I. HISTIOCYTES

The morphologic term histiocyte includes monocytes, macrophages and dendritic antigen presenting cells (DAPC). They are considered closely related cells and arise from a common precursor in the bone marrow. As differentiated cells in the periphery, macrophages and DAPC are characterized by morphologic, phenotypic and functional differences and are therefore considered to represent different cell lineages. Although their primary functions differ, macrophages and DAPC are closely related and have a lot of functions in common.

Dendritic antigen presenting cells (DAPC)--As professional antigen presenting cells, DAPC are primarily involved in processing and presenting antigens. The result is an activation of the adaptive immune system. DAPC express MHC I, MHC II and CD1, which allows them to efficiently present processed proteins and glycolipids to T lymphocytes. Moreover, professional DAPC express accessory molecules (B-7 family, CD40) that play a crucial role in the induction of the primary immune response. The DAPC system itself consists of phenotypically and functionally diverse cells, located in distinct parts of the body. Langerhans cells (LC) reside in epidermis. They have Birbeck's granules (except in dogs) and they coexpress E-cadherin. Interstitial (dermal) dendritic cels lack Birbeck's granules and reside mainly in the perivascular area of tissues. They lack expression of E-cadherin, but they coexpress CD90 and as activated cells CD4. As DAPC process the antigen, they migrate to the lymph node, where they present the peptides in context with their MHC molecules to T cells.

Macrophages perform several key functions of the innate immune system. With various receptors they interact with extracellular proteins and polysaccharides of pathogens and internalize them by phagocytosis and endocytosis. The contents of phagosomes are subsequently subjected to digestion within the phagolysosomes. During this process the macrophages secrete proteases, complement factors, cytokines (TNF-α·, IL-1, IL-6), chemokines (MIP1,2,3; IL-8), toxic oxygen metabolites (O2^-, OH^-), nitrogen metabolites (NO2^-), and arachidonate derivatives, which all have an important role in the development of inflammation.

II. HISTIOCYTIC DISEASES IN DOGS

A variety of histiocytic proliferative diseases have been recognized in the dog, including the reactive histiocytosis with its cutaneous and systemic form, cutaneous histiocytoma, localized histiocytic sarcoma, and disseminated histiocytic sarcoma (formerly called malignant histiocytosis). Their clinical presentation and behavior vary and their etiology and exact pathogenesis is largely unknown. Distinguishing them from other granulomatous inflammations or round cell tumors such as lymphoma can be difficult. In the majority of cases, lesional histiocytes display an immunophenotype most consistent with DAPC. Differences in clinical behavior, response to therapy, morphologic features and phenotypic variations of the proliferating DAPC allow the distinction between the various canine histiocytic disorders and their separation from other inflammatory processes or round cell neoplasia.

Canine cutaneous histiocytoma

Clinical presentation--Canine cutaneous histiocytoma is a common, mostly benign neoplasm in young dogs. Breed or sex predilections are not observed. It mainly develops in young dogs, but may occur in older dogs. Typically, a solitary, plaque or dome-shaped small nodule, usually less than 2.5 cm in diameter, is observed. Predilection sites are the head, ears, neck and extremities. The nodules may be alopecic and ulcerated. The majority of cutaneous histiocytomas undergo spontaneous regression, which, once started, may occur within days.

Cases of multiple histiocytomas at different sites or persistent and recurrent histiocytomas are less common. Shar-pei or Shar-pei crosses are over represented in this group. Multiple histiocytomas may persist for a long time; eventually they may regress or alternatively, additional lesions may develop. Regional draining lymph nodes can be enlarged due to migrating histiocytoma cells. The lymph nodes are not painful.

Some cases of multiple persistent histiocytomas display subsequent malignant behavior and internal histiocytic neoplasms develop (lung, lymph nodes, spleen, heart, kidneys, pancreas, and liver). This process is best referred to as Langerhans cell histiocytosis (LCH).

Histology and Immunophenotyping--Non-encapsulated, poorly demarcated intracutaneous nodules are composed of fairly monomorphic round cells with big round to oval, indented or twisted vesicular nuclei. The cells may invade the epidermis and form intra-epidermal aggregates. Mitotic figures are frequent. Histiocytoma cells are CD1⁺, CD4, CD11c⁺, MHC II⁺, ICAM-1⁺, CD90^-, and E-cadherin⁺ Langerhans cells (LC). Marked infiltration of CD8⁺ ab-T cells at a later stage indicate spontaneous regression of the tumor. Lack of cytotoxic T cells is seen in cases with delayed regression. An infiltrate of plasma cells is often seen in stead. Intralymphatic histiocytoma cells indicate migration to the draining lymph node. With LCH, the nodules tend to extend deep into the dermis and subcutis and the cells occasionally appear more atypical.

Management--Most histiocytomas spontaneously regress within weeks. Lymphadenopathy usually regresses simultaneously with the regression of the skin nodule. However, lack of regression has been seen; little follow-up information is available on these dogs as many were eventually euthanized. Immuno-suppressive drugs may interfere with spontaneous repression by inhibiting the infiltration of CD8⁺ T cells and is therefore contraindicated. In cases of delayed regression and surface ulceration, surgical excision is recommended. Antibiotics are recommended in cases with ulcerated histiocytomas. Chemotherapy has not been successful in managing cases with multiple histiocytomas and LCH.

Prognosis--Solitary lesions have a good prognosis. Lymph node involvement with solitary lesions or multiple lesions may regress subsequently to the regression of the primary skin nodules. Multiple histiocytomas may persist over a longer period of time; some eventually regress. LCH has a poor prognosis, as no chemotherapy protocol has been successful to date.

Etiology and pathogenesis--The etiology and pathogenesis of histiocytomas is unknown. A persistent antigen stimulus is possible.

Canine histiocytic sarcoma

(Solitary histiocytic sarcoma, disseminated histiocytic sarcoma, malignant histiocytosis, hemophagocytic histiocytic sarcoma)

Clinical presentation--Localized histiocytic sarcoma (LHS) presents as a rapidly growing, locally aggressive sarcoma limited to a single site. Flat Coated Retrievers, Golden Retrievers, Labrador Retrievers, Bernese Mountain Dogs and Rottweilers are predisposed; but other breeds may be affected. There is no apparent sex predilection and most dogs' age ranges from 6 to 11 years of age. However, LHS have been found in dogs as young as 2 years old. Predilection sites are skin, subcutis and underlying tissues on extremities, especially in close proximity to a joint. LHS also occur in the spleen, liver, gastric wall, CNS and tongue. LHS metastasize to the draining lymph nodes. Splenic HS metastasize to the liver. Disseminated histiocytic sarcoma, (DHS), also referred to as malignant histiocytosis, is a very aggressive multi-system diseases. Bernese Mountain Dogs, Golden Retrievers, Labrador Retrievers and Rottweilers are predisposed. DHS primarily affect the spleen, lymph nodes, lung, and bone marrow, but other organ systems, such as liver, central nervous system, kidneys, skeletal muscle, stomach and adrenal glands may be affected. Lesions in vertebral bone and spinal canal have been observed in Rottweilers. The age of the dogs ranges from 3 to 11 years and there is no sex predilection. Clinical symptoms--including weight loss, poor general condition, anorexia, dyspnoea and anemia--usually become evident at a progressed stage of the disease process. Hemophagocytic histiocytic sarcoma (HHS) originates from the splenic red pulp and/or the bone marrow. The dogs present with prominent progressive anemia and splenomegaly. With increasing involvement of the liver the hepatic enzymes become more elevated.

Histology and immunophenotyping--LHS and DHS present with identical histiocytic features. The poorly demarcated masses are composed dense proliferation of either pleomorphic, large, individualized round cells or more densely packed bundles of plump spindle cells with a large amount of pale eosinophilic cytoplasm and big round to oval, indented or twisted, vesicular nuclei. There are large round or stellate multinucleated tumor giant cells. Mitotic rate is high and there are numerous areas of necrosis. The tumor cells are CD1⁺, CD11c⁺, MHC II⁺, ICAM-1⁺, CD80⁺, CD86⁺, CD90^± dendritic antigen presenting cells. Interstitial DAPC, white pulp splenic DAPC and other DAPC may be the origin of these tumors. HHS are characterized by a diffuse neoplastic expansion of the splenic red pulp histiocytes by CD11d⁺, CD11c^-, CD1^- histiocytes of macrophage type. The cells migrate into the liver and first are seen within the liver sinusoids and later form intrahepatic tumor masses.

Management--Complete surgical excision is the therapy of choice for SHS. If a surgical excision is impossible, radiotherapy might be considered as an alternative therapy. At the time of diagnosis of disseminated histiocytic sarcomas a surgical approach is no longer possible, Chemotherapy has not been shown successful in these cases. Splenectomy at an early stage of hemophagocytic sarcoma originating from the spleen has been shown to prolong the dog's lives. However, metastatic lesions to the liver may be very subtle at early stages and liver may grossly look normal.

Prognosis--With early complete surgical excision and no lymph node involvement a favorable prognosis can be given for LHS of the subcutis and skin. The prognosis of internal LHC (for example: spleen) is guarded to poor, because often metastases have developed at the time of diagnosis. Prognosis of DHS and HHS is poor.

Etiology of histiocytic sarcomas is unknown.

Canine reactive histiocytosis

(cutaneous histiocytosis, systemic histiocytosis)

Clinical presentation--Canine reactive histiocytosis (RH) primarily targets the skin and subcutis and is characterized by solitary or more often multiple, non-pruritic and non-painful, haired or alopecic cutaneous nodules and plaques, predominantly located on head, neck, perineum, scrotum, and extremities. Cutaneous histiocytosis (CH) is limited to the skin. CH can develop in any breed. Cases with involvement of the skin and other organ systems (nasal cavity, eyes lids, sclera, lungs, spleen, liver, bone marrow, lymph nodes, retro-orbital tissues or the testicular tissue) are categorized as systemic histiocytosis (SH). Bernese Mountain Dogs, Rottweilers, Golden and Labrador Retrievers and Irish Wolfhounds are predisposed and familial increased incidence has been seen in Bernese Mountain dogs and Irish Wolfhounds. Clinical symptoms vary depending on the organ systems. RH can develop at any age. Most cases have been seen between 3 and 9 years of age. The skin lesions often have a waxing and waning clinical course and spontaneous regression has been seen, in particular early in the disease process. The majority of cases, however, exhibit a slowly progressive behavior.

Histology and immunophenotyping--The skin lesions of CH and SH are identical. They are characterized by a multinodular, coalescing to diffuse dermal and subcutaneous pleocellular infiltrate, predominantly in the deep dermis; the inflammation extends along the dermal vasculature into the superficial dermis. Numerous large round to oval histiocytes with large round to oval, vesicular, indented or twisted nuclei. These CD1⁺, CD4⁺, CD11c⁺, CD11b⁺, MHC II⁺, ICAM-1⁺, and CD90⁺ dermal DAPC are accompanied by CD8⁺, TCR-b⁺ T cells lymphocytes and neutrophils. Eosinophils and plasma cells are rare. The cellular infiltrate forms dense cellular cuffs around vessels and vaso-invasion with subsequent thrombosis and tissue necrosis are common. As a result there are small areas of necrosis. Lesions in other organ systems present with angiocentric pleocellular infiltrates similar to the lesions observed in the skin.

Management--Spontaneous regression may occur at an early stage of the disease. Surgical excision may be successful for solitary lesions, but it does not prevent development of new lesions elsewhere. Variable success is observed with administration of immuno-suppressive doses of corticosteroid and some dogs tend to develop signs of Cushing's disease fairly early. Other immuno-regulatory drugs, such as Cyclosporin A (Atopica R, Neoral R) and Leflunomide (Arava R) have been successfully used for treatment of RH. Ocular lesions tend to be more difficult to treat and require topical treatment (Cyclosporin A eye drops).

Prognosis--Spontaneous regression may occur early in the disease process. Some dogs respond well to treatment and may stay free of symptoms. However, most cases of RH display an either episodically or continuously progressive clinical course and hence, require long-term immuno-suppressive therapy.

Etiology and pathogenesis--The etiology and pathogenesis of RH is still unknown. Special stains, cultures and electron microscopic evaluations fail to reveal presence of infectious agents. The clinical behavior, response to therapy with immuno-suppressive drugs and the presence of activated DAPC suggest a dysregulatory process of the immune system in these dogs. The cytokine milieu in these lesions indicates a T_H1 response.

III. HISTIOCYTIC DISEASES IN CATS

Feline progressive dendritic cell histiocytosis

Clinical presentation--Cats may initially present with a solitary skin nodule. Usually multiple non-painful intradermal nodules develop. Predilection sites are head, neck, or lower extremities, but lesions may occur at any location. Occasionally, the lesions are limited to one extremity. The nodules may measure up to 1.5 cm in diameter. Lesions have an intact skin surface or may be ulcerated. The nodules may wax and wane in size, but complete spontaneous regression has not been seen. Some nodules progress in size over time, and may coalesce to large plaques. Sex or breed predilection has not been observed. Cats affected are usually between 2 to 13 years of age. Lymph node involvement is common and at a terminal stage, internal organs (lungs, liver, kidney, heart) may be affected. Clinical signs vary depending on the organ systems involved.

Histology and immunophenotyping--Feline progressive dendritic cell histiocytosis may be non-epitheliotropic or epitheliotropic. Early lesions may appear as multinodular histiocytic infiltrates that gradually coalesce. The nodules are composed of a dense proliferation of large round and polygonal cells with discrete cell borders and a moderate to abundant amount of lightly eosinophilic, occasionally vacuolated cytoplasm and centrally located, large, vesicular, oval or reniform and indented nuclei; the chromatin is marginated or finely clumped. The tumor cells are CD1⁺, CD11b⁺ and MHC II⁺ histiocytes of most likely DAPC lineage. With epitheliotropic lesions, single cells and aggregates of cells can be observed in the epidermis. Multinucleated tumor cells may be present. Mitotic activity varies. Intralymphatic tumor cell aggregates are occasionally seen and the surface may be intact, eroded or ulcerated. Reactive inflammatory response varies.

Management--Treatment with corticosteroids may help intermittently, but does not stop the progressive process. Interferon, nitrogen mustard (CCNU) and cyclosporin A have been tried in very few cases with little success. If there are only few nodules surgical removal is advised. However, it does not prevent development of additional lesions in other locations.

Prognosis--A guarded prognosis must be given as lesions are progressive.

Etiology of progressive dendritic cell histiocytosis is not known.

Feline histiocytic sarcoma

Clinical presentation--Histiocytic sarcomas do occur in cats, but less frequently than in dogs. Some of the progressive dendritic cell histiocytosis eventually become very anaplastic and have features of histiocytic sarcoma. Alternatively, histiocytic sarcomas develop as solitary sarcomas.

Histology and immunophenotyping--The lesions resemble histiocytic sarcomas in dogs, either individualized round cells or spindle cells can be seen. The pleomorphic tumor cells are CD1⁺, CD11b⁺, MHC II⁺ dendritic antigen presenting cells.

Management--Surgery is advised if solitary lesions are present.

Prognosis--Histiocytic sarcomas are locally invasive and can metastasize to draining lymph nodes.

Etiology of histiocytic sarcomas is unknown.