Cutaneous Rosai-Dorfman disease: histopathological presentation as inflammatory pseudotumor. A literature review.
ABSTRACT Purely cutaneous Rosai-Dorfman disease is exceptional. The disease is characterized histologically by large, proliferating histiocytes exhibiting inflammatory cells within their cytoplasm (emperipolesis). We present here a case of purely cutaneous generalized disease in which the routine histopathology was suggestive of an inflammatory pseudotumor. Positivity for S-100 protein, alpha1-antitrypsin, alpha1-antichymotrypsin, lysozyme, Mac387 and CD68 proteins, and negativity for CD1a protein confirmed the diagnosis of Rosai-Dorfman disease. The rarity of this case lies in the presence of conspicuous inflammatory pseudotumor-like histopathologic changes, masking an otherwise typical sinus histiocytosis cell infiltrate. This unusual presentation of the disease requires a high index of suspicion by clinicians and pathologists.
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ABSTRACT: Sinus histiocytosis is as a rule a benign disease of lymph nodes, infiltrated by large histiocytes. These cells show typical cytophagocytosis, particularly lymphophagocytosis. Other organs may be also involved by this disease, often including the skin. Exclusive cutaneous sinus histiocytosis without infiltration of lymph nodes seems to be very rare. To exclude other non-X histiocytoses or histiocytosis-X, it is advisable to use immunohistochemistry. We report on a patient with sinus histiocytosis and discuss the problems of differential diagnosis.Der Hautarzt 06/1998; 49(5):392-6. · 0.58 Impact Factor
Article: Cutaneous Rosai-Dorfman disease.[show abstract] [hide abstract]
ABSTRACT: We report a patient with purely cutaneous Rosai-Dorfman disease (RDD) who presented with a solitary, asymptomatic plaque on the back of her left thigh, with characteristic, large histiocytoid cells exhibiting emperipolesis histologically. Cutaneous lesions occur in 27% of patients with lymph node involvement in RDD however purely cutaneous disease has only been reported on 18 previous occasions. The aetiology is unknown, although it is though to be a reactive disorder rather than neoplastic, possibly an immunological response to an infectious agent.Clinical and Experimental Dermatology 02/1998; 23(1):40-2. · 1.20 Impact Factor
Cutaneous sinus Rosai-Dorfman disease of the skin histiocytosis (Rosai-Dorfman disease): a benign reactive process mimicking Langerhans' cell histiocytosis. 1998. Int J Dermatol J Cutan 37 267-727..
Acta Derm Venereol 2002; 82: 292–296
Cutaneous Rosai-Dorfman Disease: Histopathological
Presentation as Inflammatory Pseudotumor. A Literature Review
GEORGE KROUMPOUZOS1and MARIE-FRANCE DEMIERRE2
Departments of Dermatology,1Brigham and Women’s Hospital, Harvard Medical School and2Boston Medical Center, Boston University School of
Medicine, Boston, USA
Purely cutaneous Rosai-Dorfman disease is exceptional.
The disease is characterized histologically by large, prolif-
erating histiocytes exhibiting in?ammatory cells within
their cytoplasm (emperipolesis). We present here a case
of purely cutaneous generalized disease in which the
routine histopathology was suggestive of an in?ammatory
pseudotumor. Positivity for S-100 protein,a1-antitrypsin,
a1-antichymotrypsin, lysozyme, Mac387 and CD68 pro-
teins, and negativity for CD1a protein con?rmed the
diagnosis of Rosai-Dorfman disease. The rarity of this
case lies in the presence of conspicuous in?ammatory
pseudotumor-like histopathologic changes, masking an
trate. This unusual presentation of the disease requires a
high index of suspicion by clinicians and pathologists. Key
words: cutaneous Rosai-Dorfman disease; in?ammatory
pseudotumor; S-100 protein.
trast to RDD, in?ammatory pseudotumor never meta-
stasizes, and is not associated with systemic involvement.
Most cases of in?ammatory pseudotumor have been
treated with local excision.
The histopathologic diVerential diagnosis and man-
agement of this case are discussed, and reported cases
of cutaneous RDD are reviewed.
A 41-year-old Haitian female presented with an acute
onset of multiple cutaneous nodules over the trunk,
buttocks, thighs, groin and popliteal fossae. The patient
did not have a recent history of infection, vaccination,
trauma, insect bites or drug intake. On physical examina-
tion, approximately 15 ?rm brownish, variably tender,
occasionally lobulated, ?xed, 1–15cm nodules were
noted (Fig. 1). There was no lymphadenopathy or hepa-
tosplenomegaly. Over the following 3 years the lesions
enlarged and increased in number. A laboratory work-
up revealed mild normocytic anemia, decreased C3 and
C4, and mildly elevated erythrocyte sedimentation rate.
The T4/T8 ratio was within normal limits, and a syphilis
test proved non-reactive. A total body CT scan, tubercu-
losis and HIV tests were negative. The lesions did not
respond to intralesional corticosteroids or a 3-month
course of thalidomide (50mg/day). Many painful lesions
(Accepted April 15, 2002.)
Acta Derm Venereol 2002; 82: 292–296.
Marie-France Demierre, Director of Skin Oncology,
Department of Dermatology, Boston University School
of Medicine, 720 Harrison Ave, D.O.B. 801A Boston, MA
02118, USA. E-mail: mariefrance.demierre@BMC.org
Rosai-Dorfman disease (RDD) (sinus histiocytosis with
massive lymphadenopathy) strictly con?ned to the skin
is rare (26 published cases). Reported cases (1–23) to
date suggest that when RDD is clinically limited to the
skin, it follows a benign course, with only a small risk
of systemic disease. We report on a patient who
developed purely cutaneous generalized RDD. The rou-
tine histopathology was suggestive of an in?ammatory
pseudotumor, a benign ?broin?ammatory tumor involv-
ing deep soft tissues, and rarely the skin (24). The
clinical presentation, however, was atypical for in?am-
matory pseudotumor, which usually presents in the skin
as a solitary, discrete, ?esh-colored, usually asympto-
matic nodule (24). The histopathology of in?ammatory
pseudotumor shows a circumscribed nodular mixed cell
in?ltrate with plasma cells, lymphocytes, eosinophils
and neutrophils, and variable amounts of sclerosis.
Positivity for S-100 protein is exceptional (24). In con-
Fig. 1. Grouped hyperpigmented, ?rm, ?xed cutaneous nodules on
Acta Derm Venereol 82
© 2002 Taylor & Francis. ISSN 0001-5555
Cutaneous Rosai-Dorfman disease
Several biopsies were taken at presentation and
follow-up visits. Hematoxylin-eosin stain (Figs. 2, 3)
and stains for vimentin, muscle-speci?c actin and CD68
showed a myo?broblastic/histiocytic cell population
associated with a diVuse and ?orid mixed in?ammatory
cell in?ltrate of neutrophils, plasma cells and lympho-
cytes extending from the reticular dermis to the subcutis.
The epidermis was intact. The lesions formed a focal
multinodular pattern, and some nodules showed central
accumulation of neutrophils. Occasional lymphoid
follicle formation was seen. Large histiocytes with
abundant cytoplasm were positive for S-100 (Fig. 4),
a1-antitrypsin, a1-antichymotrypsin, lysozyme, Mac387
and CD68 proteins, and negative for CD1a protein.
Emperipolesis was subtle on hematoxylin-eosin stain
(Fig. 2) but could be clearly visualized on S-100 protein
stain (Fig. 4). Only small foci in the histologic specimens
were diagnostic of RDD as a result of extensive lymph-
Fig. 4. Histopathologic section stained for S-100 protein. The histi-
ocytes show strong nuclear and cytoplasmic staining. The pattern of
alternating dark and brown areas is characteristically seen in cutaneous
Rosai-Dorfman disease. The inset demonstrates lymphocytes within
the cytoplasm of a histiocyte (emperipolesis). The lymphocytes
remain unstained, and are surrounded by a clear halo (original
oplasmacytic in?ltrate and sclerosis. Histiocytes and
lymphocytes were identi?ed within vascular spaces.
Special stains for bacteria and fungi were negative.
The skin is the most common extranodal site in RDD
(6). Although cutaneous involvement in RDD is
common, RDD disease strictly con?ned to the skin has
been reported in only 26 cases (1–23). When compared
to nodal RDD, cutaneous RDD aVects older people
(median age 48 years, age range 15 to 77 years) with a
preponderance of cases among white females (69.2%)
(Table I). The lesions can be either solitary or multi-
focal, and run a variable clinical course. An association
with herpes virus infection (10), Epstein-Barr virus
(EBV) infection (2), varicella (12) and herpes zoster
(19) has been reported.
Constant histologic features of cutaneous RDD
include (6): (a) diVuse or nodular in?ltrates of histio-
cytes with abundant cytoplasm and feathery borders,
medium to large, round vesicular nuclei, and small
nucleoli, (b) emperipolesis, (c) thick-walled venules sur-
rounded by cuVs of plasma cells, more prominent at the
periphery of the lesions, (d) lymphoid aggregates and
germinal centers more prominent at the periphery of the
lesions, and (e) histiocytes within dilated lymphatic
Although the histopathology of cutaneous RDD
simulates nodal disease, the histologic hallmarks of the
disease are less obvious than those seen in the lymph
nodes (4, 22). Emperipolesis may be less conspicuous,
the histiocytes being frequently spindled, arranged in a
storiform pattern, and associated with ?brosis.
Fig. 2. Histopathologic section demonstrating a myo?broblastic/histi-
ocytic cell population admixed with an in?ammatory cell in?ltrate.
Lymphophagocytosis (emperipolesis) is subtle. (H&E-stain, original
Fig. 3. Histopathologic
in?ammatory in?ltrate consisting of neutrophils, plasma cells and
lymphocytes (H&E-stain, original magni?cation ´20).
section demonstratinga ?orid mixed
Acta Derm Venereol 82
G. Kroumpouzos and M.-F. Demierre
Table I. Reported cases of cutaneous Rosai-Dorfman disease
Ref.Year CasesAge/Sex/RaceSkin lesions/anatomic siteOther diseaseEvolution
Solitary nodule (shoulder)
Multiple nodules (trunk, arms,
Erythematous plaque (scapula)
papules (face, neck, legs)
Erythematous papular eruption
Crusted nodule (scalp)
Red-orange papules (face, chest)
Red-brown papules (trunk,
Painless breast mass
Tender red-violaceous nodule,
satellite papules (thigh)
Cure with thalidomide
Chronic evolution (12 years)
Partial regression (3 years)719931
Spontaneous resolution NIDDM
60/FSpontaneous resolution nodule
Cure with radiation
1019951 65/F/W Red papules, nodules (back)HSV
11 19961 38/F/W Red-brown papules, nodules
(nose, back, extremities)
Flesh-colored papules, nodules at
varicella scars (chest)
Granuloma annulare-like plaques
and subcutaneous nodules (face,
Tender enlarging mass (chest)
Indurated plaque (thigh)
Indurated nodule (abdomen)
Response to prednisone and
Incisional biopsy, no
?181998170/F/WRed-orange plaques and nodules
(face, arms, buttocks)
Nodules at herpes zoster scars
19 1998177/MHerpes zoster,
lymphoma of the
201998177/F/WTwo dusky red nodules (thighs) Surgical removal, no
recurrence (1 year)
No response to radiation,
Chronic evolution, no
recurrence of excised lesions
Erythematous plaque (cheek)
Generalized red-brown papules,
plaques and nodules
2002141/F/HaitianGeneralized tender brown nodules
M: male; F: female; W: white; B: black; A: Asian; EBV: Epstein-Barr virus, HSV: herpes simplex virus; NIDDM: non-insulin-dependent
The histopathologic diVerential diagnosis of this case
is presented in Table II. Our case could not be reliably
distinguished from in?ammatory pseudotumor on the
basis of routine histology alone because emperipolesis
was only focally present (Fig. 2), and the most notable
?nding at presentation was a diVuse and ?orid mixed
in?ammatory in?ltrate (Fig. 3). Nevertheless, the multi-
focality of lesions was rarefor in?ammatory pseudotumor
(24). Positivity for S-100 protein con?rmed the diagnosis
of RDD and facilitated the search for emperipolesis, as
it allowed the outline of the individual histiocytes to
contrast with the negative image of the phagocytized cells
(Fig. 4). The distinction between cutaneous lesions of
RDD and cutaneous in?ammatory pseudotumor is
important, as the former may be associated with systemic
involvement and necessitate a work-up for systemic
disease. Furthermore, cutaneous lesions in RDD are
often multiple, in contrast to cutaneous in?ammatory
pseudotumor which is usually a solitary lesion, never
metastasizes, and can be cured with local excision.
Acta Derm Venereol 82
Cutaneous Rosai-Dorfman disease
Table II. Histopathologic diVerential diagnosis of cutaneous Rosai-Dorfman disease
DiVerential diagnosisFeatures diVerentiating from cutaneous RDD
Malignant histiocytosis and lymphoma with feature of malignant
Hemophagocytic syndrome associated with T-cell lymphoma and/or
Langerhans’ cell histiocytosis
Emperipolesis absent, positivity for S-100 protein rare
Atypia, cellular pleomorphism
Lymphomatous in?ltrate, lobular panniculitis, negativity for S-100
Emperipolesis absent, Birbeck granules identi?ed by electron
Histiocytes with ‘‘ground glass’’ cytoplasmic appearance
Emperipolesis and plasma cells absent
Generalized eruptive histiocytoma
In?ammatory malignant ?brous histiocytoma
Atypia, cellular pleomorphism
Poorly de?ned in?ltrate, plasma cells rare, positivity for organisms on
Atypical monocytes, Reed-Sternberg cellsHodgkin’s lymphoma
Govender & Chetty (25) described a solitary lesion
with combined histologic and immunophenotypic fea-
tures of in?ammatory pseudotumor and RDD of soft
tissue. The authors suggested that these two lesions are
part of a spectrum of in?ammatory or reactive condi-
tions. They postulated that the morphological and
immunophenotypic features of their lesion could be
secondary to aberrant cytokine expression in an
in?ammatory pseudotumor, resulting in transformation
of histiocytes to resemble those seen in RDD. Never-
theless, the presence of morphologic similarities between
cutaneous RDD and in?ammatory pseudotumor does
not necessarily represent evidence that these entities
should be grouped together. Stain for S-100 protein can
reliably diVerentiate in?ammatory pseudotumor from
cutaneous RDD. Although S-100 stain has not been
performed in many cases of in?ammatory pseudotumor,
in a few reported cases of S-100-positive in?ammatory
pseudotumor (24), the histiocytes did not show the
characteristic morphology of those seen in RDD.
This report indicates that lesions of a relatively dis-
crete entity (RDD) can readily and incorrectly be
assigned to the less well-de?ned diagnostic category of
in?ammatory pseudotumor. This case also presents a
therapeutic challenge, as many lesions were symptomatic
and/or located in uncomfortable sites, thus interfering
with the patient’s daily activities. Experience in the
treatment of cutaneous RDD is limited and remains
largely empirical and/or symptomatic. Solitary lesions
have been treated with local excision (3, 5, 8). Systemic
or intralesional steroids and chemotherapy have been
administered in cutaneous RDD with minimal response
(14, 23). Responses to radiation therapy (11) and
thalidomide (11) have been reported. Our patient did
not respond to intralesional steroids or a 3-month course
of thalidomide. Surgical excision of painful lesions pro-
vided symptomatic relief. With a 3-year follow-up, the
lesions have not recurred while several others persist.
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