Histiocytes and Histiocytosis

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REVIEWARTICLE
Histiocytes and Histiocytosis
By Martin J. Cline
F
EW CATEGORIES of disease are as confusing as the
histiocytic disorders. The historical origins of this confusion are readily understandable. At the time of the initial
descriptions of these diseases, few reliable markers were
available to determine either the lineage or the stage of differentiation of the cells involved. Moreover, malignancy as
applied to the histiocytic diseases was an operational definition founded on an aggressive clinical course or aberrant
morphology rather than on knowledge of clonality and altered cellular differentiation. These uncertainties stimulated
a proliferation of multiple names for similar clinical syndromes, further adding to the confusion. Fortunately, this
situation has now begun to change. With the techniques of
modem cellular and molecular biology it is now possible to
reevaluate and catalogue the histiocytic disorders by less
ambiguous criteria than those used previously.
THE CELLULAR ORIGINS OF HISTIOCYTES
The term histiocyte was originally used to designate a large cell
normally found in lymph nodes and spleen that was morphologically
nonspecific, but had voluminous, granulated cytoplasm, sometimes
containing ingested particles, and one or more round to irregularly
shaped pale nuclei.' Subsequently, the term histiocyte was taken as
synonymous with the fully differentiated end cells of the monocyte/
macrophage lineage including sinusoidal macrophages in the spleen,
alveolar macrophages in the lung, and Kupffer cells in the liver.*
Still more recently, the term has been extended to include another
group of cells comprised of Langerhans cells of the skin, interdigitating dendritic cells ofthe lymph nodes, thymus, and spleen, and
dendritic reticulum cells found principally in the germinal centers
of lymph nodes.' Consequently, theterm histiocyte, as currently
used, embraces cells of both the monocytehacrophage series and
the Langerhans ceWdendritic cell series. Sometimes the cellular system that embraces both macrophages and Langerhans cells/dendritic
cells is called the mononuclear phagocyte and immunoregulatory
effector system (M-PIRE).
The current concept of lineage derivation of macrophages and
dendritic cells is summarized in Fig IA. Both macrophages and
Langerhanddendritic cells arise from bone marrow (BM) CD34'
stem cells, probably under the influence of granulocyt-macrophage
colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and tumor
necrosis factor a (TNFCY).'',~Macrophages develop from thestem
cell, designated colony-forming unit granulocyte-macrophage (CFUGM), committed to granulocyte and macrophage differentiation.
These stem cells give rise to promonocytes that mature in the BM
to monocytes, which then briefly circulate in the blood before entering the tissues to complete the maturation process.' The Langerhans
cell also develops from a blood cell that originates in the BM. Its
From the Department of Medicine, Centerfor the Health Sciences,
University of California Los Angeles.
Submitted December 22, 1993; accepted June 14, 1994.
Supported by funds of the Ludwig Institute for Cancer Research
(Middlesex Branch), agrant from the Leukaemia Research Fund of
Great Britain, and US Public Health Service Grant No. CA50275.
Address reprint requests to Martin J. Cline, MD, Department of
Medicine, Factor Bldg 11-232, UCLA, Los Angeles, CA 90024.
0 1994 by The American Society of Hematology.
0006-497//94/8409-0002$3.00/0
2840
maturation commences in the epidermis, but may not be completed
before these cells migrate into the lymphatics of the dermis and are
swept along to lymph nodes. There, in regions rich in T cells, they
complete the process of maturation into dendritic cells. Whether the
Langerhans cell is an obligatory intermediate in the maturation of
an interdigitating dendritic cell or whether these antigen-presenting
cells can also develop more directly from blood borne cells is not
known. Langerhans cells contain distinctive Birbeck granules that
are not found in macrophages or other cell types. These are rodand, occasionally, tennis-racquet-shaped organelles with a central
zipper-like striation.
Functionally, monocytes and macrophages are "professional
phagocytes" that defend against microorganisms and rid the body
of unwanted organic and inorganic particles by means of their phagocytic prowess. The Langerhans and dendritic cells are poor phagocytes," but are highly evolved for the efficient presentation of new
antigens to CD4+ T lymphocytes inthe initiation of the immune
re~ponse.~
They present antigen in conjunction with their rich array
of surface MHC class I1 and CDla antigens. The Langerhans cells
develop from a population ofCD4' and CD5' blood cells.7 With
continued maturation in vitro, and presumably in vivo, they develop
into dendritic cells. In the process of maturation, Birbeck granules
and cytoplasmic endosomes that are abundant inthe Langerhans
cell' become less abundant and maybe sparse or absent in the mature
dendritic cells.' CDla antigen density also diminishes.
Macrophages and dendritic cells share certain characteristics, and
it is probable, butnot certain, thatthey belong to the same cell
lineage. The evidence for a common lineage is as follows. Both cell
lines arise from blood cells that originate in BM stem cells bearing
CD34 surface antigen.4.5Differentiated macrophages and dendritic
cells have many antigens in common including CDla, CD18, CD45,
CDS4, andsurface receptors for some Ig and complement molecules,
but each also has
unique
(Table I). Both types of cells
respond tothe growth stimulatory signals of GM-CSF, IL-3, and
Tp,TFa,A,S.'Y.40 and both synthesize certain biologically active molecules including IL-I& macrophage inflammatory protein l a (MIPla), and MIP-2.3h.37
The fact that they differ in certain morphologic
features and in phagocytic and antigen-presenting abilities does not
argue against a common lineage, for it has long been known that
macrophages from different anatomic sites differ structurally and
that environmental conditions have profound influences on whether
the cell develops the characteristics of a tissue or ofan alveolar
macrophage.* The only strong argument against a common cellular
origin of macrophages and dendritic cells is the observation that in
osteopetrotic mice congenitally deficient in CSF-I production, tissue
macrophages are decreased in numbers, but dendritic cells are not:'
Balanced against this are observations, both in fetal murine development and in differentiation of human cord blood cells in vitro, that
there are phenotypic transitions between macrophages and dendritic
cells in the display of antigens such as CDla, CD14, CD33, and
receptors for Ig and C3b complement ~omponent.l'~~~~~*"
TWO other
observations, which admittedly may have alternative explanations
than a common lineage, are also pertinent. First, inthe ChediakHigashi syndrome, giant lysosomes are seen in Langerhans cells as
well as granulocytes and macrophages,"' suggesting that these cells
arise from the same abnormal stem cell. Second, diseases of Langerhans cells have occasionally been reported to evolve to acute malignancies of monocytic cells.4h
Among the antigenic, structural, and functional markers that are
helpful in identifying macrophages and Langerhans cells in disease
states are CDla and IC, CD15, CD30, CD45, CD68, acid phosphatase, and lysozyme (Table I). Two features are particularly useful
Blood, Vol 84,No 9 (November l), 1994:pp 2840-2853
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HISTIOCYTES A N D HISTIOCYTOSIS
284 1
A.
MONOCYTE
/
PROMON
CFU-GM
/
?
\
se
B.
MALIGNANT MACROPHAGES
REACTIVEMACROPHAGES
Fig 1. Theoriginofhistiocytes and the histiocytic disorders. (A) Thecellularorigin
of
macrophages, Langerhans cells,
and dendritic cells from CD34+
stem cell (SC). Langerhans cells
and, t o a lesser extent, dendritic
cells
have
distinctive
intracytoplasmic Birbeck granules. The
direct pathway between Langerhans
cells
and
the
common
granulocytelmacrophage
stem
cell (CFU-GM) is not certain. (B)
Macrophages
and
Langerhans
cells play prominent roles
in four
categories of disease: reactive
and malignant macrophage disorders and reactive and malignant Langerhans cell disorders.
ROMONOCYTE
\
LHC
LH
REACTIVELANGERHANS
CELLS
distinguishing
in
these
cells from
other
cell
types
and
from each
other:
distinctive
the Birbeck
granules
in Langerhans
the
cells
and
phagocytosis by macrophages of large particles such as blood cells.
Macrophages lack Langerhans
Birbeck
granules,
are
and
cells
only
weakly plragocytic,h
Although a variety of
cells, including
rhabdomyosarcoma cells and myeloma cells. may occasionally
exhibitphagocytosis,thephenomenonis
not commonandthesecells
are
readily
distinguished
from mononuclear
phagocytes.
MALIGNANTLANGERHANS
CELLS
CRITERIA FOR CLASSIFICATION OF
HISTIOCYTIC DISORDERS
With current
Of the
Of
the histiocyticcelllineages,itisnow
possible to formulate
a reasonable catalogue of histiocytic diseases based on Ultrastructural and phenotypic markers oflineage(Table 1) and
molecular
or
chromosomal
markers
of
malignancy.
In the
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MARTIN J. CLINE
2842
r
MACROPHAGE HISTIOCYTOSIS
"_MALIGNANT
1. MALIGNANT
HEMO-PHAGOCYTIC
3. ? TRUEHISTIOCYTIC
REACTIVEMACROPHAGE
HISTIOCYTOSIS
_" " " " " " "
2. BENIGNPROL/F€RATIVE
MACROPHAGE DISORDERS
"
\
1. STORAGEDISEASES
7
rnultlcentrlcretlcuiohistlocyt&
juvenilexanthogranuloma
xanthomadissernlnata, etc
3. FULMINANT HEMOPHAGOCYTIC SYNDOMf 9
4. H/STlOCYTOSlSWITHMASSIVE
LYMPHADENOPATHY
Letterer-Siwe disease
Histiocyticlymphoma
Fig 1. (Cont'd) (C)The reactive and malignant macrophage
and Langerhans Cell disorders
can befurther subdivided according to clinical features or behavior of the proliferating cells.
Although many of the cases reported probably represent either
reactive disorders or hemophagocytosis by
benign
macrophages inthesetting
of T-cell
lymphomas, there are probably
rare malignancies of macrophages based upon evidence
from cell lines and clonal chromosomal abnormalities. True
macrophage-type histiocytic lymphomas are very rare if they exist
at all. More evidence supports
the existence of histiocytic
lymphomasinwhich
dendritic
cells or, more rarely, Langerhans
cells are the principal element.
past, it was not always easy to determine whether a proliferare excellent markers of clonalitybut occur frequentlyin
ating cell was reactive or neoplastic, and several histiocytic
myeloid as well as lymphoid leukemia^.^^^^^ Using the above
diseasesthatwerethoughttobemalignanthave,
in fact,
criteria, one can reasonably conclude that true malignancies
never been shown to involve a clonal expansion of abnorof macrophages and Langerhans cells are uncommon, but
mally differentiated cells. In view of these uncertainties, it is
do exist.
important toprecisely define celllineage and to use objective
Classijication of Histiocytic Disorders
criteria for defining malignancy. I suggest the following criteria for defining histiocytic malignancy:
A logical approach to the classification of the histiocytic
Definite. Definite histiocytic maliganancy is a clonal disdisordersdividesthemintodiseases
of macrophagesand
ease with proliferation of cells with enzymatic, functional
those of Langerhanddendritic cells and then further subdiand/or immunophenotypic characteristics unique to macrovides these according to whether the proliferating cells are
phages or Langerhans cells. Because there are no known
malignantor "reactive;" ie, neoplastic or proliferating in
clonal markers unique to the histiocytic system, other markresponseto aninflammatorystimulus.Considered
in this
ers suchas chromosomalrearrangementsmustsometimes
way, there are four major categories of histiocytic disease:
be used to define c l ~ n a l i t y . ~ ~
(1) reactive macrophage histiocytoses, (2) malignant macroProbable. Probable histiocytic malignancy is ( I ) prolifphage histiocytoses, (3) reactiveLangerhanscell
histioeration of cells with enzymatic, functional, andor immunocytoses, and (4) malignant Langerhans cell histiocytoses. In
phenotypic characteristicsof macrophagesorLangerhans
the text that follows, I have attempted todistinguish between
cells, and disease progression to monoblastic leukemia and/
the reactive and malignant disorders based upon the criteria
or generation of a monoblastic leukemic cell line47.4x;or (2)
of malignancy described above. Where there is uncertainty
a clonal proliferation of cells, usually defined by a chromowith regard to the malignant nature of a given disorder, I
somal marker,with expression of phenotypicmarkers of
have so indicated.
more than one lineage, but including macrophage or LangerEach of these categories can then be further subdivided
hans cell markers.
according to the characteristics of the proliferating cells or
Possible. Possible histiocytic malignancy is a proliferaby clinical manifestation. For example, hemophagocytic
histion of cells with enzymatic, functional,and/or unique immutiocytoses encompasses several disorders with the common
nophenotypic characteristics of macrophages and a clonal
feature of morphologically dramatic phagocytosis of blood
rearrangement of Ig or T-cell receptor (TCR) genes.49
cells by large macrophages. Figure IB presents a schematic
The criteria listed as probable and possibletake cognisummary of the histiocytic diseases based upon cell lineage
zance of the fact that there is considerable "lineage infideland whether or not cell
proliferation is neoplastic or reactive.
ity" in acute leukemic hematopoiesis. Biphenotypic markers Fig1CandTable
2 presentan expanded version of this
are a common event,"' lineage conversion is a well-docuclassification of histiocytic diseases. In Table 2, six major
mented phenomenon," and Ig and TCR gene rearrangements categories of macrophage disease (types M-I to M-VI) and
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HISTIOCYTES AND HISTIOCYTOSIS
2843
Table 1. Markers for Macrophages, Langerhans Cells, and Dendritic Cells
Histiocytoses
Dendritic
Macrophage
Antigens
S-l00
MHC class II
CDla,c
CD4
CD11b,c
CD14 [My41
CD15A
CD18
CD25 [IL-2Rl
CD30 [Ki-l1
CD33 [My91
CD35 [C3bR)
CD45 [LCAI
CD54 [ICAM-11
ICAM-2
CD68 [KP-11
CD71 [Transf R1
FcR ICD16, 321
MAC 387
HB15
GM-CSFR
lgER
PNAR
Morphology
Birbeck granules
Lysosomes
Enzymes
Lysozyme
Acid phosphatase
ATPase
a-napthyl esterase
Antitryspsin
Antichymotrysin
Cathepsin E
a-mannosidase
Biologic
TNFa
IL-18
IL-6
Factor Xllla
MIP-la
MIP-2
Function
Phagocytosis
Antigen presentation
"
Langerhans
Cell
Cell
LHCH
MH-PH
++
++
++
++
-
++
++
++
+
+
-
f
-
++
++
+
+
?
+
-
+
-
+
+
t+
++
+
-
+
c
++
+
+
+
+
++
++
++
+
+
+
-c
++
-
-
+
2
+
+
?
+
+
t
++
+
+
+
-
++
+
+
+
+
+
diffuse
halo & dot
halo & dot
-
++
++
+
+
tt
-
-
++
+
-
-
-
+t
++
++
-
+
+
+
+
~
+
+
~
-
+
+
+
+
+
+
+
+
-
+
-
++
+
-
-
23
29
+
+
+
+
+
++
+
2
-
++
++
-+
+
-
2
10,22
8, 14, 18, 16
30
6
31
8
11,22, 32
2
+
-c
+
8, 10-14, 16
10, 11, 14
10, 17-19
8, 10, 20
8, 10
8, 10,17, 21
IO, 13, 21
10
10, 22, 23
13,15,16,21,
24
10,24, 25
13,16,21,25
10, 26, 27
10,28
16, 17, 23, 28,
4
+t
t
-
+
References
13,16,17, 21
8, 16, 23
8, 15, 33, 34
34
8. 16
8, 23
35
8
37
36, 37
36
14, 38
36
29
2, 6
3. 7
Abbreviations: LHCH, Langerhans cell histiocytosis; MH-PH, macrophage hemophagocytic histiocytosis; R, receptor; LCA, leukocyte common
antigen; PNA, peanut agglutinin; CAM-1, intercellular adhesion molecule 1; MHC, major histocompatability complex.
four categories of diseases of Langerhans cells (types L-I
to L-IV) are listed. This can be comparedwithaworking
classification proposed by the Histiocyte Society in 1987 that
has many of the same features, but does not distinguish among
thereactiveLangerhans cell disorders andgroupstogether
malignant disorders of macrophages and Langerhans cells.8
Nomenclature
A large number of clinical syndromes involving the proliferation of cells presumed or known to be histiocytes have
been described. As noted above, true malignancies have often not been distinguished from a reactive proliferation of
cells responding to antigenic or microbial stimuli. Additionally, each syndrome has been given at least one and usually
several names, and much of the relevant literature in the
past has been confusing and often chaotic. Obviously it is
desirable to use disease designations that precisely identify
the cells involved and the pathogenetic mechanisms when
these are known. The subsequent text presents suggested
names in boldface as well as historical designations in italics.
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MARTIN J. CLINE
2844
Table 2. Histiocytic Diseases
Disease
Reactive macrophage histiocytoses
M-l. Storage diseases
A. Gaucher's disease
B. Niemann-Pick disease
C. Sphingomyelinase deficiency,
etc
M 4 Benign proliferative
macrophage diseases
Xanthoma disseminata;
Multicentric reticulohistiocytosis;
Juvenile xanthogranuloma
Cell
MP
Characteristic Pathologic
Features
Clinical
EtioloavIPathoaenesis
Course
Ireferences)
Intracellular storage
material in
macrophages.
Chronic; I+_ organ
infiltration and
dysfunction.
Enzyme deficiencies
Macrophages with foamy
cytoplasm and usually
without particle
phagocytosis
Nodules in skin
joints and ?
viscera. Selflimited;
sometimes
recurrent
Unknown (38, 53-56)
MP
Macrophages
phagocytizing blood
cells
MP
Lymphocytophagocytosis
Benign to aggressive
disease in
children. Often
fatal
Benign tofatal;
lymphadenopathy,
? visceral disease
A. Reactive: viruses, bacteria,
drugs, SLE.
B. Familial of unknown cause.
(56-65, 76)
Usually unknown; rare
association with herpesvirus
6 or EBV (66-74)
Monoblast
Proliferation of primitive
hematopoietic cells in
BM
Proliferation of primitive
hematopoietic cells i n
BM
Proliferating MPS without
cellular phagocytosis
Aggressive; usually
fatal
Unknown, malignant
Aggressive; usually
fatal
Unknown, malignant
Cytopenias;
infiltration of soft
tissues and bone
Probably malignant with5q35
translocation and cell lines
(23, 47, 48)
LHC
Infiltration
with
Langerhans cells with
characteristic Birbeck
granules
Usually unknown (92-96,
99-101)
B. Relapsing Langerhans cell
histiocytosis
LHC
Infiltration
with
LHCs
C. Self-healing histiocytosis
LHC
Infiltration
with
LHCs
Variable; benign to
aggressive.
Involves bone -t
lungs, pituitary &
rarely viscera
Variable; benign to
aggressive; rarely
fatal. Relapsing
Skin involvement.
Benign
Presumptively malignant Langerhans
cell histiocytoses
L-11. Progressive Langerhans cell
histiocytosis (Letter-Siwe
disease)
LHC
Infiltration
with
LHCs
L-Ill. Langerhans cell lymphoma
LHC
L-W. Dendritic cell lymphoma
DC
M-Ill. Nonmalignant hemophagocytic
macrophage diseases
A. Fulminant hemophagocytic
syndrome
B. Histiocytosis with massive
lymphadenopathy (RosaiDorfman disease)
Malignant diseases of macrophages
M-IV. Acute monocytic leukemia
M-V. Chronic myelomonocytic
leukemia
Monoblast
M-VI. Malignant 5q35 histiocytosis
MP
Reactive Langerhans cell histiocytoses
L-l. Benign Langerhans cell
histiocytosis
A. Eosinophilic granuloma (HandSchuller-Christian disease)
Infiltration
with
LHCs
with Birbeck granules
replacement
Nodeby
cells with complex
interdigitating
processes
5
Fatal. Infiltration of
skin, marrow, and
viscera
Aggressive
lymphoma
Generally limited t o
lymph nodes
Unknown (97, 98, 102-108)
Unknown (88-91)
Possibly malignant, but
monoclonality not proven;
some progress to AMoL
(46, 111-128)
Probably malignant; only 2
cases reported (34,35)
Probably malignant; some
have aneuploidy (128-134);
13 cases reported
Historical designation of disease is given in italics.
Abbreviations: MP, macrophage; LHC, Langerhans cell; DC, dendritic cell; SLE, systemic lupus erythematosus; AMoL, acute monocytic leukemia.
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HISTIOCYTES AND HISTIOCYTOSIS
Where the historical designation is unambiguous, it has been
retained.
CATEGORIES OF DISEASE
Storage diseases involving macrophages. The storage
diseases (Table 2, Reactive Macrophage Histiocytoses, type
M-I) are a diverse group of heritable disorders that have the
common feature of macrophages filledwith nondigestible
organic material. Almost all involve an enzyme defect in a
normal degradative or catabolic pathway that leads to intracellular accumulation of material in phagocytes. These disorders are best considered under the inborn errors of metabolism rather than as histiocytic disorders and are not further
reviewed here. However, It should be noted that enzymatically normal macrophages can sometimes be overwhelmed
by excessive tissue breakdown and mimic in appearance the
cells found in the inherited enzyme deficiencies. For example, “sea blue” histiocytes may be seen in acquired idiopathic thrombocytopenic purpura as well as inherited sphingomyelinase deficiency.
Benign proliferativemacrophage diseases. The benign
proliferative macrophage diseases encompass a range of
disorders with the common feature of skinnoduleswith
macrophage infiltration (Table 2, Reactive Macrophage Histiocytoses, type M-11). Most studies suggest that in diseases
such as juvenile xanthogranuloma, xanthoma disseminata,
and multicentric reticulohistiocytosis, the predominant cells
are unequivocally macrophages, as evidenced by absence of
Birbeck granules and reactivity with antimacrophage serum
such as Mac 387.’4.’8.53-56
In juvenile xanthogranuloma, multinucleate giant cells called Touton cells are characteristic.’
Phagocytosis in these cells is notprominent. Therefore, these
disorders might be designated simply as benign proliferative macrophage diseases.
The clinical course of the benign proliferative macrophage
disorders varies from a self-limited disorder to an aggressive
disease with complications of tissue destruction and infection. In juvenile xanthogranuloma and xanthoma disseminata, nodules are widespread in the skin and mucous
membranes. Characteristically, the nodules in juvenile xanthogranuloma are 0.5 to l cm in diameter, are yellow to red
in color and are prominent on the scalp and face; however,
they can occur in the mesentery and viscera as well.” The
lesions usually appear in infancy, but may be present at birth
or may be delayed until adult life. They usually involute
spontaneously.
Multicentric histiocytosis is another rare multisystem disorder characterized by frequent joint involvement with a
destructive synoarthritis, as well as visceral and muscle
involvement, and may present problems in the differential
diagnosis of dermatoarthropathy. It is a disease of adults and
is sometimes associated with tuberculosis or with a concomitant malignan~y.’~
In one study of multicentric histiocytosis,
the cells were described as dermal dendrocytes on the basis
of factor XIIIa rea~tivity.~’
In individual cases, the issue of
cell lineage clearly can only be resolved by electron microsCOPY.
These benign proliferative macrophage disorders may all
be clinical variants of the same process; however, because
2845
the inciting agents are unknown, one cannot draw a firm
conclusion. There is no evidence for malignancy, but chemotherapy is sometimes indicated to interrupt the cycle of cell
proliferation and prevent a destructive arthropathy or a disfiguring skin lesion.56 These disorders should be distinguished from the reactive histiocytic proliferations occurring
in the setting of an immunodeficiency syndrome, such as
X-linked lymphoproliferative syndrome, or in a phagocyte
dysfunction syndrome such as chronic granulomatous disease. More familiar clinical disorders such as sarcoidosis
may also share some of the pathogenetic events leading to
proliferation and accumulation of mononuclear phagocytes.
Nonmalignant hemophagocyticmacrophage
disorders.
Several clinically distinctive hemophagocytic syndromes
have been described (Table 2, Reactive Macrophage Histiocytoses, type M-111). They are all characterized by the proliferation within lymph nodes and sometimes other tissues of
large macrophages phagocytizing and digesting blood cells
including redblood cells, lymphocytes, neutrophils, and
platelets. In all these syndromes, the predominant cell is
defined by the absence of Birbeck granules and the presence
of macrophage markers. In most cases, these macrophages
are normal cells that appear to be reacting toan inciting
stimulus. The nonmalignant hemophagocytic disorders include the following:
The fulminant hemophagocytic syndromes are aggressive and often fatal disorders most frequent in children and
characterized by fever, systemic symptoms, jaundice, multiple organ failure, coagulopathy, and phagocytosis of blood
elements with cytopenia~.~””It may be fatal in up to 40%
of cases, or recovery can occur in 1 to 8 weeks. The cells
are macrophages that have S-100, CDllc, CD14, CD33,
CD68, and receptors for Ig, complement and IL-2, and react
with antibodies to lysozyme and with Mac 387.
The etiology is usually not known, but some cases appear
to be a reaction to drugs” or infection with bacteria,” or
with viruses suchas Epstein-Barr virus (EBV)”,” and dengue
virus6’ Sometimes a cluster of cases is observed suggesting
transmission of a viral agent.59 In sporadic cases the clinical
settingisoftenassociatedwithimmunodeficiency.
A few
cases havebeenassociatedwithT-celllymphoma62-64
and
rarelywith systemic lupus.”It is uncertain in the T-cell
lymphoma cases whether viral infection, possibly with EBV,
is the inciting event to hemophagocytosis or whether in a
subset of these cases it is the malignant nature of the process
that is associated with hemophagocytosis. There is no evidence suggesting that the involved macrophages are neoplastic. The largest series of cases of fulminant hemophagocytic syndrome have been reported from Asia, where virus
infection is the usual inciting stimulus. Because of the frequency of associated viral infections, some authors have
used the designation viral-associated hemophagocytic syndrome for this disorder.
Familial forms of hemophagocytic syndrome known as
familial lymphophagocytic lymphadenopathy or familial
erythrophagocytic lyrnphohistiocytosis have also been described. They are often associated with defects in humoral
and cellular immunity. The clinical and histopathologic features of the familial form of this disorder are similar to those
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2846
MARTIN J. CLINE
of sporadic cases of hemophagocytic syndrome.8A few cases
Macrophage Diseases, types M-IV and V), true cancers of
the monocyte/macrophage lineage are rare. The monocytic
have been associated with T-cell lymphoma.h5The familial
leukemias including the acute varietyand chronic myelodisease canbean
aggressive and sometimes fatal illness.
monocytic leukemia are well characterized and will not be
Response to therapy is poor and allogeneic BM transplantafurther considered in this review.
tion has been used in treatment."
Nezelof et a1" described 20 childhood cases, collected
Sinus histiocytosis with massive lymphadenopathy
(Roover a period of 30 years, of a disorder characterized by
sai-Dorjbmn disease) is another of the hemophagocytic synfever, pancytopenia, and infiltration of lymph nodes, skin,
dromes inwhich macrophages are the main protagonists.
Lymphocytes inside of proliferating macrophages within the
bone and soft tissue by "histiocytes" that reacted positively
sinuses of lymph nodes is the predominant histologic feature.
for acid phosphatase, a-naphthyl acetate esterase, a-antichyThe macrophages are clearly defined by enzymatic and antimotrypsin, CD25, CD30, and CD68. In 1990, the same investigators described the DEL cell line isolated from the
genic analyses.66-6y
The internalized lymphocytes are frepleural effusion of one of these cases of malignant histioquently intact, suggesting that they have entered the macrocytosis. The cells react strongly for CD30 (Ki-l), CD25, and
phages by emperipolesis rather that by phagocytosis (ie, by
particle ingestion); however, the two processes may be diffiCD45, and with antibodies to HLA class I and I1 molecules.
cult to distinguish by light microscopy alone unless digestive
They have acid phosphatase, a-antitrypsin, a-antichymodegradation of phagocytized cells has already begun.
trypsin, and nitroblue tetrazolium reductase activity. They
Whereas massive lymphadenopathy usually dominates the
synthesize TNFa, show immunodependent phagocytosis,
clinical picture, some cases may involve the genitourinary
and differentiate in response to phorbol e ~ t e r . ~They
~ . ~ 'also
tract, upper airways, bone, or extranodal soft t i s s ~ e s . ~ ~ , ~ "have
, ~ ' a chromosome 5q35 rearrangement and a rearranged
Fever, systemic symptoms, and evidence of inflammation
Igheavy chain gene. In short, they are a line of clonal
including elevated erythrocyte sedimentation rate and granuleukemic cells with the characteristics of macrophages. This
locytosis are common. The outcome is usually benign, but
cell line is evidence thatatleast some of the "malignant
prognosis correlates with the number of diseased nodal
histiocytoses" are indeed malignant. Interestingly, four other
groups and withinvolvement of extranodal tissues. Over 400
malignant histiocytic cell lines with comparable phenotype
cases have been described.67Some cases have been associand 5q35 breakpoints have been reported.23These cases are
ated withEBV or herpesvirus 6 infection7' and one case
an argument for malignancies of the mononuclear phagocyte
system in addition to the monocytic leukemias. The term
with a malignant lymphoma,'' but usually the etiology is not
malignant 5q35 histiocytosis is suggested for this disorder
defined. Most cases do not require treatment, but corticosteroids, vinca alkaloids, and alkylating agents have been used
to distinguish it from other designations of malignant histiocytosis (Table 2, Malignant Diseases of Macrophages, type
in severe cases.74
M-VI).
Additional hemophagocytic disorders with names such as
There is some question as towhether there are true
hemophagic lymphohistiocytosis, and cytophagic histiocytic
lymphomas of macrophages. The great majority of lymphopanniculitis have been described, but it is unclear whether
masthatwere
originally diagnosed as true histiocytic
they are distinctive disease entities requiring separate termilymphomas of macrophage origin proved on more detailed
nology.
analysis to be T-cell or, less frequently, B-cell lymphomas.'"
A variety of names has been applied to still another rare
Those that have characteristics of true macrophage lymphoaggressive illness characterized by fever, systemic sympmas are nonexistent or constitute less than 1% of large setoms, abdominal and pleural effusions, and infiltration of
ries.7Y-81 For example, in one study of 925 cases of nonHodgskin, liver, lymph nodes, spleen, and BM by large multinukin's lymphomas, only four were considered to be true
cleate macrophages with ingested blood cells (Fig 2). The
histiocytic lymphomas and none of these was shown to be
skin lesions are polymorphous and vary from macular erupclonal." In another well studied series, 15 cases originally
tions resembling those seenin vasculitis to firm nodular
diagnosed as malignant histiocytosis were reexamined and
infiltrates (Fig 3). Survival after onset of symptoms is usually
none could be shown to be of histiocytic origin.8o On the
brief.75.76The designations for this syndrome, in order of
other hand, there are some tumors that are clonal on the
historical appearance, include histiocytic medullary reticbasis of Ig or TCR gene rearrangements and have proliferatulosis,77 adult histiocytosis X and malignant histiocytosis.
ing cells with the phenotypic characteristics of the monocyte/
The large phagocytic cells of this disorder are macrophages
macrophage lineage.4',79,82
These may possibly be biphenowhich often show positive reactions for Mac 387, KP-1, and
typic malignancies with a histiocytic component. Other rare
lysozyme.'6.21The disease behaves like a malignancy and is
lymphomas have cells with the morphologic appearance of
almost always fatal; however, most of the cases of histiocytic
histiocytes, lack B- and T-cell markers, and Ig and TCR
medullary reticulosis are probably examples of nonmaliggene rearrangements, and have macrophage markers includnant hemophagocytic disorders, some in association with
ing CD15, CD25, CD30, CD45, CD68, lysozyme, and Mac
T-cell lymphomas.76There is little evidence that the macro387.16.21.83 Clonality has not been proven for these lymphophages are neoplastic based on clonality and aberrant differmas. Given these sets of observations, one cannot say with
entiation. Two reports from Taiwan implicate fulminant
certainty that there are true histiocytic lymphomas comprised
EBV infection as the c a u ~ e . ~ ~ . ~ '
of malignant macrophages; however, for the moment, it is
Malignant diseases of monocytes and macrophages.
best to keep an open mind about this possibility.
Most students of hematologic neoplasia agree that, with the
Langerhans cell histiocytoses. In 1953, Lichtenstein,
exception of the monocytic leukemias (Table 2, Malignant
From www.bloodjournal.org by guest on October 21, 2014. For personal use only.
HISTIOCYTES AND HISTIOCYTOSIS
Fig 2. A macrophage with ingestednormoblastsfrom
the
BM of a patient with hemophagocytic histiocytosis.
drawing on the observations of earlier scholars that several
disease syndromes had similar histologic features, coined
the generic term histiocytosis X to encompass eosinophilic
granuloma of bone, Hand-Schuller-Christian disease, and
Letterer-Siwe disease.x4 Manydisorders that were classified
under this rubric are now known to involve proliferation of
Langerhans cell precursors and it has been proposed that the
generic term be changed to Langerhans cell histiocytoses.
It is convenient to divide these histiocytoses into two categories: nonmalignant disorders that are generally characterized
by chronicity and granulomatous lesions, and the progressive
and neoplastic diseases that are usually clinically acute and
characterized by lesions in which cell proliferation is prominent. The former include the many variants of unifocal and
multifocal eosinophilic granuloma and relapsing Langerhans cell histiocytosis. The presumptively malignant disorders include the childhood and adult variants of what was
formerly called Letterer-Siwe disease and the Langerhans/
dendritic cell variants of true histiocytic lymphoma. Problems frequently arise in the differential diagnosis of the
Langerhans cell histiocytoses if only conventional histologic
examination isused without ultrastructural or phenotypic
analysis. Most often the confusion arises between histiocytosis and high-grade lymphoma^."^^^'^^
Benign Langerhans cell histiocytosis. There are several
nonmalignant diseases of Langerhans cells (Table 2, Reactive
Langerhans Cell Histiocytosis, types L-l , A through C). Perhapstherarestisso-called
congenital self-healing histiocytosis which, as the nameimplies,isgenerally
a benign
disorder diagnosed at birth?'-'' The skin is the predominant
organinvolvedandlesions
may be widespread,prompting
the designation of a "bluebeny muffinbaby."Most
cases
resolve spontaneously, butoccasionally,patients die from pulmonary involvement by the proliferating cells. There is little
doubt that this is a disorder of Langerhans cells based on the
presence of Birbeck granules and other phenotypic markers.
The term Hashimoto-Pritzker-re Langerhans cell histiocytosis has been applied to this disorder when it is characterized by deep subcutaneous skin nodules? but there is little
rationale for retaining this designation.
The various disorders characterized by eosinophilic granuloma of bone and/or soft tissues are not
This term, whichiswidelyused,is
a misnomerbecause
the lesions are polymorphous with a variable mixture of
Langerhans cells, lymphocytes. foamy macrophages, fibroblasts, and
Macrophages with appropriate
markers are present in the lesions9' but the predominantcells
are clearly Langerhans cells. Although it has been proposed,
based on the composition of the cellular infiltrate, that the
granulomata may be a part of an immunologic reaction, the
granulomata are thought to be part of a benign reactive process withanunknown inciting stimulus. Occasional cases
may be associated with reaction to drugs." The disease usually starts in childhood or adolescence as a solitary bone
lesion. This is usually curable by curettage, excision, or irradiation, and the single bone lesion is considered to have an
excellent prognosis." However, unless the solitary lesion is
cured, the disease often spreads and continues to wax and
wane throughout life. Sometimes multifocalbone lesions
occur early. In its mostbenign form, the disease remains
restricted to bone; however, in about 50% of patients, the
pituitary is involved and diabetes insipidus
Loss
of other pituitary hormones is an occasional occurrence, and
one must be aware of the possibility of hypothyroidism and
estrogen deficiency as complications of this disease.
The clinical distinctions between the clinically benign
form of eosinophilic granuloma and other nonmalignant
diseases of Langerhans cells, such as Hand-Schuller-Cilristian disease, is often blurred. The latter disorder is also characterized by polymorphous lesions in bone and soft tissues
with diabetes insipidus and exophthalmos being a frequent
finding (Fig 4).
From www.bloodjournal.org by guest on October 21, 2014. For personal use only.
MARTIN J. CLINE
2848
-
are frequently used in treatment, there is no definitive evidence that the cells are neoplastic.
To emphasize the blurred margins between these reactive
Langerhans cell histiocytoses, it is not uncommon for localized eosinophilic granuloma to begin in childhood or adolescence and for the more widespread andaggressive disease
to appear later in life. For this reason, these disorders have
been provisionally grouped under a single disease category
in Table 2 (type L-I).
Localized disease is treated and often cured by local excision or radio the rap^,'^'."'^ but systemic disease is often
treated by chemotherapy including vinblastine and etoposide.l(YJ~lllA few of these cases end in leukemia, Hodgkin's
disease, or other lymphomas"'; however, the contribution
/
of years of chemotherapy to thisto evolution
difficult is
evaluate.
J
Progressive and malignant Langerhanscell histiocytoses.
Acute proliferative forms of Langerhans cell histiocytosis
are more common in children, but also occur in adults. The
common disease variant with involvement of the blood, BM,
and viscera as well as skin was, in the past, usually called
Letterer-Siwe disease or simply Itistir~cytosisX , but the term
progressive Langerhans cell histiocytosis is, for the moment, preferable (Table 2, Malignant Langerhans Cell Histiocytosis, type L-11). Cases have been reported in monozygotic infants"'and as a congenital disorder beginning in
utero."' The evidence for the neoplastic nature of these disorders
is weak and is not based
upon proven clonality, but
\
L - upon the weaker evidence of occasional progressionto
monocytic leukemia.& The rare reported associations with
mediastinal germ cell tumors"'."" may reflect observations
of the tissue phase of acute monocytic leukemia. The data
on aneuploidy of the Langerhans cells determined byflow
.,
cytometry have
been
conflicting. There are reports suggesting that abnormalities of chromosome 1 7 ~ 1 3 the
, site
"
"
1;i'
1
b
1\
k
\,
'
"
~~
~~
Fig 3. (A) Maculo-papularskin lesion in a patient with hemophagocytic histiocytosis. (B) Nodular skin lesion in a patient with hemophagocytic histiocytosis.
In the most aggressive form of Langerhans cell histiocytosis, which I have designated as relapsing Langerhans
cell histiocytosis (Table 2. type L-IB). the granulomata occur throughout the skin. in the mucous membranes of the
mouth and female genital tract, and in the lung^,"'^"'^^'''^ bone,
spleen, and lymph nodes."'"'" The viscera are occasionally
involved,"" butthe central nervous system outside of the
pituitary is usually spared.""
The disease often begins in adolescence, but continues
throughout life. I have seen a case with onset at menarche
followed by a long remission and then recurrence with pregnancy.""' This disease can be disfiguring, and lung involvement can be life threatening. In rare cases, lung transplantation has been attempted. As the name suggests, the disease
often pursues a relapsing and remitting course. There is a
poor correlation between the histologic appearance of the
Langerhans Cells and Clinical behavior of disease.Is Although
the disease maybe very aggressive and anticancer agents
'
Fig 4.
A child wkh Langerhanscell
hirtiocytosis
with prominent
exophthalmos. She also
had defects of membranous bone and diabetes insipidus.
From www.bloodjournal.org by guest on October 21, 2014. For personal use only.
2849
HISTIOCYTES AND HISTIOCYTOSIS
of the p53 gene, are common in this disease.”’ For now,
progressive Langerhans cell histiocytosis
is listed as a malignant disorder, but the reader should be aware that this
designation is uncertain.
The clinical and histologic borders that divide aggressive
relapsing Langerhans cell histiocytosis from progressive
are often indistinct. The
Langerhanscellhistiocytosis
course of progressive Langerhans cell histiocytosis
is often
acute and frequently fatal with visceral and hematopoietic
involvement. Skin lesions are prominent on the back, buttocks, and postauricular areas, and often resemble seborrheic
dermatitis. Lytic bone lesions have a predilection for the
skull and proptosis as a result of orbital involvement is a
common feature. Lymphadenopathy may be massive. Other
organs involved may include thymus, spleen, BM, kidney,
gastrointestinal tract, and muscle.LL8
The lungs often have a
honeycomb appearance on roentgenograms. The pituitary is
commonly infiltrated by tumor, but only rarely is the rest of
the central nervous system inv~lved.’’~
The proliferating
cells in the boney and visceral lesions have the morphologic
and phenotypic characteristics of Langerhans cells, and the
finding of Birbeck granules confirms the diagnosis8; however, there is a poor correlation between histologic appearance of the lesions and clinical behavior of disease.”
A variety of drugs have been used to treat these histiocytoses. The published reports do not always distinguish
between the different categories of histiocytic disease, so
one is uncertain as to whether malignancies of macrophages
or of Langerhans cells are being described. The drugs include
vinca alkaloids, doxorubicin, corticosteroids, etoposide, and
interferons given alone or in combination.120”22
Although the
rationale for using the drug was its toxicity for monocytes,
2-chlorodeoyxadenosine was reported tobe effective in a
case that appears to have been typical Langerhans cell histiocytosis.’”
Eleven patients in a series of 90 children with Langerhans
cell histiocytosis were considered to have a poor prognosis
based on organ dysfunction. They were treated with aggressive multiagent chemotherapy, but six died and three have
recurrent disease. In contrast, in good-prognosis patients, the
response to single chemotherapeutic agents is good, with
between 63% and 90% entering complete rernis~ion.’’~
Recently there have been several reports of BM transplantation
for malignant histiocytoses. At least some with Langerhans
cell histiocytosis have prolonged disease-free survival after
autologous or allogeneic BM transpiantation.’25.12h
Good results with liver tran~plantation’’~
and poor results with lung
transplantation have also been reported.”*
Malignant Langerhans cell and dendritic cell lymphomas.
There is some evidence for a localized form of malignant
Langerhans cell histiocytosis that could reasonably be called
Langerhans celllymphoma. Two cases have been described that were clinically aggressive neoplasms with
involvement of several organs. The tumor cells had prominent mitoses, Birbeck granules, and Langerhans cell markers
such as adenosine triphosphatase (ATPase). They also had
some markers found in macrophages including KP-1 and
nonspecific e~terase.”.’~
Like other malignant Langerhans
cell histiocytoses, they were negative for CD30.
There is more evidence for the existence of lymphomas
that appear to be neoplasms of interdigitating dendritic cells.
Thirteen cases have been d e ~ c r i b e d l ’ ~and
“ ~ ~recently reThe cell type is identified by ultrastructural analysis that shows long processes with complex interdigitations.
These are distinct from the proliferating cells involved in
the other forms of presumptively malignant histioc y ~ o ~ e ~ ~ 8 , 1 5 , 1 3 S ,Th
l ~ 6e cells generally lack definitive macrophage markers, but may stain weakly for acid phosphatase
and strongly for ATPase and C3b receptors. They react with
antibody CR4123, which is said to be specific for dendritic
~ e 1 l s . Although
l~~
the cells are predominantly mononuclear,
some tumors have aneuploidy by DNA analysis, suggesting
that these tumors are probably truly malignant.’32The clinical course of these dendritic cell lymphomas may be relatively benign or aggressive.’36
HISTORICALLANDMARKS IN THE
HISTIOCYTIC DISORDERS
In 1893, a 25-year-old medical resident by the name of
Alfred Hand, Jr, presented a paper to the Philadelphia Pathological Society entitled Polyuria and Tuberculosis. In it he
described the autopsy of a patient that showedseveral defects
in cranial bone.I3’ Hand reviewed the subject again, 28 years
later,’” but by that time several others had claimed a piece
of the action. In 1905, Kay described a similar case with
bone lesions, exophthalmos, and polyuria and presented the
patient to the Pennsylvania Medical Society.’3q In 1915,
Artur Schuller in Germany and, in 1920, Henry Christian of
the Peter Bent Brigham Hospital (Boston, MA), respectively,
described similar cases. Christian’s case was described in
Defects in Membraneous Bone, Exophthalmos and Diabetes
Insipidus, An Unusual Syndrome of Dy~pituitarism.‘~~
In 1924, Eurch Letterer described a 6-month-old child
with a fulminant nonleukemic proliferation of cells of the
reticuloendothelial ~ystem.’~’
Nine years later, Stem Siwe
put Letterer’s case together with two other cases to describe
ein neues Krankenheitsbild unter den HepatosplenomegaLike Hand before him, Siwe persevered in his interest
lien.142
and reviewed the histiocytic disorder again, 16 years later.I4’
In 1940 Lichtenstein and JaffeIu and Olani and EhrlichI4’
simultaneously described eosinophilic granuloma of bone,
and in 1941, Dr Sidney Farber at a meeting of the American
Association of Pathologists and Bacteriologists drew attention to the histologic similarities of Hand-Schuller-Christian
disease, Letterer-Siwe diseaseand eosinophilic granuloma of
bone.14‘ In 1953, Lichtenstein coined the termhistiocytosis X
to describe these entities. In 1966, Bassett and Nezeloff,
working in Paris, identified the Langerhans cell as being a
characteristic cellular feature of histiocytosis X.’47Nezelof
continues to work on this disease at p r e ~ e n t . ~ ’ . ~ ~ . ~ ’
SUMMARY
The term histiocyte refers to cells of either the macrophage
or Langerhans cell lineages. The histiocytic disorders are
characterized by the proliferation of cells of these lineages.
With recent advances in knowledge of the developmental
biology of histiocytic cells, it is now possible to formulate
a reasonable catalogue of histiocytic diseases based on ultrastructural and phenotypic markers of cellular origins and
From www.bloodjournal.org by guest on October 21, 2014. For personal use only.
MARTIN J. CLINE
2850
molecular or chromosomal markers of malignancy. The catalogue includes the following groups of diseases.
Nonmalignant reactive macrophage disorders include ( 1 )
macrophage storage diseases, ( 2 ) several benign proliferative
macrophage disorders that predominantly involve skin and
bone, and (3) several hemophagocytic syndromes that vary
from indolent and benign to fulminant and fatal. In some of
the latter disorders, viruses have been identified as the inciting stimulus.
The malignant macrophage disorders include ( l ) acute
monocytic leukemia and ( 2 ) chronic myelomonocytic leukemia. A rare disorder that gave rise to a permanent cell line
with an anomaly of chromosomal segment 5q35 may also
be an example of a histiocytic malignancy. The existence of
a separate category of true histiocytic lymphoma of macrophage type is uncertain.
Reactive Langerhans cell disorders include (1 ) congenital
self-healing histiocytosis, ( 2 ) the many variants of eosinophilic granuloma, and (3) a related disorder designated as
relapsing Langerhans cell histiocytosis that is characterized
by a relapsing course and infiltration of bone and soft tissues
by Langerhans cells.
Presumptively neoplastic diseases of Langerhans and dendritic cells include ( 1 ) progressive Langerhans cell histiocytosis, a disease with prominent involvement of blood and
BM as well as skinand
viscera; ( 2 ) Langerhans cell
lymphoma, and (3) dendritic cell lymphoma. However, clonality as a marker of malignancy has not been proven in these
disorders.
NOTEADDED
IN PROOF
A recent report’48provides strong evidence that all forms
of Langerhans cell histiocytosis are clonal. This means that
eosinophilic granuloma and relapsing Langerhans cell histiocytosis should be classified among the malignant disorders
of histiocytes.
ACKNOWLEDGMENT
I am grateful to a reviewer of this manuscript for pointing out
the correct sequence of historical events in defining the diseases
encompassed by the term histiocytosis X.
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