Vet Pathol 43:646–655 (2006)

Feline Progressive Histiocytosis

V. K. AFFOLTER AND P. F. MOORE
Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University
of California at Davis, Davis, CA

Abstract. Histiocytic proliferative diseases include reactive and neoplastic proliferations of dendritic
cells (DC) or macrophages. Various forms of DC proliferations have been documented in humans and
dogs; their etiology is largely unknown. With the exception of a few case reports, histiocytic
proliferations have not been characterized in cats. This study summarizes clinical, morphologic, and
immunophenotypic features of a feline progressive histiocytosis (FPH) in 30 cats. There was no breed or
age predilection. Females were more often affected than males. Solitary or multiple nonpruritic firm
papules, nodules, and plaques had a predilection for feet, legs, and face. Lesions consisted of poorly
circumscribed epitheliotropic (13/30) and nonepitheliotropic (17/30) histiocytic infiltrates of the
superficial and deep dermis, with variable extension into the subcutis. The histiocytic population was
relatively monomorphous early in the clinical course. With disease progression, cellular pleomorphism
was more frequently encountered. Histiocytes expressed CD1a, CD1c, CD18, and major histocompat-
ibility complex class II molecules. This immunophenotype suggests a DC origin of these lesions.
Coexpression of E-cadherin, a feature of cutaneous Langerhans cells, was only observed in 3 cats. FPH
followed a progressive clinical course; the lesions, however, were limited to the skin for an extended
period of time. Terminal involvement of internal organs was documented in 7 cases. Treatment with
chemotherapeutics or immunosuppressive and immunomodulatory drugs was not successful. The
etiology of FPH remains unknown. FPH is best considered an initially indolent cutaneous neoplasm,
which is mostly slowly progressive and may spread beyond the skin in the terminal stage.

Key words: Cats; CD1; dendritic antigen presenting cells; histiocytes; histiocytosis; histopathology;
immunohistochemistry; MHC II; skin.

Histiocytic proliferative diseases include prolif- and a systemic form.1 The lesions are characterized
erations of dendritic cells (DC) and macrophages.38 by a nodular, pleocellular infiltrate composed of
The latter are most efficient in phagocytosis of activated dermal DC, lymphocytes, and fewer
pathogens, whereas DC are primarily involved in neutrophils.1 The morphologic features and the
antigen presentation. Different DC sublineages clinical behavior of canine reactive histiocytosis as
home to specific tissues.2,8,21,29,33,38 Langerhans cells well as its response to therapy with immune-
populate the epidermis, the epithelia of mucous suppressive drugs suggest a dysregulation of the
membranes, and the follicular epithelium, and a few immune system.1 The canine solitary or dissemi-
cells may be seen in the perivascular dermis. nated histiocytic sarcomas, also referred to as
Interstitial DC are encountered in many organs; malignant histiocytosis, are malignant tumors and
in the skin (dermal DC) they mainly live in the have a poor prognosis.3 The majority of cases are
perivascular dermis. The plasmacytoid DC consti- of DC origin. However, the exact sublineage of DC
tute a major DC population of the peripheral involved in these malignant tumors is mostly
lymphoid organs in humans.29,33 The latter DC unknown. Some canine histiocytic sarcomas are
population has not been identified in companion of macrophage origin and primarily arise in the
animals to date. splenic red pulp or the bone marrow.26
Histiocytic proliferative diseases have been well Histiocytic proliferative diseases are uncommon
documented in humans and dogs.1,3,5,24,27,28,31 Their in cats, and their documentation is limited to a few
etiology and pathogenesis are largely unknown. case reports.10,12–14,18 The goal of this study was to
Canine cutaneous histiocytomas occur as solitary characterize a histiocytic proliferative disease ob-
or multiple skin nodules and are composed of served in 30 cats. Feline progressive histiocytosis
Langerhans cells.28 Histiocytomas are mostly self- (FPH) presents with solitary or multiple skin
limiting and regress spontaneously.28 Canine re- nodules. Although initially limited to the skin, the
active histiocytosis presents with a cutaneous form lesions have the potential to evolve into a malignant
646
Vet Pathol 43:5, 2006 Feline Progressive Histiocytosis 647

Table 1. Feline progressive histiocytosis in 30 cats.* histology and immunohistochemistry. Clinical history
and follow-up were received upon submission of the
Age Internal biopsies and by contacting referring veterinarians or
Cat Breed Sex (years) Lesions Euthanasia Necropsy owners. Seven cats were necropsied, and internal organ
samples were evaluated.
1 u u u
2 DSH mc 8 + + + Tissue handling
3 u u 2 + + –
Fresh skin samples obtained from 16 cats were
4 DSH f 3 + + +
bisected, and one-half of each sample was fixed in 10%
5 DSH fs 5
neutral buffered formalin and embedded in paraffin.
6 Mix m 3
The other half was embedded in OCT-compound
7 u u u – + –
(Finetek, Sakura USA, Torrance, CA) and snap frozen
8 DLH mc 13
in methylbutane cooled to the point of freezing with
9 DSH fs 10 – + –
liquid nitrogen. Formalin-fixed, paraffin-embedded
10 DSH fs 17 + + +
tissue blocks containing one or more skin samples were
11 DSH fs 16
submitted from 9 cats. Morphologic features were
12 u mc 4 + + +
evaluated on 4–6-mm hematoxylin and eosin (HE)–
13 u u u + + +
stained paraffin sections. Immunohistochemistry was
14 DLH mc 9
performed on 6-mm cryosections (16 cats) or on 6-mm
15 DSH f 5
paraffin sections (9 cats). Postmortem samples of
16 DSH mc 8 – + –
internal organs (7 cats) were handled as described
17 DSH fs 11
above. For the remaining 5 cats, only HE-stained
18 DSH m 14
paraffin sections were available.
19 Siam m 11
20 DSH fs 11 Antibodies
21 DSH fs 10 – + –
22 DSH fs 12 A panel of monoclonal antibodies specific for
23 Siam mc 14 leukocyte cell surface molecules (Table 2) was used to
Mix evaluate tissues from 25/30 cats. Most of these
24 DSH f 15 + + + antibodies are specific for feline leukocyte antigens
25 DSH f 10 (Table 2) and have been fully characterized by the
26 TS f 12 Leukocyte Antigen Biology Laboratory at the Univer-
27 DSH m 4 – + – sity of California.25 A few antibodies are specific
28 DSH f 4 – + – for canine leukocyte antigens, but cross-reactive for
29 DLH fs 7 + + + feline antigens.25 Anti-E-cadherin, anti-CD3e, and
30 DSH fs 8 – + – anti-CD79a are antibodies specific for conserved
cytoplasmic domains of the respective human proteins.
* u 5 unknown; DSH 5 Domestic Shorthair cat; Mix 5 These antibodies have been characterized as cross-
mixed breed cat; DLH 5 Domestic Longhair cat; Siam 5 reactive and have been used extensively in veterinary
Siamese; TS 5 Tortoise Shell cat; m 5 male; mc 5 male immunohistochemistry.17,22
castrated; f 5 female; fs 5 female spayed.
Immunohistochemistry
histiocytic neoplasia with metastases to lymph Immunohistochemistry was performed as previously
nodes and various internal organs. described.1 Cryosections were fixed in acetone, and
endogenous peroxidase was quenched with hydrogen
Material and Methods peroxide (0.3%) and sodium azide (0.1%) in phosphate-
Animals and tissue samples buffered saline (PBS). Blocking of nonspecific binding
was achieved with 10% heat-inactivated horse serum in
Tissue samples from 30 cats (Table 1) were submitted PBS (20 minutes at room temperature). Most primary
by veterinary practitioners, the Veterinary Medicine antibodies (Table 2) were applied as a 1 : 10 diluted tissue
Teaching Hospital at the University of California at culture fluid in PBS containing 10% inactivated horse
Davis, or other veterinary schools throughout the serum (30 minutes at room temperature). Anti-CD3e
United States and Canada to the Leukocyte Antigen and anti-CD79a were used as previously described.17,20
Biology Laboratory at the University of California for Omission of the primary antibody or application of an
a second opinion and immunohistochemical stains to isotype-matched, non–cross-reactive antibody was used
determine cell lineage of the lesions. As such, the true as a negative control in each run. Secondary biotiny-
incidence of this disease is difficult to estimate, but is lated horse anti-mouse IgG (Vector, Burlingame, CA)
likely to be very low. The samples submitted included was applied on each section, and subsequently the
punch biopsies or excisional biopsies of skin nodules. In sections were stained by the biotin-streptavidin-horse-
7 cats samples were collected at different times radish-peroxidase method according to the manufac-
throughout the disease process and submitted for turer’s instructions (Zymed, South San Francisco, CA)
648 Affolter and Moore Vet Pathol 43:5, 2006

Table 2. Monoclonal antibodies (MABs) used for immunophenotyping of 25 cats with feline progressive
histiocytosis: fresh, snap-frozen tissue from 16 cats, formalin-fixed tissues from 9 cats.*

Antigen MAB Species-Specificity Source Fresh Tissues Fixed Tissues Main Cell Reactivity
CD1a Fe1.5F4 Feline LABL X DC, Subpopulation-B Cells,
Monocytes
CD1c Fe5.5C1 Feline LABL X DC, Subpopulation-B Cells,
Monocytes
CD3e CD3-12 Human{ SE X X T Cells
CD4 Fe1.7B11 Feline LABL X T Cell Subpopulation
CD5 Fe1.1B11 Feline LABL X T Cells
CD8a Fe1.10E9 Feline LABL X T Cell Subpopulation
CD8b Fe5.4D2 Feline LABL X T Cell Subpopulation
CD11b Ca16.3E10 Canine{ LABL X Neutrophils, Monocytes,
Macrophages, Activated DC
CD11d Ca11.3D3 Canine{ LABL X Macrophages (splenic red pulp, bone
marrow), T Cell Subpopulation
CD18 Fe3.9F2 Feline LABL X X All Leukocytes
CD21 Ca2.1D6 Canine{ LABL X B Cells
CD45R B220 Mouse{ BD-PH X X B Cells, T Cell Subpopulation
* LABL 5 Leukocyte Antigen Biology Laboratory, Peter F. Moore, University of California, Davis; DC 5 dendritic cells; SE
5 Serotec, Oxford, UK; BD-PH 5 BD Biosciences Pharmingen, San Diego, CA; MHC 5 major histocompatibility complex; TL
5 Transduction Laboratories, Lexington, KY.
{ Cross-reactive with feline tissue.

and as previously described.11 Amino-9-ethyl-carbazole applied for 30 minutes at a 1 : 50 dilution. Subsequent

(Sigma Chemicals Co, St. Louis, MO) was used as to the terminal wash the slides were air-dried and
chromogen. Subsequently the sections were counter- cover-slipped with aqueous mounting medium (Far-
stained with hematoxylin (Gill’s formulation 2; Fischer, amount, Dako).
Fair Lawn, NJ) and cover-slipped with an aqueous
mounting media (Faramount; DAKO, Carpinteria, Results
CA).
Clinical features and management
Paraffin sections were deparaffinized in xylene and
hydrated through graded ethanol solutions. Hydrated The 30 cats included 18 Domestic Short Hair, 3
sections were steamed in 10-mM Citrate buffer, pH6 Domestic Long Hair, 1 Siamese and 1 Siamese-
(DAKO, Carpinteria, CA) at 95–98uC for 20 minutes. cross, 1 Tortoise Shell, and 1 mixed breed cat. The
Samples were subsequently stained as described above. breed of 5 cats was not known. The age was known
Double-labeling immunofluorescence for 27/30 cats and ranged from 2 to 17 years with
a mean age of 8.79 years; 14 cats were older than
Lesions from 4 cats were also evaluated by double- 10 years of age, 5 cats were between 7 and 10 years
label immunofluorescence to evaluate coexpression of
old, and 8 cats were younger than 5 years of age.
CD1 and CD5 by the lesional histiocytes and coexpres-
sion of CD3e and CD5 by admixed lymphocytes. Sixteen (61%) cats were female or female spayed,
Cryosections were fixed in acetone and washed in and 10 (39%) cats were male or male castrated. In
PBS. Blocking of nonspecific binding was achieved with 4 cats the sex was not indicated.
10% heat-inactivated horse serum in PBS (20 minutes at All 30 cats presented with skin lesions. Occa-
room temperature). All antibodies were diluted in PBS sionally solitary, but mostly multiple, intradermal
containing 10% inactivated horse serum. Anti-feline firm papules and nodules were observed. They
CD5 or anti- CD3e, respectively, was applied as a 1 : 10 measured up to 1.5 cm in diameter. The nodules
dilution of tissue culture fluid for 30 minutes at room did wax and wane in size, but complete spontane-
temperature. After a wash in PBS, the secondary ous regression did not occur. The nodules pro-
antibody Texas red anti-mouse IgG (Vector) was gressed in size over time, and some coalesced to
applied as a 1 : 100 dilution for 30 minutes. A subsequent
wash in PBS was followed by an additional blocking
larger plaques. Early lesions had an intact skin
with an irrelevant, non–cross-reactive, canine-specific, surface, which was either normally haired or
anti-CD3 antibody (Ca17.2A12; ascites; dilution at partially or completely alopecic. Pruritus was not
1 : 100). Without an additional wash, biotinylated anti- observed. Initially the lesions were not painful.
feline CD1a was applied for 30 minutes. After washing Over time some lesions became eroded, ulcerated,
with PBS, fluorescein anti-biotin antibody (Vector) was and painful. The locations of the skin lesions are
Vet Pathol 43:5, 2006 Feline Progressive Histiocytosis 649

Table 3. Location of skin lesions of feline pro- exact duration of the disease process after diagnosis
gressive histiocytosis in 22 cats. was monitored in 10/30 cats and ranged from
1 month to 3 years with a mean of 13.4 months.
Location Skin Lesions Number of Cats Information about clinical management was
Legs and Feet 21 available in 15/30 cats. If number and location
Head (Face, Nose, Eyelids, Lips, Ears) 18 permitted, the lesions were removed surgically (8/
Abdomen 6 15). Postsurgical local recurrence was seen in 4 of
Inguinal Region 6 these cats; all 4 cats had infiltrative lesions on
Flank 6 extremities. However, all 8 cats developed addi-
Thorax 4 tional lesions distant from the surgery site.
Back 3 Corticosteroids were administered to 11 cats with
Scapula 3 multiple lesions, including some cats with previous
surgery. Other therapies, including antibiotics (3/
listed in Table 3. Predilection sites for primary 15), interferon-c (2/15), retinoids (1/15), vincristine
lesions were the feet, legs, and head (Fig. 1), but and vinblastine (2/15), cyclosporine A (1/15),
lesions were also described less frequently in other nitrogen mustard (2/15), leflunomide (1/15), and
topographic locations (Table 3). In 8/30 cats the L-asparaginase (1/15) were administered in an
exact locations of the primary lesions were not attempt to manage this disease. In all 15 cats the
indicated. skin lesions progressed over time despite these
At the time of diagnosis, 18/30 cats were bright various therapies.
and alert and had no clinical evidence of internal Fifteen cats were euthanized (Table 1). In 7/15
disease. The lesions remained limited to the skin for cats the owners elected euthanasia because of
a prolonged period of time. At the terminal stage, 4 marked progression of the skin lesions. There was
of these cats presented with clinical evidence of no clinical evidence of internal disease, and
internal involvement. The clinical signs included necropsies were not performed. Necropsy con-
anorexia, weight loss, lymphadenopathy, respira- firmed the presence of internal disease in 7/15 cats.
tory signs, and anemia. An additional 4 cats Lesions were found in lymph nodes (7/7), lungs (4/
presented with skin masses and concurrent clinical 7), kidneys (3/7), pancreas (3/7), spleen (2/7), liver
signs of internal involvement at the time of (2/7), heart (2/7), adrenals 1/7), and the mediasti-
diagnosis. For the remaining 8 cats no clinical num (1/7). Necropsy was not performed in 1 cat
history of their general health was provided. The with clinical signs of systemic involvement.
Histopathologic features
Characteristically, poorly circumscribed, non-
encapsulated dermal nodules or masses with a top-
heavy configuration were noted (Fig. 2). The
cellular infiltrate extended from the superficial
dermis into the deep dermis and occasionally into
the subcutis. Biopsies from newly developing skin
nodules revealed superficial and deep multinodular
aggregates of large round cells. With progression,
the nodules coalesced and formed a poorly de-
marcated mass.
Typically, the nodules were composed of a dense
population of large round-to-polygonal cells with
discrete cell borders (Fig. 3). The cells had centrally
located, large vesicular round-to-oval or indented
nuclei with marginated, finely clumped chromatin
and often inconspicuous or single and rarely
multiple nucleoli. A moderate-to-abundant amount
of lightly eosinophilic cytoplasm was observed
Fig. 1. Skin, histiocytic nodules, cat No. 16. Mul- (Fig. 3). Occasionally, the cytoplasm was vacuo-
tiple, coalescing, partially alopecic and eroded skin lated, resulting in a foamy, xanthomatous appear-
nodules involving the forehead and dorsal nasal planum ance of the lesion. No cytoplasmic granules were
and dorsum of the nose. noted. These morphologic features are consistent
650 Affolter and Moore Vet Pathol 43:5, 2006

numerous. A higher mitotic index (.4 mitotic

figures per high-power field) and rare bizarre
mitotic figures were seen. Intralymphatic cell
aggregates were often noted.
Internal lesions (lymph nodes, lungs, kidneys,
pancreas, spleen, liver, heart, adrenals, and medi-
astinum) were evaluated in 7 cats. Invasive and
expansile masses effaced and replaced normal
parenchymal tissues (Fig. 7). The masses com-
prised dense proliferation of large, moderately to
markedly pleomorphic, round cells. Cytologic
features, degree of anisocytosis and anisokaryosis,
and the mitotic rate were most comparable with
late-stage lesions in the skin.
Immunohistochemistry and double-label
Fig. 2. Skin, histiocytic nodule, cat No. 10. The immunofluorescence
poorly circumscribed, nonencapsulated dermal and
subcutaneous nodule has a slightly base-narrow and
Fresh, snap-frozen tissues from 16 cats were
top-heavy configuration and is composed of a dense cell evaluated with the entire antibody panel (Table 2).
proliferation. HE. Bar 5 1 mm. A limited antibody panel (Table 2) was applied on
formalin-fixed, paraffin-embedded tissues of 9 cats.
The lesional, large, round cell population consis-
with histiocytes. A mild-to-moderate degree of tently expressed CD18, the leukointegrin b subunit,
anisocytosis and anisokaryosis were noted, and 0– and variably expressed the a subunit, CD11b. They
1 mitotic figures were observed per high-power lacked expression of CD3e and CD79a. This
field (403) throughout most of the lesions. On immunophenotype supports the presence of histio-
rare occasions, 2–3 mitotic figures were seen per cytes. The strong and consistent coexpression of the
high-power field. A small-to-moderate number of antigen-presenting molecules CD1a, CD1c (Fig. 8),
multinucleated giant cells were present. Few to and major histocompatibility complex (MHC) II
numerous small reactive lymphocytes and neutro- supports DC origin of these histiocytes. Further-
phils were dispersed throughout the dermal nodules more, it rules out the differential diagnosis of
(Fig. 3). amelanotic melanoma, because melanocytes do not
The overlying epidermis was either intact or express leukocyte markers, and poorly granulated
eroded and ulcerated. In most samples the cellular mast cell tumors, which lack expression of CD1 and
infiltrate abutted the basement membrane zone variably express CD18. The admixed reactive
(Fig. 4). In 17/30 cats the lesions lacked epidermal lymphoid infiltrate was mostly composed of
involvement (Fig. 4). Occasionally, the dermal CD3e+, CD8+, and CD5+ cytotoxic T cells.
cellular infiltrate was separated from the overlying The majority of cases, including samples from
epidermis by a small zone of normal dermis (Grenz epitheliotropic and nonepitheliotropic lesions,
zone). In the remaining 13/30 cats intraepidermal lacked expression of E-cadherin, a molecule usually
infiltrates were noted (Fig. 5). Intraepithelial in- expressed by Langerhans cells.6,15,36 Expression of
volvement was characterized by the presence of E-cadherin was detected in 3/25 cats only. Two cats
single cells or small aggregates of cells within the had epitheliotropic lesions; the third had none-
overlying epidermis. On rare occasions larger pitheliotropic lesions. E-cadherin expression was
aggregates were noted (Fig. 5). The cytologic seen in a subpopulation of the lesional histiocytes
features of these intraepidermal aggregates resem- and was usually weak.
bled those of the dermal nodules. Involvement of In 7/16 cats diffuse CD5 expression was observed
follicular epithelium was not evident. In some skin throughout the skin lesions. CD5 is a molecule
lesions intralymphatic cell aggregates were noted. usually expressed by lymphocytes.19 Double-label
In samples collected during the later phase of the immunofluorescence in 4 cats confirmed the coex-
disease and in skin lesions collected at necropsy, the pression of CD1 and CD5 by a subpopulation of
cellular infiltrate often extended deep into the the lesional histiocytes, as well as coexpression of
subcutis. Increased cellular pleomorphism was CD3e and CD5 by reactive T cells in 3/4 cats tested.
noted with marked anosicytosis and anisokaryosis In the remaining cat the CD5+ cells coexpressed
(Fig. 6). Multinucleated giant cells were more CD3e only.
Vet Pathol 43:5, 2006 Feline Progressive Histiocytosis 651

Discussion canine histiocytic sarcomas arise from the splenic

red pulp and the bone marrow; their immunophe-
This investigation documents FPH in 30 cats,
notype and marked hemophagocytic activity in-
a disease process characterized by a progressive
dicates a macrophage origin.26
histiocytosis of the skin with potential for in-
Histiocytic proliferative diseases are uncommon
volvement of internal organs. The cutaneous
in cats and their documentation is limited to a few
masses are composed of histiocytes with a dendritic
case reports. Most cases were not associated with
cell immunophenotype.
cutaneous lesions, but presented with internal
DC are a complex cell population, which include disease and prominent weight loss.10,14,18,37 The cats
several different subpopulations.2,8,16,33 Their on- had a low packed cell volume (19–20%), normo-
togeny, characteristics, and immunophenotype chromic or hypochromic, regenerative or nonre-
vary markedly between species.2,16,30,33 Regardless generative anemia, hypoproteinemia, hyperbiliru-
of their differences, DC are primarily involved in binemia, thrombocytopenia, and prolonged
antigen presentation. Three major populations of thromboplastin time.10,14,18,37 Hepatosplenomegaly
DC have been documented in humans. A common with ascites and mediastinal and pulmonary masses
CD34+ precursor cell in the bone marrow gives with hydrothorax were observed. Histologic eva-
origin to the myeloid DC, which include Langer- luations of the tumor masses revealed a prolifera-
hans cells and interstitial DC.8,38 Langerhans cells tion of pleomorphic histiocytes, which usually
populate the epidermis and epithelia of mucous displayed marked hemophagocytosis. The diagno-
membranes. They express CD1, CD11c, MHC II, sis of malignant histiocytosis was based on the
langerin, and E-cadherin.2,6,8,15,33 In some species, morphology of the tumor cells, the hemophagocy-
including the cat, the Langerhans cells also possess tic activity, and the variably positive immunohis-
Birbeck’s granules, a cytoplasmic structure induced tochemical stains for lysozyme and Mac38714,18,37
by transforming growth factor-b.8,15,30 The intersti- or positive reactions with a-1 antitrypsin, acid
tial DC have been documented in many organs phosphatase, or nonspecific esterase.10,18 These
and, in the skin, include dermal DC. Dermal DC findings are most consistent with disseminated
express CD1, CD11c, MHC II, and CD90, but lack hemophagocytic histiocytic sarcomas of macro-
expression of E-cadherin; they reside mainly phage origin rather than histiocytic sarcomas of
adjacent to the dermal microvasculature.2,8,21,23,32,38 DC origin. One case report describes a progressive
The evaluation of CD11c and CD90 expression in multinodular cutaneous round cell proliferation
feline DC is not possible because of the lack of similar to the cases described in this study.12 Based
feline-specific or cross-reactive reagents. The third on cytologic features and a MHC II+, CD79a–, and
DC population in humans and rodents are the CD32 immunophenotype, the diagnosis of multiple
plasmacytoid DC.29,33 Their expression of some histiocytomas was made.12 More extensive immu-
lymphoid markers is indicative of a lymphoid nophenotyping of the tumors was not performed
origin.16 Plasmacytoid DC have not been identified on this cat. Hence, it was not possible to confirm
in dogs and cats. a macrophage or DC origin.
Various histiocytic proliferations of either DC or The presence of multiple cutaneous nodules, the
macrophage origin have been documented in initially mostly benign cytologic features of the
humans and dogs.1,3,5,24,27,28,31 Canine cutaneous lesional histiocytes, and the slowly progressive
histiocytoma, a mostly benign neoplasm of Lang- clinical course of the disease separates FPH from
erhans cells, is predominantly seen in young dogs.28 primary histiocytic sarcoma. Clinical follow-up in 10
It tends to regress spontaneously.9,28,35 Canine cats revealed that FPH may remain limited to the
reactive histiocytosis occurs as a cutaneous or skin for an extended period of time, in some cats as
systemic form;1,24 both forms are characterized by long as 3 years. The fairly monomorphic tumor cells
a pleocellular, angiocentric process with numerous display mild anisocytosis and anisokaryosis, a low
dermal DC. Reactive histiocytosis, a proliferation mitotic index, and occasional multinucleated cells. It
of activated dermal DC, is likely induced by is only at a late stage of the disease that pleomor-
dysregulation of the immune system.1 Canine phism, anisocytosis, increased mitotic index, and
solitary and disseminated histiocytic sarcomas of more numerous multinucleated giant cells were seen.
DC origin—the latter has been referred to as Then histologic differentiation from a primary
malignant histiocytosis—develop as subcutaneous, histiocytic sarcoma was no longer possible. Histio-
periarticular, or internal tumor masses.3,27 Histio- cytic sarcomas are characterized by a markedly
cytic sarcomas originate from interstitial DC based aggressive behavior with fast progression and
on tumor location and immunophenotype. Some metastasis to draining lymph nodes and subsequent
652 Affolter and Moore Vet Pathol 43:5, 2006

Fig. 3. Skin, histiocytic nodule, cat No. 10. The mass is composed of a dense cell proliferation of large round-
to-polygonal cells with discrete cell borders. The large vesicular round-to-oval nuclei have marginated or fine
granular chromatin and inconspicuous or single nucleoli. The cells have a moderate-to-large amount of pale
eosinophilic cytoplasm. Note the mild-to-moderate degree of anisocytosis and anisokaryosis. A small number of
reactive lymphocytes and neutrophils are dispersed throughout the lesion. HE. Bar 5 50 mm.
Fig. 4. Skin, histiocytic nodule, cat No. 9. Nonepitheliotropic form: histiocytes abut the basement membrane
zone, but there is no evidence of epidermal invasion. HE. Bar 5 50 mm.
Fig. 5. Skin, histiocytic nodule, cat No. 10. Epitheliotropic form: histiocytes have penetrated the basement
membrane zone and form an intraepidermal aggregate. HE. Bar 5 50 mm.
Vet Pathol 43:5, 2006 Feline Progressive Histiocytosis 653

development of distant metastasis. Histiocytic sar- tion of the lesional CD1+ DC was confirmed. CD5
comas have been well described in dogs.3 The expression has been observed on plasmacytoid
authors have encountered 5 cats with solitary dendritic cells in rats, which indicates that CD5
histiocytic sarcoma, which were essentially similar expression is not limited to lymphoid cells in some
to the canine counterpart (V. K. Affolter and P. F. species.16 Because of a lack of appropriate cell
Moore, unpublished data). Therefore, differentia- differentiation markers, we are not able to identify
tion between late-stage FPH and primary histiocytic plasmacytoid DC in the cat. Plasmacytoid DC in
sarcoma should be based on the clinical history with humans and rats lack expression of CD1 when they
an emphasis on the course. first enter lymphoid tissue. However, they can
The DC sublineage involved in FPH is unknown. upregulate this molecule upon activation.29 Alter-
Epitheliotropism of the tumor cells was observed in natively, expression of CD5 by lesional histiocytes
13 cats, suggesting that, similar to canine histiocy- in some cats with FPH may be ectopic and
tomas, FPH may originate from Langerhans cells indicative of disordered cell regulation.
or their precursors.28 However, only 2/13 cats with The etiology of FPH is not known. Chronic
epitheliotropic lesions expressed E-cadherin, antigen stimulation was considered as a possible
a marker of Langerhans cell differentiation.6,34 For triggering factor. However, a reactive process,
the remaining 11/13 cats Langerhans cell origin was similar to reactive histiocytosis in dogs,1 is unlikely
unlikely, as they consistently lacked expression of as all cats failed to respond to immunomodulatory
E-cadherin. After activation, Langerhans cells drugs. Moreover, the presence of a monomorphic
downregulate their expression of E-cadherin as they cell infiltrate is more indicative of neoplasia than
migrate to the dermis.6,34 Hence, Langerhans cell a pleocellular, inflammatory process. FPH likely
origin cannot entirely be ruled out, because lesional represents a primary low-grade neoplasia of
histiocytes may have downregulated their expres- cutaneous DC with initial indolent behavior. Over
sion of E-cadherin. This issue could be resolved by time, accumulated mutations in a subpopulation of
electron microscopic evaluation of future lesions to the lesional histiocytes may lead to the evolution of
detect the presence of Birbeck’s granules, a cyto- histiocytic sarcoma.
plasmic organelle characteristic of feline Langer- Neoplasia of histiocytic origin tends to respond
hans cells.30 Wet tissue suitable for ultrastructural poorly to chemotherapy.3–5,7,27 Follow-up data
evaluation is not available from cats in the current regarding attempted therapy for FPH was available
series. Alternatively, FPH may arise from dermal in 8 cats. The lack of long-term response to
DC. Unfortunately, the lesions cannot be evaluated high doses of corticosteroids, vincristine, vinblas-
for coexpression of CD1 and CD90, a molecule tine, nitrogen mustard, and L-asparaginase in these
expressed by canine dermal DC and not by cats is consistent with observation in humans and
Langerhans cells, because feline-specific anti-CD90 dogs with histiocytic neoplasia.3–5,7,27 Surgical
antibodies are not available.1 Furthermore, the excision was performed in 8 cats with solitary
coexpression of CD5 by the CD1+ lesional DC in masses or a small number of skin lesions. Local
3 cats was unexpected. CD5 is a molecule that is recurrence occurred in 4 cats. All surgically treated
usually only expressed by lymphocytes.19 Evalua- cats developed additional lesions in other locations.
tion of frozen tissue sections in 16 cats revealed In summary, we have described a histiocytic
that the reactive CD3+ T cell population was proliferative disorder of unknown etiology, which
invariably positive for CD5 as expected. However, originated in the skin of 30 cats. We have chosen to
in 3 cats the coexpression of CD5 by a subpopula- call it ‘‘feline progressive histiocytosis’’ to highlight

Fig. 6. Skin, histiocytic sarcoma, cat No. 24, sample collected upon necropsy. The infiltrative mass is composed
of a pleomorphic population of individualized large round and polygonal cells embedded in a loose myxomatous
stroma. There is marked anisocytosis and anisokaryosis, and binucleated cells are noted. The nuclei have granular
or dense chromatin and are often in paracentral location. A small number of reactive lymphocytes and neutrophils
are dispersed throughout the lesion. HE. Bar 5 50 mm.
Fig. 7. Lymph node, metastasis, cat No. 29. The majority of the lymph node tissue is replaced by a dense
infiltrate of pleomorphic large histiocytes. Small remnants of cortical lymphoid tissue are still present in upper left
corner. HE. Bar 5 100 mm.
Fig. 8. Skin, histiocytic nodule, cat No. 10. The lesional dermal histiocytic infiltrate expresses CD1c. The
stained intraepidermal cells may represent resident Langerhans cells or individual lesional histiocytes.
Immunohistochemistry; chromogen: amino-9-ethyl-carbazole, hematoxylin counterstain. Bar 5 50 mm.
654 Affolter and Moore Vet Pathol 43:5, 2006

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histologically indistinguishable from histiocytic 13 Freeman L, Stevens J, Loughman C, Tompkins M:
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sarcoma.
J Vet Intern Med 9:171–173, 1995
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We thank all clinicians from private practice and heilkd 130:349–356, 1988 [in German]
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these cases. entiation of human peripheral blood monocytes into
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Request reprints from V. K. Affolter, Department of Pathology, Microbiology and Immunology, School of
Veterinary Medicine, University of California at Davis, Davis, CA 95616 (USA). E-mail: vkaffolter@ucdavis.edu.