Systemic Histiocytosis (SH) was originally recognized in closely related Bernese Mountain Dogs. SH is a generalized histiocytic proliferative disease with a marked tendency to involve skin, ocular and nasal mucosa, and peripheral lymph nodes. The disease predominately affects young to middle aged male dogs (2-8 years), although cases in females have been observed. SH has been observed in other breeds less commonly (eg Irish Wolfhounds, Basset Hounds and others). Clinical signs vary with the severity and extent of the disease and include anorexia, marked weight loss, stertorous respiration and conjunctivitis with marked chemosis. Multiple cutaneous nodules may be distributed over the entire body, but are especially prevalent in the scrotum, nasal apex, nasal planum and eyelids. Peripheral lymph nodes are often palpably enlarged. The disease course may be punctuated by remissions and relapses, which may occur spontaneously especially early in the disease course. In severe disease, lesions become persistent and do not respond to immunosuppressive doses of corticosteroids.

Systemic histiocytosis, Bernese Mountain Dog   Nodular lesions and alopecia affect the skin AND the visible ocular and nasal mucosae are involved. Note the chemosis in the conjunctiva and corneal edema. The nasal apex is swollen and depigmented; there is a crusty nasal discharge and the dog had stertorous respiration indicating infiltration and swelling of the internal nasal mucosa.

Cutaneous histiocytosis (CH) is a histiocytic proliferative disorder that primarily involves skin and s ubcutis and does not extend beyond the local draining lymph nodes. CH occurs in a number of breeds. Evidence of spread beyond the skin would invoke the diagnosis of SH, a closely related disorder. Lymphadenopathy has not been emphasized in published reports, and has only been documented in a small number of our cases. The lesions occur as multiple cutaneous and subcutaneous nodules up to 4 cm diameter. They may may disappear spontaneously, or regress and appear at new sites simultaneously. Topographically lesions may be found on the face, ears, nose, neck, trunk, extremities (including foot pads), perineum and scrotum. Cutaneous histiocytosis, Golden Retriever   Nodular lesions adjacent to the nares - notice that the ocular and nasal mucosae are uninvolved in contrast to SH. Lesions were also present on the trunk.

Treatment options in SH and CH. SH has proven to be a difficult and frustrating condition to treat. Consequently, many of the early cases were euthanized. Originally we treated dogs with Thymosin (derived from bovine thymus) because of reports of its effectiveness in human LCH cases. Some dogs appeared to respond to this, but not consistently. The original rationale for using thymosin was that SH was likely an immunoregulatory disorder and not cancer. In the majority of instances corticosteroid treatment is ineffective, although in some instances of CH (about 10% of cases), steroid administration is very effective in controlling lesions so steroids are worth trying in this disease given the expense of the alternatives. More recently we have had success with immuno-suppressive doses of Cyclosporin A or Leflunomide. These drugs are potent inhibitors of T cell activation and their ability to abrogate clinical disease gives further support for SH and CH being disorders of immune regulation. Treatment with these drugs is exorbitantly expensive and may be needed for life in dogs with continuously active disease, which usually is the case in advanced SH. It is preferable not to invoke such powerful immuno-suppressive therapy in most cases of CH in which spontaneous regression of lesions or episodic disease activation is more likely to occur. Systemic histiocytosis, Bernese Mountain Dog   After treatment with thymosin (6 weeks). Modern immunosuppressive drugs (Leflunomide or cyclosporin) have achieved more consistent and better responses.

Microscopic features of SH and CH. The lesions of SH in most tissues consist of perivascular infiltrates of large histiocytes and variable populations of lymphocytes, neutrophils and eosinophils. The histiocytes frequently invade vessel walls and this may lead to vascular compromise and infarction of surrounding tissues. The widespread distribution of lesions of SH is only fully appreciated at necropsy. Histiocytic lesions have been observed in skin, lung, liver, bone marrow, spleen, peripheral and visceral lymph nodes, kidneys, testes, orbital tissues, nasal mucosa and others. In skin, the lesions of SH and CH are virtually identical - they consist of perivascular histiocytic infiltrates containing lymphocytes and other inflammatory cells in variable proportions (neutrophils, plasma cells, and occasionally eosinophils). The lesions usually involve the deep dermis and subcutis. Involvement of the superficial dermis is inconsistent and epidermotropism of the histiocytes is not observed. In CH the lesions are limited to the skin and draining lymph nodes. Topography Systemic (and cutaneous) histiocytosis   Skin lesions in CH and SH occur as perivascular infiltrates in the mid to deep dermis. Lesions tend to become confluent in the subcutis. Tropism for epidermis is rarely manifest - the dermal epidermal junction is usually not infiltrated. Systemic histiocytosis, skin   This is an early lesion which clearly illustrates the topographical features - vasocentric orientation in dermis and subcutis with relative sparing of the superficial dermis. In later lesions, perivascular infiltrates coalesce especially in the deep dermis and subcutis. Cutaneous histiocytosis, skin   Lymphohistiocytic infiltrate surrounds deep dermal blood vessel (arrow). The histiocytes merge into the adventitial layer of the vessel wall. Cutaneous histiocytosis, skin   Histiocyte rich lesion with involvement of vessel walls (arrow) in the subcutis. Histiocytes have twisted and folded nuclei and a fine lacy chromatin; the cell membranes are indistinct, but the cells generally have a spindle shape. Cutaneous histiocytosis, skin   Lymphocyte rich lesion in the subcutis with a background population of histiocytes.

Immunophenotypic Studies Histiocytes in SH and CH express markers expected of dendritic cells (DC) such as CD1a, CD1b, CD1c, MHC II, and CD11c. However, the lack of consistent epidermotropism in SH and CH lesions, and the expression of Thy-1 (expressed by dermal DC) and CD4 (a marker of DC activation) suggest that histiocytes in these diseases are activated interstitial type DC. In skin, dermal DC are mostly of interstitial DC type. Expression of Thy-1 and CD4 in SH and CH clearly distinguishes these diseases from histiocytoma, in which an epidermal Langerhans cell (LC) phenotype is observed (recall that LC are epithelial DC; they express CD1, CD11c, MHC II and E-cadherin. LC lack expression of Thy-1, and don't express CD4 in the non-activated state). Dermal (intersitial type) DC   Distinctive surface markers and chemokine receptors. Dermal DC stained for CD1c   Dermal DC are closely associated with the adventitia layer of blood vessel walls. Cutaneous histiocytosis, CD1b   Large numbers of CD1+ DC infiltrate the deep dermis. Cutaneous histiocytosis, CD4   Large numbers of CD4+ DC infiltrate the deep dermis. Cutaneous histiocytosis, CD8   Large numbers of CD8+ lymphocytes infiltrate between histocytes in the deep dermis. Cutaneous histiocytosis, Thy-1   Infiltrating cells (DC and lymphocytes) express Thy-1.

Pathogenesis The clinical behavior and consistent clinical response to immuno-suppressive therapy with agents capable of profoundly inhibiting T cell activation has reinforced the concept that SH and CH occur in the context of disordered immune regulation arising from defective interaction of DC and T cells. The end result of this dysregulated immune interaction is chronic proliferation of DC and T cells. The initiation of the process is probably antigen driven, although studies to identify the nature of the antigens involved have been unrewarding. The lesions can wax and wane over a considerable period of time and spontaneous regression without therapy has been observed. The lymphoid component of the lesion consists of predominately CD8+ alpha beta T cells, whose numbers can vary markedly between lesions. These T cells can comprise up to 50% of the cells in some instances. The role played by T cells is unknown. They could be attempting to induce regression of the dendritic APC proliferation. Alternatively, T cells may be involved in a key way in the exaggerated proliferation and activation of DC via T cell derived cytokines such as GM-CSF and TNFa, which are known to influence the proliferation and differentiation of DC. Current Research. Our current direction is to investigate the expression of molecules crucial to the successful interaction of T cells and DC in immune responses. These include the T cell molecules CD28 and CTLA-4, and the DC co-stimulatory molecules B7-1 and B7-2. Defects in the temporal upregulation of these molecules in an antigen driven response could lead to dysregulated interactions of T cells and DC. For instance, a systemic lympho-histiocytic proliferative disorder occurs a few weeks after birth in CTLA-4 knockout mice; this reinforces the key negative role played by CTLA-4 in regulating T cell proliferation in antigen driven responses. We have already developed mAb specific for canine B7 and now we are attempting development of mAb specific for canine CD28 and CTLA-4. Availability of these mab would allow the mapping of important receptor ligand pairs known to be involved in the regulation of interactions of DC and T cells. Our hypothesis is that defects in these interactions are likely to be involved in the pathogenesis of reactive DC proliferations in dogs. Activation of T cells   Activation of T cells requires the co-ordinated activity of the T cell receptor complex and CD28 on T cells with costimulatory molecules (B7 family) on DC. The interaction of B7-1 (upregulated on DC) and CTLA-4 (upregulated on T cells) serves to abrogate the immune response. Concluding remarks We believe that the continued distinction of SH and CH as separate entities, in the light of our research, is probably no longer justifiable. It would be preferable to consider them within the spectrum of reactive histiocytoses of interstitial DC origin, in which clinical outcome is predictable more by the distant migratory potential of the proliferating histiocytes beyond the skin. In this view, CH and SH would be regarded as skin limited and systemic interstitial DC proliferations, respectively. A wide range of clinical behavior is to be expected within each grouping, with SH usually exhibiting more aggressive disease. CH and SH should not be confused with malignant DC disorders (HS and MH), which can occur in similar topographical locations. Cytological and immunophenotypic differences can distinguish these diseases in most instances.

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