

with

apa

lisad

ing

gran

ulom

atou

sre

spon

se

NR

NR

Betm

etha

sone

dipr

oprio

nate

0.05

%oi

ntm

ent

Flow

cyto

met

ryne

gativ

e

Nar

gane

s(1

8)20

1337

MG

ener

aliz

ed,

spar

ing

skin

fold

s

Dis

pers

eYe

llow

3,+

;Dis

pers

eRe

d1,

++

;Dis

pers

eO

rang

e,+++

;D

ispe

rse

Red

17,

++

;am

inop

heno

l,+++

;am

inob

enze

ne,

+++

;and

Dis

pers

eBl

uem

ix10

6/12

4,+++

Text

iledy

esin

blue

wor

kov

eral

l

+++

Yes

(sew

age

trea

tmen

tpl

ant

wor

ker)

Con

sist

ent

with

patc

hst

age

cuta

neou

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The spectrum of allergens capable of producing lym-phomatoid contact dermatitis is broad, and includesrubber chemicals, dyes, metals, and preservatives. Vari-ous metal compounds (including gold sodium thiosulfate,cobalt naphthenate, and nickel sulfate), phosphorussesquisulfide and isopropylamino diphenylamine werethe most common allergens related to lymphomatoidcontact dermatitis in our review. However, following theappropriate allergen exposure in an immunologicallysusceptible host, many allergens may evoke lymphoma-toid contact dermatitis. Therefore, extended patch testingwith a broad allergen panel is key; dimethyl fumarate andMI were only recently identified as allergens, and limitedpatch testing would not have identified these allergens.Ultimately, the degree of inflammation seen during patchtesting and on pathological examination suggests thatlymphomatoid contact dermatitis arises in the setting ofa very brisk immune response or in response to highlypotent allergens.

To our knowledge, we describe the second case ofMCI/MI lymphomatoid contact dermatitis. Lymphoma-toid contact dermatitis caused by baby wipes (moistwipes) containing MCI/MI was initially described byMendese et al. in 2010 (15). MCI/MI is a common cos-metic and industrial antimicrobial preservative that hasbeen implicated as the allergen in many cases of babywipe dermatitis (24, 25). Other potentially allergenicingredients in moist wipes have been identified, includingMI alone, quaternium-15, iodopropynyl butylcarbamate,DMDM hydantoin, and various fragrances. AlthoughMCI/MI is certainly allergenic, in our review we did notfind it to be particularly likely to cause lymphomatoidcontact dermatitis.

By definition, the histopathology of lymphomatoidcontact dermatitis resembles that of mycosis fungoides,and shows a superficial band-like T cell infiltrate withepidermotropism (26). Intraepidermal collections ofmononuclear cells may be seen in lymphomatoid contactdermatitis, and can be impossible to differentiate fromthe Pautrier’s microabscesses of mycosis fungoides (14).If present, epidermal spongiosis or spongiotic microvesic-ulation may favour lymphomatoid contact dermatitisrather than mycosis fungoides. Prior treatment mayfurther alter the clinical and histological appearance.Accurate diagnosis depends on consideration of theclinical history, and pathological, immunohistochemicaland molecular data (27). Although immunohistochem-istry can highlight a predominance of CD4+ or CD8+

cells, the technique does not predict the behaviour ornature of these cells. Additionally, there are rare casesof CD8+-predominant cutaneous T cell lymphoma (28).Therefore, the distinction between a benign reactive

process and early mycosis fungoides by immunohis-tochemistry alone is clearly not reliable (29–31).Classically, pseudolymphomas are characterized aspolyclonal, whereas lymphomas are most often mono-clonal. In early mycosis fungoides, the disease may notshow T cell receptor gene rearrangement. Clonal T cellpopulations are not always identifiable in early mycosisfungoides, and clonal heterogeneity may be seen (32).Among our reviewed cases from the literature, only 1patient had a positive T cell receptor gene rearrangement;this rearrangement did not persist with subsequent biop-sies. Furthermore, T cell receptor gene rearrangementsare not diagnostic of malignancy; they have been detectedin skin lesions of patients with benign conditions suchas pityriasis lichenoides et varioliformis acuta, lichenplanus, and lichen sclerosus (33–37). Frequently, thisis attributable to pseudoclonality. As a well-establishedfinding in the lymph nodes, pseudoclonality has beendescribed in T and B cell processes in the skin as the detec-tion of an initial clone that is not identified in subsequentclonality studies (38). Thurber et al. recently showedthat identical clones present in two or more biopsiesfrom different skin sites are highly specific for mycosisfungoides, and this may be a suitable diagnostic tool fordifferentiating true clonality from pseudoclonality (39).

Adding to this potential, but fortunately uncommon,diagnostic overlap, controversy exists regarding thepotential for malignant transformation of inflammatorydiseases. Data defining the link between chronic antigenstimulation and mycosis fungoides are sparse, but alarge case–control study did not support a relationshipbetween contact allergens, chronic inflammation, andthe development of mycosis fungoides (40). Nevertheless,persistent antigenic stimulation continues to be impli-cated in the aetiology of cutaneous T cell lymphoma,owing to a relatively high incidence of positive patch testreactions in patients with this disorder. Khamaysi et al.noted that 45% of patients with cutaneous lymphomaand 38% of patients with all pseudolymphomas hadpositive patch test reactions, often to metals (41, 42).More recently, Abraham et al. reported the case of a74-year-old woman who was initially diagnosed with abilateral, symmetric upper eyelid lymphomatoid contactdermatitis caused by her eye drops and subsequentlydeveloped fatal T cell prolymphocytic leukaemia (43). Itis thus important to stress that the presence or absenceof a positive patch test reaction cannot solely or primarilybe relied on as a marker of benign disease.

Like lymphomatoid contact dermatitis, chronic actinicdermatitis or actinic reticuloid has been difficult to define.These entities have been variably described as inflam-matory dermatoses, pseudolymphomas, allergic contact



or photocontact dermatoses caused by sesquiterpene lac-tone, fragrance, or colophonium, or precursors or pho-tosensitive variants of mycosis fungoides with variablebehaviour (44). Here too, routine histology, immunohis-tochemistry and T cell receptor gene rearrangement anal-ysis have not been able to unequivocally define the disease(45–47).

Limitations

Our review is limited by the small number of publishedcases available. Although this is possibly representativeof the low incidence of lymphomatoid contact dermatitis,it is likely that lymphomatoid contact dermatitis is infre-quently recognized outside of subspecialists who are wellversed in contact dermatitis or skin oncology. Neverthe-less, the small numbers of cases reported limit our abilityto extrapolate distinct features of lymphomatoid contactdermatitis. Finally, we only considered topical allergensassociated with cutaneous T cell pseudolymphoma. Oralmedications, tattoos, infections and arthropod reactionsas potential triggers for pseudolymphoma have beenreviewed elsewhere (26).

Conclusion

The distinction between allergic contact dermatitis,lymphomatoid contact dermatitis and cutaneous Tcell lymphoma can present a diagnostic dilemma. Thehistopathology, clinical presentation and even molec-ular appearance of these diseases can be strikinglysimilar. The challenging cases of lymphomatoid con-tact dermatitis described herein highlight the need foradvanced diagnostic tests and astute, multifactorialclinicopathological correlation. Lesions unresponsive toconservative treatment and allergen avoidance shouldbe re-evaluated to exclude a true lymphoma. Con-versely, cutaneous contact delayed hypersensitivity-typeallergy should be considered in patients with an atyp-ical presentation of cutaneous lymphoma. Ultimately,clinical, histological and immunophenotypic featuresand genetic analysis and patch testing with a broadallergen panel must be considered for a diagnosis of lym-phomatoid contact dermatitis. The consequences of notdiagnosing allergic contact dermatitis or misdiagnosingmycosis fungoides can be significant and potentiallyserious.

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