Extranodal rosai-dorfman disease with cutaneous and periodontal involvement: a rare presentation.

Abstract

Sinus histiocytosis with massive lymphadenopathy (SHML) or Rosai-Dorfman disease (RDD) was first described as a distinct clinicopathological entity by Rosai and Dorfman in 1969. SHML is commonly characterized by painless cervical lymphadenopathy, and its clinical course is generally benign and self-limiting. This disorder commonly involves the lymph nodes but may secondarily involve the skin. However, purely cutaneous disease without lymphadenopathy or internal organ involvement rarely occurs. In the absence of the massive lymphadenopathy that is characteristic of RDD, the diagnosis of purely cutaneous RDD may be complicated by the rare, nonspecific clinical appearance of skin lesions and the broad histopathological differential diagnosis of this disorder. A high level of suspicion of this disease on the part of the clinician or pathologist is often required. We present a case of cutaneous RDD associated with involvement of periodontal tissue.

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Case Rep Oncol 2011;4:96–100
DOI: 10.1159/000324760
Published online:
February 16, 2011
© 2011 S. Karger AG, Basel
ISSN 1662–6575
www.karger.com/cro
This is an Open Access article licensed under the terms of the Creative Commons Attribution-
NonCommercial-NoDerivs 3.0 License (www.karger.com/OA-license), applicable to the online
version of the article only. Distribution for non-commercial purposes only.

M.J. Molina-Garrido, MD, PhD

Hospital Virgen de La Luz in Cuenca
Hermandad Donantes de Sangre 1
ES–16002 Cuenca (Spain)
Tel. +34 969 179 900, E-Mail mjmolinagarrido @ hotmail.com

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Extranodal Rosai-Dorfman
Disease with Cutaneous and
Periodontal Involvement:
A Rare Presentation
M.J. Molina-Garridoa C. Guillén-Ponceb
Departments of Medical Oncology, aHospital General Virgen de la Luz, Cuenca,
and bHospital Ramón y Cajal, Madrid, Spain

Key Words
Cervical lymphadenopathy · Chemotherapy · Cutaneous disease · Histiocytosis ·
Rosai-Dorfman disease
Abstract
Sinus histiocytosis with massive lymphadenopathy (SHML) or Rosai-Dorfman disease
(RDD) was first described as a distinct clinicopathological entity by Rosai and Dorfman in
1969. SHML is commonly characterized by painless cervical lymphadenopathy, and its
clinical course is generally benign and self-limiting. This disorder commonly involves the
lymph nodes but may secondarily involve the skin. However, purely cutaneous disease
without lymphadenopathy or internal organ involvement rarely occurs. In the absence of
the massive lymphadenopathy that is characteristic of RDD, the diagnosis of purely
cutaneous RDD may be complicated by the rare, nonspecific clinical appearance of skin
lesions and the broad histopathological differential diagnosis of this disorder. A high
level of suspicion of this disease on the part of the clinician or pathologist is often
required. We present a case of cutaneous RDD associated with involvement of
periodontal tissue.
Case Report
A 43-year-old man with a past medical history of Wolff-Parkinson-White syndrome presented with
a 2-month history of an asymptomatic parieto-occipital skin lesion (a 1.5-cm red-yellow nodule).
Superficial lymph nodes were not enlarged. The skin lesion was removed. The microscopic examination
revealed numerous histiocytes with abundant pale cytoplasm invading the lymph sinuses. Occasionally,
engulfed lymphocytes were noted in the cytoplasm of the histiocytes. Immunological staining showed
that the invading histiocytes were positive for CD68 and S-100 protein and were negative for CD1a and
CD20. These findings were consistent with the characteristics of Rosai-Dorfman disease (RDD). The
leukocyte count was normal. No anemia or hypergammaglobulinemia was noted, and there was no
reversal of CD4/CD8. The tests for hepatitis B surface antigen and antibodies to hepatitis C virus were
negative. Neither antibodies to human T-cell leukemia virus 1 or human immunodeficiency virus nor

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Case Rep Oncol 2011;4:96–100
DOI: 10.1159/000324760
Published online:
February 16, 2011
© 2011 S. Karger AG, Basel
ISSN 1662–6575
www.karger.com/cro


97
Epstein-Barr virus RNA were observed. Thoracic and abdominal CT showed a normal lung field with
no mediastinal lymphadenopathy, no hepatosplenomegaly and no large lymphadenopathy.
Hemophagocytic cells were absent in the bone marrow. The patient was eventually diagnosed with sinus
histiocytosis with massive lymphadenopathy involving the skin. Because he also described a 1-year
history of pain in his right inferior maxillary area, a positron emission tomography (PET) scan was
performed, which showed fluorodeoxyglucose uptake in the right inferior maxillary area (SUV 8.7).
Histological examination of the mucosal biopsy specimen showed large histiocytic cells with small
round-to-oval nuclei, which were strongly positive for S-100 and CD68, without emperipolesis. The
lesion was completely removed during surgery. A repeat PET was normal. The patient remained
asymptomatic with no signs of recurrence at the 3-month follow-up.
Discussion
Sinus histiocytosis with massive lymphadenopathy (SHML) is a rare disorder that is
characterized by non-malignant proliferation of distinctive histiocytic/phagocytic cells
within lymph node sinuses and the lymphatic system in extranodal sites. This condition
primarily affects children and young adults. In the literature, 423 cases of RDD have been
reported [1].
Although SHML is relatively rare, purely cutaneous RDD is even less common,
accounting for approximately 3% of SHML cases in one large study [2]. SHML skin
lesions may be diverse and can be found in virtually any location, including the face, ears,
trunk, extremities or genitalia [1, 3]. Several authors have suggested that cutaneous RDD
is a distinct clinical entity because of its unique epidemiology and the lack of systemic
involvement even with long-term follow-up [3–5]. The characteristics of nodal and purely
cutaneous RDD are shown in table 1.
Extranodal disease is documented in 30–40% of patients, and in some patients it
presents without associated lymphadenopathy, which may develop later in the course of
disease [1]. Extranodal involvement of at least one site is not uncommon, and it is rarely
the initial and only manifestation of the disease. The most commonly affected extranodal
sites include the skin and soft tissue, the upper respiratory tract and bone followed by the
genitourinary tract, the lower respiratory tract, the oral cavity, the gastrointestinal tract
[6], the orbit [7] and the testes. In cutaneous RDD, extranodal disease may also develop at
other sites, e.g. the eye, most commonly leading to uveitis [8, 9]. Central nervous system
involvement is very rare (<5%) [10].
Clinical laboratory findings include hematologic abnormalities, such as normocytic or
microcytic anemia [1, 11] and polyclonal hypergammaglobulinemia (90%). Rarely,
patients exhibit rheumatoid factor, antinuclear antibodies and a reversal of the CD4/CD8
ratio among peripheral lymphocytes. Immunological abnormalities are found in a
significant number of patients and often lead to a clinically unfavorable disease course.
Consistent serologic findings are lacking, although antibodies to pathogens, including
EBV and human herpesvirus (HHV-6), have been reported [12]. A small subset of
patients also has concurrent neoplasia, including non-Hodgkin lymphoma, other
histiocytic proliferations, myeloma, melanoma and carcinoma. In the case presented
herein, there was no relation to EBV, HIV or HHV-6 infection, or to any other neoplasia.
The hallmark of the SHML histiocyte is the presence of a variable number of intact
lymphocytes within the cytoplasm of the cell, which is a phenomenon referred to as
lymphophagocytosis or emperipolesis [1]. The histological differential diagnosis includes

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Case Rep Oncol 2011;4:96–100
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ISSN 1662–6575
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Langerhans cell histiocytosis, histiocytic sarcoma, storage disorders such as Gaucher’s
disease, classical Hodgkin’s lymphoma, metastatic melanoma and carcinoma, as well as
infections caused by Histoplasma and mycobacteria that involve the lymph nodes.
The most useful immunohistological markers for SHML histiocytes are the S-100
protein and the pan-macrophage antigens (CD86, CD14, CD15 and CD64). Whereas
Langerhans cells positively stain for the S-100 protein and CD1a, only rare CD1a-positive
cells are found in SHLM.
The clinical course of SHML is characterized by spontaneous resolution in most cases,
especially in those presenting with localized lymph node involvement. Sometimes, there
are episodes of exacerbation alternating with periods of remission that continue for many
years. Persistence of lymphadenopathy or progression to widespread dissemination may
occur, particularly in SHML that involves the kidneys, the lower respiratory tract or the
liver with associated immunological dysfunction. The reported mortality rate is 7%, with
many patients who have a fatal outcome having concomitant immune dysfunction [13].
The pathogenesis of this disease is poorly understood, although some researchers have
suggested that either infection or immunodeficiency might play a role [14]. Recently,
cases of SHML associated with the autoimmune lymphoproliferative syndrome have been
described [15].
The disease is self-limiting in most cases. In a recent review of treatment strategies for
SHML, 50% of patients (40/80) did not require any treatment. Patients given antibiotics
or anti-tuberculous drugs showed no response. Steroid therapy resulted in a reduction in
lymphadenopathy and associated fever. Only 2 of a total of 12 patients achieved complete
and durable remission after treatment with methotrexate. High-dose interferon-α was
given to 1 patient, which resulted in long-term remission [16]. In a recent report, the use
of the purine analogue 2-chlorodeoxyadenosine was found to be of clinical utility in these
cases [17]. The ideal treatment for SHML has not yet been determined. Cutaneous lesions
have been reported to respond to radiotherapy [4], cryotherapy, excision [4, 5], topical
and oral corticosteroids [4], and high-dose thalidomide [5].
The diagnosis of RDD should be considered in any atypical chronic inflammatory
lesion with a histiocytic component involving multiple organ systems, especially the skin.
In our case, the inflammatory lesion was localized to the maxillary area.
Immunohistochemical stains for the S-100 protein should be performed in these cases. To
our knowledge, this is the first case reported with such characteristics.

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Case Rep Oncol 2011;4:96–100
DOI: 10.1159/000324760
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February 16, 2011
© 2011 S. Karger AG, Basel
ISSN 1662–6575
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Table 1. Differential characteristics of nodal and purely cutaneous Rosai-Dorfman disease
Characteristics Nodal Rosai-Dorfman Purely cutaneous Rosai-Dorfman
Frequency
Predominant sex
Age
Race
Presenting symptoms
General symptoms
60–70%
male
20.6 years
no race predominant
painless lymphadenopathy
typically fever, malaise,
night sweats
yes
cervical region (90%)

very common
not very common
positive
negative most times
observation
steroids
chemotherapy
methotrexate
alkylating agents
high doses of interferon-α
3%
female
43.7 years
Asian/white
cutaneous lesion
usually none
Nodal involvement
Involved area
Biopsy
Emperipolesis
Fibrosis
S-100
CD1a
Treatment
no
face, ears, trunk, extremities, genitalia

not very common
very common
positive
usually negative
observation
steroids (oral or local)
radiotherapy
cryotherapy
surgery
high doses of thalidomide



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