Overview of Histiocytic Diseases - DVM Version

Overview of Histiocytic Diseases - DVM Version

There are several well-defined histiocytic proliferative diseases that have been recognized in dogs. These disorders represent a frustrating group of diseases because it may be difficult to differentiate them from granulomatous, reactive inflammatory disorders or from lympho-proliferative diseases in regular paraffin sections. The clinical presentation and behavior and responsiveness to therapy vary tremendously between the syndromes observed. 

Canine cutaneous histiocytoma, which exhibits evidence of LC differentiation, usually occurs as a solitary lesion in young dogs and spontaneously regresses. Cutaneous Langerhans cell histiocytosis (LCH) covers a spectrum of disease, in which multiple cutaneous lesions are consistently observed. In some cases, lymph node and systemic metastasis is also observed. Individual skin lesions otherwise resemble those in histiocytoma. Hence these 2 diseases could be considered part of a larger spectrum of disease with diverse biological behavior. Feline counterparts of canine cutaneous histiocytoma and cutaneous LCH have not been reported. 

The reactive histiocytoses have only been identified in dogs; there is no known feline counterpart. The reactive histiocytoses, cutaneous (CH) and systemic histiocytosis (SH), are related disorders arising from activated interstitial DCs. Reactive histiocytoses are histiocyte and lymphocyte rich inflammatory disorders associated with a degree of immune dysregulation, which promotes lesion persistence. Cutaneous histiocytosis presents with single or multiple lesions, which tend to wax and wane, and may even spontaneously regress. Few cases respond to corticosteroids, some respond to tetracycline and niacinimide, the remainder persist and may require more aggressive immunosuppressive therapy. Systemic histiocytosis is a familial disease of Bernese mountain dogs, and also occurs sporadically in other breeds. SH presents with prominent skin manifestations identical to those seen in CH, but mucous membranes (ocular and nasal) and a variety of other organ systems, including lymphoid organs, lung, and bone marrow may also be involved. Although the lesions may wax and wane, SH is a progressive disease that often requires continuous immunosuppressive therapy with cyclosporine (Atopica) or leflunomide (Arava).

The histiocytic sarcoma complex (HS) occurs in dogs and cats. Histiocytic sarcomas occur with a high incidence in Bernese mountain dogs, Rottweilers , Flat coat retrievers, Golden retrievers and sporadically in many other breeds. The incidence of HS in cats is much lower than in dogs. Histiocytic sarcomas occur as localized lesions in spleen, lymph nodes, lung, bone marrow, skin and subcutis, brain, and articular tissue of appendicular joints. Histiocytic sarcomas may occur as multiple lesions in single organs (especially spleen and skin), and rapidly disseminate to involve multiple organs. This form of the disease was formerly called malignant histiocytosis (MH), but is now more appropriately termed disseminated HS. Histiocytic sarcomas mostly arise from interstitial DCs. However, the hemophagocytic form of HS is a distinctive clinic-pathologic entity, which arises from splenic red pulp (± bone marrow) macrophages. Durable responses to chemotherapy are difficult to achieve.

There are two feline histiocytic diseases that do not have a canine equivalent: feline progressive histiocytosis (FPH) and pulmonary LCH. Feline progressive histiocytosis is the most common histiocytic disease in cats, and invariably begins as cutaneous nodules and plaques. Feline progressive histiocytosis is essentially a low grade HS with indolent behavior initially. Pulmonary LCH is a disease of aged cats (10 to 15 years), which causes progressive respiratory failure due to extensive obliteration of the pulmonary parenchyma by an infiltrate dominated by LCs.

An Overview of Cell Marker Studies in Canine Histiocytic Disease

The development of canine specific monoclonal antibodies for many of the functionally important molecules on macrophages and DC has enabled the identification of the cell lineages involved in canine histiocytic disorders. Despite the large variation of clinical and pathological features of canine histiocytic diseases, the majority represent proliferations of cells of various DC lineages. Histiocytes in cutaneous histiocytoma express markers characteristic of epidermal Langerhans cells such as CD1a, CD11c, MHC class II, and E-cadherin, but not Thy-1 or CD4. This disease is a localized, regressing Langerhans cell histiocytosis. Aberrant cases of histiocytoma which behave more aggressively have been observed; these cases are uncommon and behave more like some forms of human Langerhans cell histiocytosis. Cutaneous and systemic histiocytosis involve proliferation of activated interstitial DC (e.g. dermal DC in skin); these cells express CD1a, CD11c, MHC class II, Thy-1 and CD4. Histiocytic sarcomas (and MH) have more varied origins. Splenic histiocytic sarcomas largely arise from cells sharing the phenotype of interdigitating DC of the white pulp and express prominent CD1a, CD11c, and MHC class II. Hemophagocytic histiocytic sarcomas of spleen (and bone marrow) arise from cells, which express the phenotype of splenic red pulp (and bone marrow) macrophages (prominent CD11d expression and low expression of CD1a and CD11c). Periarticular histiocytic sarcoma likely arise from subsynovial perivascular DCs which are interstitial type DCs; in contrast synovial lining cells (type A cells) express markers shared by macrophages (prominent CD11b and moderate MHC class II expression, lack of CD11c and CD1a expression). Histiocytic sarcomas of lung have more obscure origins, but prominently express CD1a, CD11c and MHC class II, a phenotype expected of the DC lineage.