THE CUTTING EDGE

SECTION EDITOR: GEORGE J. HRUZA, MD; ASSISTANT SECTION EDITORS: MICHAEL P. HEFFERNAN, MD; SUMMER R. YOUKER, MD

Dapsone as a Potential Treatment

for Cutaneous Rosai-Dorfman Disease
With Neutrophilic Predominance
Chih-Chieh Chan, MD; Chia-Yu Chu, MD; Department of Dermatology, National Taiwan University Hospital, Taipei, Taiwan

The Cutting Edge: Challenges in Medical and Surgical Therapeutics

REPORT OF A CASE with oral isotretinoin (100 mg/d). However, the lesion
had continued to worsen and the symptoms of pruri-
tus and intermittent episodes of fever had progressed
A 31-year-old Taiwanese woman, who from her medi- during the treatments. Superficial irradiation was sug-
cal history was generally well, presented with 1 slowly gested, but the patient refused owing to its potential
enlarging elevated plaque on the posterior aspect of hazards.
her right shoulder. This had first been detected 3
months before the visit to our clinic. The lesion had
originated as a small, tender, erythematous papule and THERAPEUTIC CHALLENGE
had since grown into a large confluent plaque with
satellite papules. She claimed that the lesion was The patient was treated unsuccessfully with a variety
increasing in size, and this was accompanied by of therapeutic modalities, including topical and sys-
intense itching and fever. On physical examination, temic corticosteroids just noted, as well as oral
there was 1 palm-sized, dusky red, elastic firm plaque isotretinoin. She refused superficial radiation treat-
on the right shoulder. The main lesion was sur- ment and the large size of the lesion prevented the
rounded by multiple 2- to 8-mm erythematous satel- tumor from being simply excised. A safe and effective
lite papules (Figure 1). There were no palpable cervi- alternative treatment was needed.
cal, supraclavicular, axillary, or inguinal lymph nodes.
A systemic workup that included head, neck, and
chest computed tomographic scans showed no
involvement of other organs. Workups done to deter-
mine the source of her febrile episodes yielded no evi-
dence of active infection. The only abnormal labora-
tory finding was polyclonal hypergammaglobulinemia
found on serum protein electrophoresis. An incisional
biopsy was performed. Microscopically, a dense der-
mal infiltrate extended from the upper dermis deep to
the subcutis (Figure 2). The infiltrating cells were
mainly composed of histiocytes with large vesicular
nuclei. They also had abundant cytoplasm with spi-
dery borders. Neutrophils, lymphocytes, and plasma
cells were scattered between the histiocytes, and the
presence of lymphocytes engulfed within the histio-
cytic cytoplasm, a feature called emperipolesis, was also
noted. The mixed infiltration was neutrophil predomi-
nant. Immunohistochemical studies revealed histio-
cytes that stained positively for S100 protein and
CD-68. Notably, the dermis surrounding the histio-
cytes was infiltrated by numerous neutrophils. Clini-
cally and histologically, she was diagnosed as having
cutaneous Rosai-Dorfman disease (CRD).
Before visiting our hospital, she had been treated at Figure 1. A palm-sized, dusky erythematous plaque with several satellite
a dermatologic clinic for 2 months, first with topical reddish papules located on the right shoulder that was tender and intensely
triamcinolone, oral prednisolone (30 mg/d), and then itchy.

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428

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Figure 2. Microscopically, a dense dermal infiltrate was seen composed
mainly of histiocytes. Scattered neutrophils, lymphocytes, and plasma cells
were also found in the background. Engulfed cells were found within the
cytoplasm of some histiocytes (a feature called emperipolesis)
(hematoxylin-eosin, original magnification ⫻200).
SOLUTION
We administered oral dapsone, 100 mg daily, to treat the
patient since the skin biopsy findings revealed profuse
neutrophilic infiltration, which clinically corresponded
to an inflamed component of the disease. Ten days after
starting dapsone therapy, the patient felt an obvious im-
provement in the itching and local erythema. Within 3
months, the extensive and disfiguring skin lesion had un-
dergone significant regression (Figure 3). After 3 months
of treatment, the histologic characteristics of a skin bi-
opsy specimen taken from the right shoulder showed only
residual scar tissue; dapsone therapy was therefore dis-
continued. No recurrence of the skin lesion was noted
during the year that followed the discontinuation of dap-
sone therapy.
COMMENT
In 1969, Rosai and Dorfman1 first described the dis-
ease of sinus histiocytosis with massive lymphadenop-
athy (SHML), a histiocytosis syndrome that usually
presents with cervical lymphadenopathy. Extranodal
involvement is frequently seen and the skin is the
most common organ of involvement.2 The pure cuta-
neous form of this histiocytosis without involvement
of the lymph nodes or other organs is known as CRD.
The pathogenesis of SHML and CRD remains unclear.
Most cases of CRD have a limited distribution and are
self-limiting, requiring no treatment. However, the
disease has an unpredictable duration before reaching
spontaneous remission.3 Patients who have extensive
cutaneous involvement may be subjected to intoler-
able disfigurement and mental stress. In addition,
some patients are significantly disturbed by the symp-
toms and need careful evaluation and active treatment.
Various treatment modalities for localized CRD have
been introduced including superficial radiation treat-
ments, surgical excision, intralesional or systemic cor-
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429
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Figure 3. The lesions had regressed after 3 months of dapsone therapy.
Biopsy findings showed the presence of residual scar tissue only.
ticosteroids, retinoids, and thalidomide. 4-6 In our
patient, the previous treatments included systemic and
topical corticosteroids as well as oral isotretinoin, but
these drug regimens failed to relieve her symptoms.
We tried dapsone therapy because we noticed clini-
cally severe inflammation of the skin lesion with the
microscopic finding of profuse neutrophilic infiltra-
tion within the lesion. The skin lesions of CRD in the
presenting case regressed after 2 months of dapsone
treatment alone. The regression of her cutaneous
lesion could have been related to the incisional biopsy,
but progression of the skin lesions after she under-
went the first incisional biopsy for diagnosis at
another dermatology clinic makes the beneficial effect
of surgical intervention unlikely.
Dapsone (4,4⬘-diaminodiphenylsulfone) is an anti-
microbial substance that has anti-inflammatory activ-
ity, which has been attributed to its ability to inhibit
myeloperoxidase (MPO), a human enzyme in the
azurophilic granules of neutrophils and in the lyso-
somes of monocytes. During the process of neutro-
philic inflammation, MPO catalyzes the conversion of
hydrogen peroxide and chloride ions into hypochlo-
rous acid, a potent oxidant that causes cell damage,
thus forming a killing zone around activated neutro-
phils. Successful dapsone treatment, which targets
the neutrophilic component by inhibiting the MPO–
hydrogen peroxide–chloride system, may have
brought about the surprising regression of the major
histiocytic component of the lesion in our case. There-
fore, dapsone may be a useful treatment for neutro-
philic CRD. Dapsone has been found to be metabo-
lized to hydroxylamine in neutrophils, monocytes,
and activated mononuclear leukocytes.7 Since mono-
cytes and their derivatives, tissue macrophages and
histiocytes, also have MPO, dapsone may change their
inflammatory response too and it has been reported
to be a successful treatment for lymphohistiocyte-
predominant diseases such as erosive lichen planus.8
We surmise that similar effects should also contribute
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 A B
Figure 4. High-power view of the specimen. A, Centrally, there is 1
large histiocyte with eosinophilic cytoplasm (arrow) and several engulfed
cells (a feature called emperipolesis). The arrowhead indicates a typical
polymorphonucleated cell (hematoxylin-eosin, original magnification
⫻ 600). B, With a special stain for myeloperoxidase, not only the
polymorphonucleated cells (arrowhead) but also the histiocytes (arrow)
stained positive within their cytoplasm (original magnification ⫻ 600).
to the regression of the histiocytic component of CRD,
which was supported by the positive reaction of both
histiocytes and neutrophils to an MPO immunohisto-
chemical study in our presenting case (Figure 4).
Though the precise mechanisms of pathogenesis and
treatment response in CRD remain unknown, the sig-
nificance of our finding allows for an alternative thera-
peutic option when treating CRD, especially in those
cases where there is dense neutrophilic infiltration.
Correspondence: Chia-Yu Chu, MD, Department of
Dermatology, National Taiwan University Hospital, 7,
Chung-Shan South Road, Taipei, Taiwan (chiayu.chu
@gmail.com).
Financial Disclosure: None.
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430
©2006 American Medical Association. All rights reserved.
REFERENCES
1. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: a newly
recognized benign clinicopathological entity. Arch Pathol. 1969;87:63-70.
2. Chu P, LeBoit PE. Histologic features of cutaneous sinus histiocytosis (Rosai-
Dorfman disease): study of cases both with and without systemic involvement.
J Cutan Pathol. 1992;19:201-206.
3. Kang JM, Yang WI, Kim SM, Lee MG. Sinus histiocytosis (Rosai-Dorfman dis-
ease) clinically limited to the skin. Acta Derm Venereol. 1999;79:363-365.
4. Chang LY, Kuo TT, Chan HL. Extranodal Rosai-Dorfman disease with cutaneous,
ophthalmic and laryngeal involvement: report of a case treated with isotretinoin.
Int J Dermatol. 2002;41:888-891.
5. Tjiu JW, Hsiao CH, Tsai TF. Cutaneous Rosai-Dorfman disease: remission with
thalidomide treatment. Br J Dermatol. 2003;148:1060-1061.
6. Lu CI, Kuo TT, Wong WR, Hong HS. Clinical and histopathologic spectrum of cuta-
neous Rosai-Dorfman disease in Taiwan. J Am Acad Dermatol. 2004;51:931-939.
7. Uetrecht J, Zahid N, Shear NH, Biggar WD. Metabolism of dapsone to a hydrox-
ylamine by human neutrophils and mononuclear cells. J Pharmacol Exp Ther. 1988;
245:274-279.
8. Falk DK, Latour DL, King LE Jr. Dapsone in the treatment of erosive lichen planus.
J Am Acad Dermatol. 1985;12:567-570.
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