Five cases of cutaneous Rosai-Dorfman disease

Five cases of cutaneous Rosai-Dorfman disease

H. V. Pitamber* and W. Grayson†‡

*Division of Dermatology, Department of Medicine, University of the Witwatersrand, †Division of Anatomical Pathology, School of Pathology,

University of the Witwatersrand, and ‡National Health Laboratory Service, Johannesburg, South Africa

Summary Rosai-Dorfman disease (RDD), previously known as sinus histiocytosis with massive

lymphadenopathy, is a benign, idiopathic histiocytic proliferative disorder. It

commonly affects lymph nodes, but any organ of the body may be involved.

Histological findings include characteristic large, pale, histiocytic cells (Rosai-Dorfman

cells) exhibiting cytophagocytosis. Immunohistochemically, these histiocytes are

positive for S-100 protein and CD68, but stain negatively for CD1a. On electron

microscopy, Birbeck granules are absent. RDD limited to the skin is rare, less than 30

cases having been reported to date. We present five further cases of purely cutaneous

RDD. Three presented as solitary nodules and one as a large, well-circumscribed

plaque. The fifth patient, who was HIV positive, had a rosacea-like facial eruption.

Introduction

In 1969, Rosai and Dorfman described a clinicopatho-

logical entity in which severely enlarged cervical lymph

nodes were infiltrated by large histiocytes exhibiting

cytophagocytosis.1 The patients had fever, leukocytosis

and hypergammaglobulinaemia. These authors named

the condition sinus histiocytosis with massive lympha-

denopathy (SHML).1 By 1988, when it was apparent

that lymph nodes were not always affected and that any

organ of the body may be involved, the designation

Rosai-Dorfman disease (RDD) was preferred.2 Lymph

node involvement alone is found in 57% of patients,

15% present with extranodal disease only, and in 28%

of patients both nodal and extranodal sites are

involved.3 The skin and the upper respiratory tract are

the most common extranodal sites, each involved in

approximately 11% of cases.3

RDD limited to the skin (now referred to as cutaneous

RDD)4 is rare, with only 29 cases documented to date.3–20

We report five new cases of cutaneous RDD. Three

presented as solitary nodules and one as a large, well-

circumscribed plaque. The fifth patient, who was

infected with the human immunodeficiency virus

(HIV), had a rosacea-like facial eruption.

Case reports

Five cases of RDD limited to the skin were diagnosed

between 1997 and 2001 by the Division of Dermatology

(cases 2 and 3) and by the Division of Anatomical

Pathology of the University of the Witwatersrand (cases

1, 4 and 5).

All five patients were South African. The clinical

details, treatment and follow-up are summarized in

Table 1. The age of onset varied from 28 to 67 (mean

45.4) years and the duration of the disease ranged from 4

to 36 (mean 19.3) months. In three cases (cases 1, 4 and

5), the lesions consisted of solitary nodules. Case 2 had a

large (8 cm · 4 cm), solitary, oval, hyperpigmented

plaque with an infiltrated raised border in the right

groin (Fig. 1a). The lesions in case 3 consisted of multiple

erythematous papules confined to the face (Fig. 1b).

All patients were asymptomatic and in good health,

with no associated lymphadenopathy or extranodal sites

of involvement apart from the skin.

Laboratory investigations

In cases 2 and 3 investigations consisted of a full

blood count, erythrocyte sedimentation rate (ESR),

Correspondence: W. Grayson, Division of Anatomical Pathology, N.H.L.S.,

PO Box 1038, Johannesburg 2000, South Africa.

Tel.: 27 11 489 8476. Fax: 27 11 489 8512.

E-mail: [email protected]

Accepted for publication 27 August 2002

Clinical dermatology • Original article

� 2003 Blackwell Publishing Ltd • Clinical and Experimental Dermatology, 28, 17–21 17

urea and electrolytes, liver function tests and serum

protein electrophoresis, as well as Epstein-Barr virus

(EBV) and human herpesvirus-6 (HHV-6) serology.

Serological tests for syphilis and HIV were performed

in cases 2, 3 and 5. Abnormal findings are shown in

Table 1.

The two patients (cases 2 and 3) who showed a

polyclonal gammopathy also had positive HHV-6 serol-

ogy and their EBV serology was indicative of a past

infection. Case 3 was HIV positive.

Skin biopsies

Multiple punch biopsies (cases 2 and 3) and excisional

biopsies (cases 1, 4 and 5) were routinely processed and

stained with haematoxylin and eosin. Additional paral-

lel sections were obtained for immunohistochemistry,

namely, S-100 protein (1 : 500; DAKO, Glostrup,

Denmark), CD68 (1 : 100; DAKO, Glostrup, Denmark)

and CD1a (undiluted; Immunotech, Marseille, France).

Ultrastructural examination was performed on addi-

tional punch biopsies taken from cases 2 and 3, and

tissue was sampled from the remainder of the gross

specimen in case 4.Tab

le1

Ro

sai-

Do

rfm

an

dis

ease

lim

ited

toth

esk

in:

clin

ica

l,la

bo

rato

rya

nd

ad

dit

ion

al

pa

tho

log

ica

lfi

nd

ing

sin

fiv

eca

ses.

Cas

eA

ge⁄s

ex⁄r

ace

Cuta

neo

us

lesi

on(s

)an

dsi

te

Dura

tion

(month

s)La

bora

tory

findin

gs

Additio

nal

his

tolo

gic

alfe

ature

sTr

eatm

ent

and

cours

e

148⁄M

⁄WSo

litar

y,in

dura

ted

nodule

(�1

cm);

left

should

er

36

NA

Exci

sion

246⁄F

⁄BSo

litar

y,hyp

erpig

men

ted

pla

que

(8·

4cm

);right

gro

in

18

ESR

47

mm

⁄hH

HV

-6+

veEB

VIg

M–v

e;

IgG

+ve

Poly

clonal

gam

mopat

hy

6an

d12

month

sla

ter:

few

erRD

cells

,

acco

mpan

ied

by

xanth

om

atous

mac

rophag

esan

dm

arke

dder

mal

fibro

sis

Topic

alst

eroid

s;par

tial

invo

lution

at12

month

s

328⁄F

⁄BM

ultip

leer

ythem

atous

pap

ule

s;fa

ce4

HH

V-6

+ve

EBV

IgM

–ve;

IgG

+ve

HIV

+ve

Poly

clonal

gam

mopat

hy

Topic

alst

eroid

s;im

pro

vem

ent

at2

month

s

467⁄F

⁄BSo

litar

ynodule

(1.5

cm);

scal

p?

NA

Scat

tere

dag

gre

gat

esof

neu

trophils

Exci

sion

538⁄F

⁄BSo

litar

y,in

trad

erm

alnodule

(3cm

);

mons

pubis

?H

IV–v

eST

S–v

eEx

tensi

on

of

infiltra

tein

tosu

bcu

tis

Exci

sion

M¼

ma

le;

F¼

fem

ale

;W

¼w

hit

e;B¼

bla

ck;

NA

¼n

ot

av

ail

ab

le;

ES

R¼

ery

thro

cyte

sed

imen

tati

on

rate

;H

HV

-6¼

hu

ma

nh

erp

esv

iru

s6

;E

BV¼

Ep

stie

n-B

arr

vir

us;

RD¼

Ro

sai-

Do

rfm

an

;?¼

un

kn

ow

n;

HIV

¼h

um

an

imm

un

od

efici

ency

vir

us;

ST

S¼

sero

log

ica

lte

sts

for

syp

hil

is.

Figure 1 (a) Hyperpigmented plaque with infiltrated edge, located

in the right groin in case 2. (b) Erythematous papular facial

eruption in case 3.

Cutaneous Rosai-Dorfman disease • H. V. Pitamber and W. Grayson

18 � 2003 Blackwell Publishing Ltd • Clinical and Experimental Dermatology, 28, 17–21

Pathological findings

Histological findings were similar in all five cases.

Additional microscopic features observed in some of

the cases are shown in Table 1. In all cases the

epidermis was normal, while the dermis contained

sheets of large, pale histiocytic cells with a dense

background infiltrate of lymphocytes and plasma cells

(Fig. 2a). Lymphoid follicles with reactive germinal

centres were present. The histiocytes (Rosai-Dorfman

cells) displayed phagocytosis of lymphocytes, plasma

cells and occasional polymorphonuclear leucocytes

(Fig. 2b); they showed diffuse cytoplasmic and nuclear

staining for S-100 protein, were weakly immunoreac-

tive for CD68, but stained negatively for CD1a.

Follow-up biopsies in case 2, taken 6 and 12 months

after initial presentation, showed a paucity of large

histiocytic cells, with predominant dermal fibrosis and

conspicuous aggregates of xanthomatous macrophages

(Table 1).

Electron microscopy showed large histiocytic cells

with ill-defined, undulating cell membranes and abun-

dant cytoplasm containing engulfed lymphocytes and

plasma cells. Some of the ingested mononuclear cells

were present within phagocytic vacuoles. Birbeck

granules were absent.

Discussion

Purely cutaneous RDD is rare, with less than 30 cases

reported to date. In 1978, Thawerani and coworkers

reported the first case in a 48-year-old man with a

solitary nodule on the shoulder and hypergammaglob-

ulinaemia.21

The lesions in cutaneous RDD may be solitary or

multiple. They usually present as papules,5,7 nod-

ules5,6,16,18,20 or plaques,4,13,15,17,19 or as a combina-

tion of these.4,10–12,17 Cutaneous RDD has also presented

as subcutaneous masses (panniculitis)7,10,13 and has

mimicked a breast mass.9,22 Three of our patients

presented with solitary nodules, two of which were

superficial, while the third had a deeper component

involving the subcutis. One patient had a large, solitary,

granuloma annulare-like plaque with a raised infiltrated

edge. Previous cases most resembling ours were multiple

giant granuloma annulare-like plaques reported by

Scheel et al.13 and a solitary hyperpigmented plaque

reported by Child et al.15 Our patient with a rosacea-like

papular facial eruption differed from the case of Ang

et al.,4 in whom an acneiform eruption consisted of

comedones and cystic nodules. Our patient was HIV

positive and is, to our knowledge, the second case of

isolated cutaneous RDD in an HIV-positive patient. The

first reported case presented as nasal nodules.18

Histological findings in RDD are characteristic and

essentially similar in all sites. A dense histiocytic

infiltrate is accompanied by a background infiltrate of

lymphocytes and plasma cells; lymphoid follicles with

germinal centres may occur.22,23 The large histiocytic

cells (Rosai-Dorfman cells) have indistinct, �feathery�borders, abundant pale eosinophilic cytoplasm and large

vesicular nuclei, exhibiting the phenomenon of emperi-

polesis (cytophagocytosis of lymphocytes and plasma

cells).3,22,23 Less often, the cytoplasm may contain

neutrophils and red blood cells.4,15 These histiocytes

stain positively for S-100 protein and CD68, but

negatively for CD1a, which confirms the diagno-

sis.3,17,19 Ultrastructurally, the large histiocytes show

Figure 2 (a) Sheets of pale histiocytes surrounded by dense dermal infiltrate of lymphocytes and plasma cells; lymphoid follicle on the left

(haematoxylin and eosin, ·230). (b) Rosai-Dorfman cell showing cytophagocytosis of lymphocytes, plasma cells and a neutrophil

(haematoxylin and eosin, ·736).



undulating villous cytoplasmic processes and emperi-

polesis. Birbeck granules are absent,3 ruling out the

possibility of Langerhans cell histiocytosis.8,16 Histolog-

ical features were similar in all our cases. The large

histiocytes, several exhibiting emperipolesis, stained

positively for S100 protein and CD68 but negatively

for CD1a, and the absence of Birbeck granules con-

firmed the diagnosis of RDD.

The aetiology of RDD remains uncertain. Two hypo-

theses have been proposed; a disturbance of cell-mediated

immunity,24 and a primary viral infection.11,15,24,25 The

immunohistochemical findings in RDD confirm the

presence of functionally activated macrophages; the acti-

vation possibly following an immune or infectious

challenge.26 EBV and HHV-6 have been implicated in

RDD.25 Luppi et al. detected a very unusual pattern of

late HHV-6 viral antigen expression in two cases

of RDD.27 Serological tests for HHV-6 were positive in

two of our cases. However, serological tests alone are not

conclusive for an aetiological role; Levine et al. recom-

mend in situ hybridization to detect HHV-6 in the

tissues.25 Both of these patients also had serological

evidence of past EBV infection, and a polyclonal gamm-

opathy. The frequent association of polyclonal gammop-

athy with RDD is supportive of an exaggerated

immunological response to an infectious agent in this

disorder.

Cutaneous RDD has a good prognosis and tends to

resolve spontaneously over months to years.4 Cutane-

ous lesions usually do not require treatment but surgical

excision may be indicated for cosmetic reasons or

symptomatic relief.4,12,15,28 Cutaneous lesions have

also responded to radiotherapy12 and thalidomide.29

Acknowledgements

We thank Prof. E. J. Schulz, Division of Dermatology,

Department of Medicine, University of the Witwaters-

rand, for her assistance with this article. We also thank

Mrs L. van der Walt, Electron Microscopy Unit, National

Health Laboratory Service (NHLS), and Mr G. Hall

(NHLS) and Mr E. Liebenberg (University of the Witwa-

tersrand) for the microphotography.

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Five cases of cutaneous Rosai-Dorfman disease