Clinical features

. Letterer-Siwe disease
. Hand-Schuller-Christian disease
. Eosinophilic granuloma
. Congenital self-healing reticulohistiocytosis
 most commonly develops in children ages
1-3 years, though disease can develop at any age.
 annual incidence of at least 5 per million children,
with the adult incidence suspected to be less than
one-third that of children.
 male:female ratio of nearly 2: I
• HHV-6
• genetic basis
• elevated levels of cytokines
Clinical features
 Letterer-Siwe disease
•always develops prior to age 2 years, and commonly presents in children less
than 1 year of age
•1-2-mm pink to skin-colored
papules, pustules and/or vesicles in the scalp, flexural areas of the
neck, axilla and perineum, and on the trunk . The lesions
tend to coalesce and become tender. Scale and crust with secondary
impetiginization, and the development of petechiae and purpura are
•Lung,liver, lymph node and bone involvement commonly occur at some
• Occasionally, the hematopoietic system can be involved, with
thrombocytopenia and anemia portending a poor prognosis.
• triad of diabetes insipidus, bone lesions and exophthalmous.
•begins between the ages of 2 and 6 years
• Approximately 30% of patients develop skin or mucous
membrane lesions While early cutaneous lesions are similar
to those seen in Letterer-Siwe disease, older lesions may become
xanthomatousUlcerative nodules may develop in the oral and
genitalareas, with premature loss of teeth possible secondary to
gingival lesions.
•At least 80% of patients with Hand-Schuller-Christian disease
develop bone lesions, the cranium being preferentially involved.
Diabetes insipidus, secondary to infiltration of the posterior
pituitary by LCH cells, develops in approximately 30% of patients
Eosinophilic granuloma
• generally affects
older children
•a single asymptomatic granulomatous lesion of the bone
the most common manifestation .
• The cranium is most frequently affected.
Congenital self-healing reticulohistiocytosis
(Hashimoto-Pritzker disease)
• generally limited to the
skin and rapidly self-healing.
•It presents at birth or in the first few days of life
• characteristic eruption of widespread red to brown
•After several weeks, the lesions crust and involute.
• Solitary papules, nodules and vesicles have also been
•Adults rarely develop LCH but, when they do, the most
commonly involved sites are the skin, lung and bone.
• In a typical papule, a proliferation of LCH cells is present
in the papillary dermis . These cells are large, 10-15!lm in
diameter, with a reniform (kidney-shaped) nucleus.
•LCH cells show positive immunostaining for CDla and
SlOO ,Langerin (C0207)
•Electron microscopy demonstrates Birbeck granules,
which are rod- or racquet-shaped cytoplasmic structures
pathognomonic for Langerhans cells and LCH cells.
•evaluation of the hematologic, pulmonary, hepatic, renal and
skeletal systems
•For mild single-system skin disease (if treatment is required),
topical corticosteroids, topical antibacterial agents, PUVA,and
topical nitrogen mustard (mechlorethamine) have been reported
to be effective in case Series
•For more extensive disease, thalidomide may be effective.
Benign Cephalic Histiocytosis
• rare
• typically begins by the age of I year and always within the
first 3 years of life.
given a similar histopathology, ultrastructural appearance
xanthogranuloma and generalized eruptive histiocytoma,
several investigators have suggested that benign cephalic
histiocytosis may represent a variant of juvenile
xanthogranuloma or generalized eruptive histiocytoma.
Clinical features
•2-5-mm, red to red-brown macules and papules, first
on the face, with subsequent appearance on the ears
and neck.
• The lesions spontaneously resolve after months or
•The papules flatten, become briefly hyperpigmented,
and often disappear completely.
three histologic patterns in benign cephalic
histiocytosis: a papillary dermal pattern, a diffuse
pattern, and a lichenoid pattern.
generally a self-limiting disorder and no treatment is
Generalized Eruptive Histiocytoma
•very rare
•Onset in adults is from the third to sixth decade.
In children, onset is usually before age 4 years.
Clinical features
•recurrent crops of red to brown papules. At each
occurrence, hundreds of papules, less than 1 cm, are
distributed on the face, trunk and proximal extremities.
In adults, there may be a symmetric arrangement of
papules; mucosal surfaces are occasionally involved.
Within several months, the lesions resolve completely
or leave behind hyperpigmented macules or small Scars.
Internal involvement has not been observed.
•The superficial and mid dermis contain a nearly uniform
infiltrate of histiocytes with a few lymphocytes.
• The histiocytes stain for lysozyme, ai-antitrypsin, CD II
b,CD14b, Mac387, CD68 and factor XIIIa.
No treatment is required as the disorder is self-limited.
Indeterminate Cell Histiocytosis
•extremely rare
•The disorder occurs in adults, adolescents and infants,
and a congenital form has also been reported.
•The pathogenesis of indeterminate cell histiocytosis is
•However, it has most recently been speculated that
indeterminate cells are dendritic cells en route from the
skin to the regional lymph nodes.
Clinical features
•most cases of indeterminate cell histiocytosis have involved
the trunk and extremities.
• Both a generalized form and a solitary form have been
documented. In the generalized form, cutaneous lesions usually
begin as firm red to brown papules, each less than 1 cm. In the
solitary form, there is a single soft erythematous lesion,
approximately 1cm in diameter.
• The course may wax and wane, though most patients experience
a partial or complete regression of lesions.
•Mucous membrane involvement has not been observed. However,
ocular involvement has been described, and visceral involvement
and death have been reported in two instances.
• monomorphous
infiltrate of vacuolated! xanthomatized
mononuclear histiocytes throughout the entire dermis.
•Lesional cells show expression of S100, CD la, HAM56,
CD68, Mac387, lysozyme, ai-antitrypsin, HLA-DR, CDllc,
CD14b and factor XIIIa.
•no Birbeck granules are found.
Treatment of cutaneous lesions is not usually required as
the condition is often self-limited and the lesions are
There are case reports of the beneficial effects of PUVA
and 2-chlorodeoxyadenosine.
Juvenile Xanthogranuloma
•fairly common disorder and the most common histiocytic disease
of childhood.
•Almost 75% of cases appear during the first year of life, with over
15% being noted at birth. Juvenile xanthogranuloma is rare in
adults, in whom its peak incidence is in the late twenties to early
The cause of juvenile xanthogranuloma is not known. however, it
is often suggested that the condition is reactive with histiocytes
possibly responding to a traumatic or infectious stimulus.
Clinical features
•two common clinical variants a small nodular form and
large nodular form.
• Patients with the small nodular form, also known as the
micronodular form, can present with many pink to redbrown, dome-shaped papules, 2-5 mm in diameter. The
lesions are widely scattered on the upper part of the body
and rapidly become yellow.
•the more common large nodular form is characterized by
one or a few nodules 1-2 cm in diameter. Both forms
frequently coexist.
•The most common location for juvenile xanthogranuloma is
the head and neck ,followed by the upper torso, the upper
extremities and the lower extremities.
•Extracutaneous lesions have been reported in many
organs,the eye being most commonly affected. Visceral, bone
and CNS involvement is rare.
•The lung is the second most frequent extracutaneous site of
•Hyphema (hemorrhage into the anterior chamber) and
glaucoma are serious complications which can result in
•As well-recognizedassociation exists between juvenile
xanthogranuloma and cafe-au-lait macules.
•'triple association' consisting of juvenile xanthogranuloma, NF
1 and juvenile myelomonocytic leukemia.
•In the majority of patients with disease limited to the skin, the
course is self-limited and benign. These patients are otherwise
in good health and lesions usually regress within 3-6 years.
•dense infiltrate of histiocytes in the superficial dermis in
small lesions, extending into the subcutis in larger lesions.
•In the mature lesions, the histiocytes develop lipid in their
cytoplasm, creating a foamy 'xanthomatous' appearance.
Touton giant cells are a characteristic Finding
•stain positively for HAM56, CD68 and factor XIIIa. Some
cases have shown expression of S100. CDla is usually
Due to the self-limiting nature of the eruption, no treatment
is required.
Necrobiotic Xanthogranuloma
•The average age of onset is the sixth decade
The strong association of necrobiotic xanthogranuloma with
paraproteinemia has led to several hypotheses regarding
the pathogenesis of necrobiotic xanthogranuloma. The
paraprotein has been suspected either to be the primary
inciting agent or to act as a cofactor in eliciting a giant cell
granulomatous reaction.
Clinical features
•The classic skin lesion is an asymptomatic indurated papule,
nodule or plaque with a yellow 'xanthomatous' hue. Other
features can include telangiectasias, atrophy, ulceration of lesions
and scarring, with scars being common sites for development of
new lesions.
• The periorbital region is the most common site of involvement.
The trunk, remainder of the face, and proximal extremities are
also frequently involved.
•Approximately 50% of patients have ophthalmic manifestations,
which include orbital masses, ectropion, ptosis, conjunctival
lesions, keratitis and scleritis, episcleritis, anterior uveitis, and
•A hallmark feature of necrobiotic xanthogranuloma is the
associated paraproteinemia, an IgG monoclonal gammopathy,
which is found in at least 80% of cases.
• Other common findings include hepatomegaly, splenomegaly,
an increased ESR, leukopenia, hypocomplementemia, and
underlying myeloma or plasma cell dyscrasia. Less commonly,
cryoglobulinemia and/or an underlying Iymphoproliferative
disorder are observed.
•A palisading xanthogranuloma is found in the middle dermis
extending through the panniculus The granulomas consist
of histiocytes, foam cells, lymphoid follicles, plasma cells and
giant cells with zones of necrobiosis.
• Cholesterol clefts are found in areas of 'necrobiosis' (altered
collagen, in which there appears to be necrosis,loss of collagen
bundle integrity, and nuclear debris).
• A prominent feature is the presence of both Touton giant cells
and large, bizarre foreign body giant cells.
•stain positively for lysozyme, CD68, Mac387 and CD lIb.
No controlled clinical studies are available regarding the
treatment of necrobiotic xanthogranuloma.
Resolution or improvement of skin lesions has been seen in
some patients treated with low-dose chlorambucil,
melphalan or cyclophosphomide (systemic corticosteroids),
radiation therapy, CO2 laser, and plasmapheresis.
Reticulo histiocytosis
All forms of reticulohistiocytoses occur predominantly in
Caucasian adults.
•The pathogenesis of the reticulohistiocytoses is unknown.
However, it has been speculated that it represents an abnormal
histiocytic response to various stimuli. Mycobacteria have been
suggested as a possible trigger for multicentric
•Others have suggested that the histiocytic response in
multicentric reticulohistiocytosis is an immunologic process
related to an underlying autoimmune or neoplastic disorder.
•The cause of giant cell retieulohistiocytoma is even less clear.
Some lesions are believed to occur after trauma.
Clinical features
Giant cell reticulohistiocytoma presents as a single, asymptomatic,
yellow to red nodule. It can develop at any cutaneous site but is
thought to favor the head. The patients are otherwise healthy and
lesions tend to spontaneously resolve. Nodules are generally less
than 1 cm.
Multicentric reticulohistiocytosis is a disease characterized by
cutaneous and mucous membrane reticulohistiocytomas and
severe arthropathy. There is an association with hyperlipidemia,
positive tuberculin skin test, systemic vasculitis, and autoimmune
disease. Up to 28% of multicentric reticulohistiocytosis patients
have reportedly had an associated malignancy, with bronchial,
breast, stomach and cervical carcinomas being most common.
An elevated ESR and anemia have been noted in approximately
half of patients, and one-third demonstrate hypercholesterolcmia.
Occasionally, IgG hypergammaglobulinemia and cryoglobulincmia
have been observed. Fever and weight loss can occur.
•Cutancous lesions range from a few millimetcrs to 2 cm and are
skin-colored to red, brown or yellow. Lesions tend to be acrally
distributed. Favored sitcs include the head, hands, fingers, ears,
and articular regions of the limbs .
•Small papules aligned alongthe periungual regions result in a
characteristic 'coral bead' appearance. Approximately one-half of
patients develop papules and nodules of the oral, pharyngeal and
nasal mucosa.
•A 6-8-year course of symmetric, erosive arthritis of multiple
joints is common and there is progression to arthritis mutilans in
45% of cases. The joints of the fingers and hands, as well as the
knees and wrists, are most commonly involved.
• Rarely, there is histiocytic involvement of the heart, eye, lungs,
thyroid, liver, kidney, muscle, salivary gland and or bone marrow.
The disease spontaneously remits in 5-10 years, though patients
are often left with significant disability.
•dermal infiltrate of lymphocytes and histiocytes,with occasional
plasma cclls and eosinophils. The histiocytes have a characteristic
appearance. They are both mononuclear and multinuclear, with
abundant eosinophilic, homogenous, and finely granular cytoplasm,
creating a 'ground glass' effect.
reticulohistiocytosis histiocytes stain positively for lysozyme and aiantitrypsin and also express CD68, CDl1b, CD14 and HAM56.
•found that factor XIIIa was positive in cases of giant cell
reticulohistiocytosis lesions.
•Surgical excision of giant cell reticulohistiocytoma is curative.
•Most systemic therapy for multicentric reticulohistiocytosis has
not been effective. Although not in controlled clinical trials,
NSAIDs, oral corticosteroids, azathioprine, cyclophosphamide and
chlorambucil have been tried, but with limited or no benefit.
However, there are multiple case reports of substantial benefit
with methotrexate, either alone or in combination with
cyclophosphamide and corticosteroids.
Rosai-Dorfman Disease
(Sinus histiocytosis with massive lymphadenopathy)
•almost 600 cases had been reported by 1995.
•most commonly in children and young adults.
•The etiology of Rosai-Dorfman disease has not been identified,
though a viral pathogenesis has been postulated.EBV,HHV-6
•More recently, it has been suggested that Rosai-Dorfman disease
may be closely related to autoimmune lymphoproliferative syndrome,
an inherited disorder associated with defects in Fas-mediated
Clinical features
•The characteristic clinical feature is massive, painless, bilateral
cervical lymphadenopathy.
•elevated ESR and an IgG polyclonal hypergammaglobulinemia. A
common finding is mild anemia.
•There are multiple reports of non-Hodgkin lymphoma occurring
in association with Rosai-Dorfman disease.
•Immune disorders occur in approximately 15% of patients with
Rosai-Dorfman disease. Anti-red blood cell autoantibodies and
joint disease are the most common findings.
•Over 40% of patients with Rosai-Dorfman disease have at least
one extranodal site of involvement. The most common extranodal
sites are the skin and soft tissue, the eyelid and orbit, the upper
respiratory tract, major salivary glands, CNS and bone.
•Cutaneous involvement occurs in approximately 10% of cases.
•Cutaneous lesions are often multiple and appear as non-specific
red to red-brown or xanthomatous macules, papules, nodules or
•The eyelids and malar regions are frequent sites of involvement.
•dense dermal infiltrate of histiocytes with scattered
lymphocytes, plasma cells and neutrophils.The histiocytes
have large vesicular nuclei, small nucleoli, and abundant
foamy, eosinophilic cytoplasm with feathery borders.
•Rosai-Dorfman disease histiocytes stain positively for
S100, CD lIe,CD14, CD68, laminin 5 and lysozyme .Mac387
is occasionally expressed and examples positive for factor
XIIIa have been reported.
•Many lesions are asymptomatic and heal spontaneously,
thus not requiring treatment.
•When treatment is indicated due to destructive lesions,
disseminated disease or lesions causing physical
compromise, radiotherapy, surgical excision, systemic
corticosteroids, and alkylating agents have been used with
some success.
Xanthoma Disseminatum
•Age of onset ranges from 8 months to 85 years, though more than
60% of patients develop the disease before age 25 years.
The etiology of xanthoma disseminatum is unknown. As most
patients have normal lipid levels, it has been suggested that
xanthoma disseminatum represents a reactive proliferative
disorder of histiocytes with secondary accumulation of lipid.
Clinical features
•Patients with xanthoma disseminatum may demonstrate the
triad of cutaneous xanthomas, xanthomas of mucous
membranes, and diabetes insipidus.
•The primary xanthomatous lesion is a yellow, red or brown
•The onset of disease is marked by the eruption of hundreds
of papules, symmetrically arranged, on the face and in the
flexural and intertriginous areas of the trunk and proximal
extremities The lesions tend to cluster into well-formed,
potentially disfiguring Plaques.
•Mucous membrane lesions are found in 40-60% of patients
with xanthoma disseminatum, the upper airway and oral
mucosa being commonly involved.
•Corneal and conjunctival lesions can threaten vision. CNS
involvement of the hypothalamus and pituitary stalk results in
diabetes insipidus in 40% of patients.
• Rare associations with xanthoma disseminatum have
included plasma cell dyscrasia, monoclonal gammopathy and
thyroid disorders.
•that patients follow one of three clinical courses: (1) a rare
self-healing form with spontaneous resolution of lesions; (2)
the common persistent form in which lesions may never
resolve; and (3) the very rare progressive form with organ
dysfunction and CNS involvement.
•Fully developed lesions, however, demonstrate many foam cells and
scattered histiocytes, lymphocytes, plasma cells, Touton cells and
neutrophils. When intercellular accumulation of iron, or siderosis, is a
prominent feature, the disorder has been called 'disseminated
•siderosis is also found in juvenile xanthogranuloma .
•Xanthoma disseminatum histiocytes stain for lysozyme and aIantitrypsin and also express CD68, CDllb, CD14, CDllc and factor XIIIa.
For cutaneous and mucosal lesions, oral corticosteroids have not been
of value, while the effectiveness of clofibrate has been mixed.
Cyclophosphamide has been effective in the control of mucosal
lesions. Cutaneous lesions have been treated hy CO2 laser,
dermabrasion, radiotherapy, electrocoagulation, intralesional
corticosteroids, cryotherapy and surgical excision.

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