Histiocytic infiltrates of the skin
Philip E. LeBoit, M.D.
Depts. of Pathology and Dermatology
University of California, San Francisco
The topic of this lecture is infiltrates of “histiocytes”, i.e. those of a cell that does not
exist. The term histiocyte is usually used to connote a cell derived from blood
monocytes, which in tissue acquires a distinctive phenotype- more abundant cytoplasm,
which contains abundant lysosomes, and the ability to phagocytize. A synonym for this
cell type is macrophage. It is worth keeping in mind that the ability to eat debris or engulf
other cells is not unique to histiocytes.
Over the course of the twentieth century, a variety of conditions began to be considered
as histiocytic infiltrates, largely because their cells resembled histiocytes
morphologically. Some of these have proven to have other similarities to monocyte
derived macrophages, such as shared antigens or similar lineages. It is worth reviewing
the various “histiocytes” before embarking on an exploration of their proliferations.
Macrophages are monocyte derived cells that have exited the blood stream, as noted
above, and acquired phagocytic capacity. When they predominate in a focus in an
inflammatory condition, they can be said to have formed a granuloma. When
granulomata are the predominant finding in a specimen of an inflammatory skin disease,
one has a granulomatous dermatitis; when they are focally present in a condition in which
other features predominate, one has a dermatitis with granulomatous features.
Macrophages are usually identified in tissue sections by morphology, but one can try to
confirm their nature by immunohistochemistry. CD68 is the most commonly used
marker. CD68 is widely distributed, and antibodies such as PG-M1 may be a bit more
specific for macrophages than conventional CD68. Lysosyme also reacts with
macrophages. Mac387 was also widely used, but cross reacts with neutrophils.
Enzymatic and lectin stains for histiocytes are now largely of historic intersest.
Langerhans cells are derived from the bone marrow. The progenitors of Langerhans cells
are myeloperoxidase (MPO) negative or low in MPO, as are monocytes. They undergo
a set of immunophenotypic changes as they mature from precursor cells to mature
dendritic cells in a position in the mid-spinous layer of the epidermis. They were first
identified by Paul Langerhans with a gold chloride stain, and later by electron
microscopy as containing distinctive, squash racket shaped Birbeck granules. S100
proteins are a family of calcium binding proteins that are of relatively low weight (10-11
kDa), and are encoded on several different chromosomes, including 1q, 4p16, and 21.
These include S100a, b and p variants. S100ab is found on melanocytes, while
Langerhans cells contain S100bb. The S100 stains used in most surgical pathology
settings are polyclonal, and stain Langerhans more strongly than they do quiescent
melanocytes. The advent of an antibody to CD1a that reacts with that antigen in
routinely processed tissue has made it the method of choice for identifying Langerhans
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cells and their proliferations in biopsy specimens. Indeterminate cells are the dermal
analogue of Langerhans cells, being S100 and CD1a+, but lacking Birbeck granules.
Scholz W, Platzer B, Schumich A, Hocher B, Fritsch G, Knapp W, Strobl H.
Initial human myeloid/dendritic cell progenitors identified by absence of
myeloperoxidase protein expression. Exp Hematol. 2004 Mar;32(3):270-6.
Laman JD, Leenen PJ, Annels NE, Hogendoorn PC, Egeler RM.
Langerhans-cell histiocytosis 'insight into DC biology'.
Trends Immunol. 2003 Apr;24(4):190-6.
McNutt NS.
The S100 family of multipurpose calcium-binding proteins.
J Cutan Pathol. 1998 Nov;25(10):521-9.
Headington JT.
The histiocyte. In memoriam.
Arch Dermatol. 1986 May;122(5):532-3.
Sinus histiocytes are monocyte-macrophage derived cells found in the dilated sinusoids
of reactive lymph nodes. Their presence results in pale, sinuous swaths traversing nodal
tissue at scanning magnification. They are positive for most macrophage associated
markers, and weakly positive for S100 protein. They contain S100 aa heterodimers,
while most polyclonal S100 stains in general use stain more strongly with S100 b. In
sinus histiocytosis with massive lymphadenopathy (Rasai-Dorfman disease), S100
staining is strong, implying that more S100 b is present in the cells.
Dermal dendrocytes are a group of dendritic cells found within the dermis. The concept
of the dermal dendrocytes comes from the work of Terry Headington, who first noticed
on enzymatic staining for NADPH that cells that one might have mistaken for fibroblasts
had long dendrites. They include factor XIIIa+ dendrocytes and CD31+ dendrocytes.
FXIIIa+ dendritic cells are derived from monocytes, and modulate fibroblast responses to
inflammation and wound healing. Factor XIIIa polymerizes fibrin monomers, but also
has many other functions.
CD34+ dendritic cells are currently believed to be undifferentiated stromal reserve cells,
thought to be capable of giving rise to fibrocytes, myofibroblasts, adipocytes, endothelial
cells, and perhaps smooth muscle cells.
Silverman JS, Tamsen A. CD34 and Factor XIIIa-positive microvascular dendritic cells and the family of
fibrohistiocytic mesenchymal tumors. Am J Dermatopathol 1998; 20: 533.
Zelger and colleagues have proposed a morphologic spectrum of “histiocytes”. One can
scrutinize a lesion, looking for foamy, oncocytic (ground glass), scalloped and other
types.
Zelger BW, Sidoroff A, Orchard G, Cerio R.
Non-Langerhans cell histiocytoses. A new unifying concept.
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Am J Dermatopathol. 1996 Oct;18(5):490-504.
Langerhans cell histiocytosis
Long known as histiocytosis X, because the exact nature of the “histiocytes” was not
known, we now know that Langerhans cell histiocytosis is a neoplasm of Langerhans
cells. The various clinical forms of the condition and their eponyms reflect a spectrum of
disease in which there are varied homing sites and affinities of the neoplastic cells. Louis
Lichtenstein recognized that eosinophilic granuloma, HandSchullerChristian and (Abt)LettererSiwe diseases were proliferations of the same cell type, and coined the term
'histiocytosis X'. Later, Nezelof proposed that the Langerhans cell was responsible for
the disease spectrum. The clinical spectrum of Langerhans cell histiocytosis can be
viewed as:
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Acute disseminated Langerhans cell histiocytosis (LettererSiwe disease)
Chronic modified Langerhans cell histiocytosis (HandSchullerChristian
disease)
Chronic focal Langerhans cell histiocytosis (eosinophilic granuloma)
Congenital self-healing reticulohistiocytosis
Indeterminate cell histiocytosis
Clincial features:
The clinical presentations of these conditions vary somewhat:
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In acute disseminated Langerhans cell histiocytosis (LettererSiwe disease) about
half of patients present with skin lesions, and most develop them at some time
during the course of the disease. Most commonly, these are pink to yellow
papules that develop scales, and affect the scalp and other seborrheic dermatitisprone areas. Pustular and purpuric lesions can occur, as can ulcerative lesions in
mucous membranes.
In chronic modified Langerhans cell histiocytosis (HandSchullerChristian
disease), lesions are present in the skin in less than half of cases, and tend to be
fewer. The temple is a site of predilection. Xanthomatous lesions are said to be a
distinctive feature.
Cutaneous lesions are rare in patients with eosinophilic granuloma of bone.
Ulceration is common in periorificial sites, to which the lesions tend.
In congenital self-healing reticulohistiocytosis, lesions occur at or shortly after
birth, and tend to be papules of various sizes and nodules that ulcerate before they
disappear. In some patients, lesions re-appear later in childhood.
Indeterminate cell histiocytosis presents with red to yellow papules.
Histopathologic features:
The histopathologic findings in Langerhans cell histiocytosis are sufficiently similar that
one cannot look at a slide and know what type of Langerhans cell histiocytosis the patient
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has. All have in common dermal infiltrates of Langerhans cells, which are recognizable
via moderately large cell size, pale cytoplasm with indistinct borders, and reniform or
oval, vesicular nuclei that often have a longitudinal nuclear groove, imparting a coffee
bean-like shape. There are two main patterns, lichenoid and nodular.
Lichenoid infiltrates of Langerhans cell histiocytosis are bandlike in the papillary dermis
and sometimes, superficial reticular dermis, with variable degrees of (usually,
psoriasiform) epidermal hyperplasia, and of infiltration of the epidermis by Langerhans
cells. There are often extravasated erythrocytes and ulcers are common. The Langerhans
cells may form small clusters in the epidermis, simulating Pautrier collections of mycosis
fungoides. The dermal papillae are often edematous.
Nodular infiltrates of Langerhans cells occupy the reticular dermis. There can be
admixtures of eosinophils and/or neutrophils in either type of lesion.
In congenital self-healing reticulohistiocytosis, the findings are usually those of the
nodular form. In lesions that are regressing, zones of necrosis en masse can occur.
Confirmation of the diagnosis is usually by staining with CD1a; S100 positivity is less
specific. Without electron microscopy one cannot rule out the possibility of
indeterminate cell histiocytosis, but whether this has implications for treatment is no
known. Birbeck granules have not been identified in most cases of congenital selfhealing reticulohistiocytosis.
The differential diagnosis of the lichenoid form is with mycosis fungoides (esp. with
transformed cases) and spongiotic dermatitis, in which collections of Langerhans cells
can be present in the epidermis. That of the nodular form is with large cell lymphoma.
Treatment of limited forms is not necessary; widespread disease is treated with etoposide
or vinblastin. A lack of response after 6 weeks of treatment is an ominous sign.
Nezelof C, Basset F, Rousseau MF: Histiocytosis X: histogenetic arguments for a Langerhans cell origin.
Biomedicine 1973; 18: 365372.
Arceci RJ, Longley BJ, Emanuel PD. Atypical cellular disorders. Hematology (Am Soc Hematol Educ
Program) 2002; 297314.
Howarth DM, Gilchrist GS, Mullan BP, Wiseman GA, Edmonson JH, Schomberg PJ. Langerhans cell
histiocytosis: diagnosis, natural history, management, and outcome. Cancer 1999; 85: 22782290
Hashimoto K, Bale GF, Hawkins HK, Langston C, Pritzker MS. Congenital self-healing
reticulohistiocytosis (HashimotoPritzker type). Int J Dermatol 1986; 25: 516523.
Willman CL, Busque L, Griffith BB, Favara BE, McClain KL, Duncan MH,
Gilliland DG. Langerhans'-cell histiocytosis (histiocytosis X)--a clonal proliferative
disease. N Engl J Med. 1994 Jul 21;331(3):154-60.
Xanthomas
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The xanthomas can be grouped into:
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Eruptive
Tuberous
Tendinous
Plane
Eruptive xanthomas present with yellow papules on the buttocks, thighs and extensor
surfaces of arms and legs, as well as other sites. Their appearance is correlated with high
levels of chylomicra. They occur in crops, and tend to wane after several weeks.
Tuberous xanthomas form via the confluence of papules on the elbows, knees and
buttocks. They are characteristic of familial beta-lipoproteinemia, but can complicate
other lipid disorders.
Tendious xanthomas tend to occur in tendons and fascia of the hands and feet. They are
hard and persistent.
Plane xanthomas can occur in the skin folds of the palms (xanthoma striatum palmaris),
diffusely (diffuse, generalized plane xanthoma) and most commonly on the eyelids as
xanthelasma. They are flattish, yellow-orange lesions.
All of the xanthomas are characterized by collections of foamy histiocytes in the dermis.
In eruptive xanthoma, there are clusters of foamy histiocytes, neutrophils and
extracellular lipid, which can simulate the urate crystals of gout. Mucin also occurs in
the dermis.
Cooper PH.
Eruptive xanthoma: a microscopic simulant of granuloma annulare.
J Cutan Pathol. 1986 Jun;13(3):207-15.
Walsh NM, Murray S, D'Intino Y.
Eruptive xanthomata with urate-like crystals.
J Cutan Pathol. 1994 Aug;21(4):350-5.
Large nodular masses of these cells are present in tuberous and tendinous xanthomas. In
xanthelasma, small nests of foamy histiocytes are present around vellus follicles in the
eyelid.
Xanthoma disseminatum
Xanthoma disseminatum is a rare condition in which cutaneous lesion are sometimes
coupled with pituitary ones. It usually affects children or adolescents. There are mucosal
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lesions in about half of affected patients. The pituitary lesions result in diabetes insipidus
in about 40% of cases. Associated findings include Waldenstrom’s macroglobulinemia,
monoclonal gammopathy, growth retardation and hypothyroidism.
The cells of xanthoma disseminatum have some features of histiocytes and others of
factor XIIIa+ dermal dendrocytes. The clinical lesions are yellow to orange to red brown
plaques with a propensity to affect the axillae.
The infiltrates include both foamy histiocytes, Touton giant cells and histiocytes with
scalloped outlines in the dermis. Over time foamy histiocytes predominate, and fibrosis
can supervene. Variable numbers of lymphocytes, neutrophils and plasma cells can be
present. The process spares the epidermis and a zone of the papillary dermis. The
histiocytes stain for CD68, factor XIIIa and other macrophage markers, are CD1a- and
lack Birbeck granules by electron microscopy.
Aggressive cases may require treatment with cytostatic agents.
Seaton ED, Pillai GJ, Chu AC.
Treatment of xanthoma disseminatum with cyclophosphamide.
Br J Dermatol. 2004 Feb;150(2):346-9.
Necrobiotic xanthogranuloma with paraproteinemia
Necrobiotic xanthogranuloma with paraproteinemia is the description for a condition that
has some features of an inflammatory disease, and others of a neoplasm. A serum
paraprotein is almost always, but not invariably present. Prior to its description by
Winkelman and Kossard in 1980, many cases were undoubtedly regarded as necrobiosis
lipoidica, for reasons that will become apparent.
The clinical lesions of necrobiotic xanthogranuloma are well circumscribed yellow,
orange or brown plaques that can ulcerate. In most patients with the conditions, at least
one lesion is present in periorbital skin. Extensive local destruction can occur (including
loss of eyes and limbs). The other clinical manifestations include:
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Leukopenia
Paraproteinemia (usually IgG )
Plasmacytosis of the bone marrow (rarely myeloma)
Hyperlipidemia and hypercholesterolemia
Hypocomplementemia
Rare cases of myeloma have complicated the condition.
The histopathologic findings vary, but usually include:
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Infiltrates of foamy histiocytes and both more conventional, and Touton giant
cells
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Infiltrates of plasma cells
Lymphoid follicles
Palisading of foamy histiocytes around cholesterol clefts
Infiltration of the subcutis (lobules in addition to septa, sometimes with massive
necrosis)
The term “Touton cell panniculitis” was coined to describe the massive infiltrates of
foamy cells often present in the fat. The non-Touton type giant cells were initially
described as atypical, but do not seem to be.
Kossard S, Winkelmann RK.
Necrobiotic xanthogranuloma with paraproteinemia.
J Am Acad Dermatol. 1980 Sep;3(3):257-70.
Verruciform xanthoma
Verruciform xanthoma is a condition in which there are some features of a “reaction
pattern” rather than a true condition; it may better be termed “verruciform
xanthomatosis”. The cases that fit best as a disease are those in which warty plaques
present near mucous membranes. The mouth and genitalia are the most frequently
affected sites. The cases in which “verruciform xanthomatosis” is more apt complicate
blistering and other inflammatory diseases, and some neoplasms.
On microscopic examination, verruciform xanthoma shows papillated epithelial or
epidermal hyperplasia, with collections of foamy histiocytes in dermal papillae. There
are hyper- and parakeratosis in the clefts between papillations. Some studies have
suggested that the lipid in the foamy histiocytes is derived from the breakdown of
corneocytes.
Xanthogranuloma, juvenile and adult
Initially described as juvenile xanthogranuloma, it has been recognized that the condition
is not limited to children; the designation “xanthogranuloma” is more accurate.
Xanthogranulomas are yellow to red papules and nodules. They can present as either
single or multiple lesions in both children and adults. Multiple lesions can occur; in the
so-called papular form, papules are present in large number and can affect the eyes and
pericardium. Nodular xanthogranuloma tends to have fewer but larger lesions (up to 2 or
3 cm. in diameter- the larger lesions sometimes called “giant juvenile xanthogranuloma),
and no internal involvement. In most instances in children, the lesions appear at birth or
in infancy. The lesions tend to persist for years.
Café au lait spots, juvenile chronic myeloid leukemia or both are associated with juvenile
xanthogranuloma; the former two conditions are also associated with neurofibromatosis.
Children with NF-1 and JXG should be screened for leukemia.
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Xanthogranulomas in adults are similar to the nodular form in children, and lack
association with systemic complaints.
The histopathologic findings in xanthogranulomas are similar whether papular or
nodular, juvenile or adult. Early lesions feature diffuse dermal proliferations of small oval
mononuclear cells with moderate amounts of amphophilic cytoplasm and oval, vesicular
nuclei. The epidermis is spared. The upper dermis, or the entire dermis and upper
subcutis can be involved. Foamy cells can be rare and difficult to detect. If there are
multinucleated cells, careful scrutiny can be helpful in revealing a trace of foaminess in
their periphery cytoplasm- the first steps in the formation of Touton giant cells.
In fully developed xanthogranulomas, foamy histiocytes and Touton giant cells become
more plentiful. Lymphocytes, neutrophils, eosinophils and plasma cells may be present
in the background. Waning lesions acquire fibrosis, often with parallel lamellae of
collagen separated by clefts, superficially resembling a dermatofibroma.
The most useful immunoperoxidase stain at all stages of xanthogranuloma is factor XIIIa,
which strongly stains the cytoplasm of the histiocytes. The stain is especially useful in
the differential diagnosis of the early stages, in which leukemic infiltrates are a
consideration, and of the late stages, in which the cells more uniformly stain than do
those of dermatofibroma.
Shapiro PE, Silvers DN, Treiber RK, Cooper PH, True LD, Lattes R.
Juvenile xanthogranulomas with inconspicuous or absent foam cells and giant
cells. J Am Acad Dermatol. 1991 Jun;24(6 Pt 1):1005-9. No abstract available.
Burgdorf WH, Zelger B.
JXG, NF1, and JMML: alphabet soup or a clinical issue?
Pediatr Dermatol. 2004 Mar-Apr;21(2):174-6.
Solitary retoculohistiocytic granuloma
Solitary retoculohistiocytic granuloma is often viewed as part of a continuum with
multicentric retoculohistiocytosis, a point of view that is legitimized by morphologic
similarities, but is difficult to evaluate because of the rarity of the latter condition and the
blunt tools for distinguishing among popultions of “histiocytes”.
The lesions of solitary retoculohistiocytic granuloma are papules or nodules, yellow,
pink, tan or red-brown. They can be up to 2 cm. in diameter. They features cells with
“ground glass” cytoplasm, which deeply eosinophilic, granular appearing and has been
said to be “muddy rose” in color. Multinucleated cells with this type of cytoplasm and
central nuclei are scattered in the infiltrate. Histiocytes with foamy cytoplasm can be
present as a minority population. A background of neutrophilsis frequent.
Muticentric retoculohistiocytosis
In this rare condition, disseminated cutaneous papules are present, along with a
destructive arthropathy. The face, forearms and hands are prone to lesions, as are the
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joint spaces of the fingers. “Lipoid dermatoarthritis” is a synonym for the condition,
capturing both of its important components. The cutaneous lesions can arise before,
along with or after the synovial ones. The papules and nodules often persist for up to a
decade, and then wane; the destructive effects in the joints are permanent.
In diffuse cutaneous histiocytosis, widespread cutaneous papules are not accompanied by
synovial lesions. Both forms can be associated with a variety of extracutaneous
malignancies, both solid and hematopoietic.
The cutaneous lesions resemble those of solitary retoculohistiocytic granuloma
microscopically, with multinucleated cells that tend to be more uniformly rounded and
somewhat smaller than in the former condition. The infiltrates of multicentric
retoculohistiocytosis can be more patchy. There are often perivascular lymphocytes, but
fewer neutrophils in between the giant cells than in solitary retoculohistiocytic
granuloma. Foamy histiocytes, as represent a minority population in solitary
retoculohistiocytic granuloma are few. Factor XIIIa and the actin stain HHF-35 are
positive in solitary xanthogranuloma but not in multicentric retoculohistiocytosis.
Zelger B, Cerio R, Soyer HP, Misch K, Orchard G, Wilson-Jones E.
Reticulohistiocytoma and multicentric reticulohistiocytosis. Histopathologic and
immunophenotypic distinct entities.
Am J Dermatopathol. 1994 Dec;16(6):577-84.
Goette DK, Odom RB, Fitzwater JE Jr.
Diffuse cutaneous reticulohistiocytosis.
Arch Dermatol. 1982 Mar;118(3):173-6.
Snow JL, Muller SA.
Malignancy-associated multicentric reticulohistiocytosis: a clinical,
histological and immunophenotypic study.
Br J Dermatol. 1995 Jul;133(1):71-6.
Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease)
The condition initial described by Destombes, later by Reed, and more widely recalled
for the description by Rosai and Dorfman most often presents with cervical
lymphadenopathy, along with fever, anemia and polyclonal hypergammaglobbulinemia.
The stereotypic patient is a teenager, and in the United States the condition is especially
frequent in African Americans. Extranodular lesions are present in about a third of cases,
and cutaneous lesions in about 10%. The skin can be the presenting site, or the only site
of disease. In the cases in which it affected alone, lesions seldom are found elsewhere (a
situation analogous to that in primary cutaneous lymphoma). In patients with nodal
disease and skin lesions, the latter tend to be found on the face or head; cutaneous lesions
without systemic ones can occur anywhere, tend to occur in older patients than in those
with the systemic condition and occur more in Caucasians and Asians than in Africans.
The condition in lymph nodes causes massive expansion of the sinusoids by the
characteristic cells, which have abundant, pale vacuolated cytoplasm and variably large
vesicular nuclei with large central nucleoli. These cells often have other inflammatory
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cells in small vacuoles in their cytoplasm, evidence of ingestion without digestion, or
emperipolesis. Plasma cells are a frequent accompaniment.
The cutaneous lesions are often nodular or diffuse dermal infiltrates of similar cells (sinus
histiocytes). Emperipolesis can be evident in skin lesions, as can sinus histiocytes
appearing to float in the lumens of dilated lymphatic channels. Thick walled vessels
cuffed by plasma cells are common.
The cells of sinus histiocytosis with massive lymphadenopathy are S100+, but are CD1a-.
The S100 stain is particularly useful in demonstrating emperipolesis.
Brenn T, Calonje E, Granter SR, Leonard N, Grayson W, Fletcher CD, McKee PH. Cutaneous rosaidorfman disease is a distinct clinical entity. Am J Dermatopathol. 2002 Oct;24(5):385-91.
Thawerani H, Sanchez RL, Rosai J, Dorfman RF.
The cutaneous manifestations of sinus histiocytosis with massive
lymphadenopathy.
Arch Dermatol. 1978 Feb;114(2):191-7.
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 Jun;19(3):201-6.
Other “histocytic” conditions
Benign cephalic histiocytosis seems to be a variant of juvenile xanthogranuloma in
which lesions have a propensity to occur on the face. Progressive nodular histiocytosis
may also be a variant of juvenile xanthogranuloma in which multiple larger lesions are
present. Generalized eruptive histiocytoma is characterized by hundreds of papules,
which sometimes spontaneously resolve. Some cases have proven to be xanthoma
disseminatum.
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