An overview of canine histiocytic disorders

Canine histiocytic proliferative diseases represent a range of disorders with different pathologic features as well as clinical behavior.1,2 At least three well-defined syndromes have been reported in dogs that arise from histiocyte proliferation, including cutaneous histiocytoma, reactive histiocytosis (cutaneous and systemic), and histiocytic sarcoma (localized and disseminated).3 Malignant fibrous histiocytoma was previously grouped with canine histiocytic diseases but is now more appropriately considered a soft tissue sarcoma (see boxed text titled "Difficult to delineate: Malignant fibrous histiocytoma and histiocytic disease").4,5 The dendritic cell lineage of this elusive complex of histiocytic disease syndromes has been recently clarified through the use of immunohistochemical staining and specific monoclonal antibodies (Table 1).1,2,6-9

A quick guide to histiocytic disorders in dogs

In this article, we focus on how to diagnose the various histiocytic disorders by using routine imaging modalities, cytologic and histologic examination, and immunohistochemistry when needed to accurately distinguish elusive cases. We also discuss the recommended treatment and prognosis for each disease process.

Difficult to delineate: Malignant fibrous histiocytoma and histiocytic disease

HISTIOCYTE ORIGINS

Most histiocytes differentiate from CD34+ (CD = cluster of differentiation) stem cell precursors in the bone marrow into macrophages and one of three dendritic cell lineages: epithelial dendritic cells or Langerhans cells in the skin, interstitial dendritic cells in many organs (Figure 1), and interdigitating dendritic cells (antigen-presenting cells located in the T cell zone in peripheral lymphoid organs).3,10 The interdigitating dendritic cells are not yet known to arise in histiocytic disease.

Figure 1. Adapted from Withrow SJ, Vail D. Histiocytic diseases. In: Small animal clinical oncology. 4th ed. St. Louis, Mo: Saunders Elsevier, 2007;814-823.

The fate of the CD34+ stem cells is largely influenced by cytokines and specific combinations of them. For example, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) induce macrophage development from CD34+ stem cells, while GM-CSF, transforming growth factor beta, tumor necrosis factor alpha, and interleukin-4 influence dendritic cell development.3,11

HISTIOCYTOMA

Histiocytomas are benign skin tumors that occur most commonly in young dogs, accounting for 3% to 14% of skin tumors in this species.12

Signalment and clinical findings

Although histiocytomas can occur in dogs of any age, the incidence drops after 3 years of age.7 A breed predilection has been documented in boxers, dachshunds, cocker spaniels, Great Danes, Shetland sheepdogs, and bull terriers.12,13 No apparent sex predilection exists.14 Histiocytomas are usually < 2- to 3-cm, fast-growing, raised, buttonlike, hairless lesions (Figure 2). Solitary tumors most commonly arise on the extremities, head, ears, or neck. Despite their rapid growth, the tumors are benign. Some dogs have multiple lesions at diagnosis,14 and histiocytomas with regional lymph node involvement have been reported, most commonly in Shar-Peis.13

Figure 2. A cutaneous histiocytoma in the medial canthus of a 10-year-old spayed female boxer. Surgical resection was curative.

Diagnosis

Histiocytomas are round cell tumors and are easily diagnosed. Cytologic examination of fine-needle aspirates reveals sheets of pleomorphic round cells with abundant pale-grey cytoplasm; centrally located, round to slightly indented nuclei; and inconspicuous nucleoli (Figure 3). Varying amounts of inflammatory cell infiltrate can be present and typically indicate lesion regression.15

Figure 3. A fine-needle aspirate of a histiocytoma in a dog. Note the monomorphic population of round cells with round to oval nuclei, ropy chromatin, indistinct nucleoli, and scant light-blue-grey cytoplasm with poorly defined cell borders (Wright-Giemsa, 500X). (Photo courtesy of Dr. Elizabeth Little, DACVP.)

Histologically, histiocytomas are characterized by sheets and cords of pleomorphic histiocytes infiltrating the dermis and subcutis. Interestingly, despite the tumor's benign behavior, the mitotic index is often high.13 The presence of CD8+ (cytotoxic) T cells is common in regressing lesions. Studies have demonstrated that histiocytomas express surface markers descriptive of their epidermal Langerhans cell origin (CD1a, CD1b, CD1c, major histocompatibility complex [MHC] II), CD11c, and E-cadherin).3,7,16 Their lack of CD4 and thymocyte differentiation antigen 1 (Thy1) expression distinguishes them from other histiocytic diseases, which consistently express these surface markers.3,6 Immunohistochemical staining by using a panel of surface markers is recommended to obtain an accurate diagnosis only when the cell of origin cannot be clearly determined by routine histology.

Treatment and prognosis

In most cases, histiocytomas spontaneously regress within three months.13,14 Metastases to the lymph nodes have rarely been reported.3 The more aggressive behavior in some cases resembles Langerhans cell histiocytosis in people, a disease characterized by extensive regional cutaneous histiocyte infiltration (resembling cells in a histiocytoma), although widespread systemic involvement occurs.17 In dogs with multiple histiocytomas, the clinical course can be protracted, with new nodules forming while others regress. Eventually, spontaneous resolution of all nodules is expected.18 In general, surgical excision is often curative and should be used in patients with nodules that are ulcerated, infected, or pruritic. Adjunct therapy (such as corticosteroids) is generally unnecessary. The prognosis for solitary regressing cutaneous histiocytoma is excellent.18 In dogs with multiple nodules, the regression may be more prolonged,14,18 but ultimately regression occurs and a good prognosis can be given.

REACTIVE HISTIOCYTOSIS

Two forms of reactive histiocytosis occur in dogs—cutaneous and systemic.

Signalment and clinical findings

Cutaneous histiocytosis is a proliferative disorder confined to the skin and subcutis with rare involvement of regional lymph nodes. The clinical presentation is commonly described as multiple cutaneous nodules, crusts, or areas of depigmentation that appear to wax and wane on the face, ears, nose, neck, trunk, extremities (including footpads), perineum, and scrotum (Figures 4A & 4B).6,18 Middle-aged to older dogs are commonly affected; no reported breed or sex predilection exists.6

Figure 4A & 4B. The nasal planum (4A) and scrotum (4B) of a 4-year-old intact male German shorthaired pointer with cutaneous histiocytosis. Note the areas of depigmentation around the nares (4A; arrows). The lesions initially responded to immunosuppressive therapy. (Photos courtesy of Dr. Karen Farver, DACVD.)

Systemic histiocytosis is a disseminated form of cutaneous histiocytosis that involves the skin (high prevalence at mucocutaneous junctions), ocular and nasal mucosa, and peripheral lymph nodes.6 Lesions can also develop in the lungs, spleen, liver, or bone marrow.18 The severity of the clinical signs, including weight loss, anorexia, conjunctivitis, and stertor, varies with the extent of disease.16 Systemic histiocytosis was first reported in young to middle-aged male Bernese mountain dogs, and a polygenic mode of inheritance has been proved.19 A breed predilection for systemic histiocytosis has also been documented in rottweilers and golden and Labrador retrievers.6,18

Pathogenesis

The cause of both cutaneous and systemic histiocytosis is unknown, but the prevailing hypothesis implicates dysregulation of the proliferation, activation, and function of dendritic cells and T cells or their direct interactions after antigenic stimulation.2,6 This theory is supported by the fact that some cases respond to immunosuppressive therapy. However, the specific antigenic process leading to the immuno dysregulation has not been identified.6

Diagnosis

Cytologically, both cutaneous and systemic histiocytosis resemble granulomatous inflammation. Benign histiocytes possess abundant cytoplasm, round to indented nuclei, and inconspicuous nucleoli. Variable numbers of inflammatory cells are present, while multinucleate giant cells and erythrophagocytosis are seen infrequently.19

The histologic features of cutaneous and systemic histiocytosis are identical. Systemic histiocytosis is diagnosed based on the involvement of organ systems in addition to the skin. Biopsy specimens contain numerous large, pale, round to oval histiocytes with indented vesicular nuclei.18 Numerous neutrophils and lymphocytes are often present, with eosinophils and plasma cells seen less commonly. The lesions are usually located perivascularly, with subsequent vascular invasion, thrombosis, and tissue necrosis frequently described.13,18,19

Immunohistochemistry can help distinguish reactive histiocytoses from granulomatous disease and nonepitheliotropic cutaneous lymphoma. Histiocytes of both cutaneous and systemic histiocytosis express CD1b, CD1c, CD11c, and MHC II surface markers, indicative of their derivation from dendritic antigen-presenting cells.6 Additionally, both cutaneous and systemic histiocytosis are thought to be of activated dermal (interstitial) dendritic cell origin given the expression of Thy1 and CD4 surface markers,3,6 which differentiates them from histiocytoma and histiocytic sarcoma (Table 1).13 More than 50% of the infiltrating lymphocyte population is consistent with CD8+ T cells,6 the role of which is unclear, although their presence does not appear to be associated with lesion regression as in the case of cutaneous histiocytoma. Rather, the T cell infiltrate may be a secondary phenomenon induced by the cytokine microenvironment or may be the primary infiltrating cell population that attracts and retains migrating dendritic cells.6

Table 1: Immunohistochemical Characteristics of Canine Histiocytic Diseases*

Treatment and prognosis

Cutaneous and systemic histiocytosis lesions tend to wax and wane, with spontaneous regression in the early stages of disease. Partial remission (regression of some lesions) with simultaneous development of new lesions in other locations is typical.18 Because cutaneous and systemic histiocytosis likely develop as a result of immune system dysregulation, treatment in later stages often includes immunosuppressive therapy. About 50% of dogs with cutaneous histiocytosis experience a partial or complete response to immunosuppressive doses of cortico steroids.6,18 Similar immunosuppressive corticosteroid treatment for systemic histiocytosis is largely ineffective.13 Dogs with reactive histiocytosis (cutaneous and systemic) have responded to other immunosuppressive agents including cyclosporine, leflunomide, and doxorubicin hydrochloride.6

Some animals can be weaned off of therapy without relapse, while others require lifelong medical management to avoid immediate relapses and the development of new lesions.6,18 In general, the long-term prognosis is poor as disease progression typically renders most dogs nonresponsive to corticosteroids as well as other immunosuppressive therapies. Targeted therapy designed to block dendritic cell and T cell activation may prove useful in treating these diseases.16

HISTIOCYTIC SARCOMA

The histiocytic sarcoma complex is a single disease entity referred to as localized histiocytic sarcoma, disseminated histiocytic sarcoma, and malignant histiocytosis. Localized histiocytic sarcoma refers to a neoplasm that arises from a focal site, typically the extremities.1,20 The terms disseminated histiocytic sarcoma and malignant histiocytosis are often used interchangeably to denote a histiocytic disorder that is systemic in nature with multiple sites of involvement. Since malignant histiocytosis is an antiquated term, we use disseminated histiocytic sarcoma in the remainder of this article when referring to histiocytic sarcoma presenting with widespread lesion distribution.

Signalment and clinical findings

Although histiocytic sarcoma was first described in Bernese mountain dogs, recent reports have also demonstrated a breed predilection for rottweilers and retriever breeds.20-22 The breed-associated risk for developing histiocytic sarcoma has been reported as 225, 26, and 3.7 times as likely for Bernese mountain dogs, rottweilers, and golden retrievers, respectively, when compared with other breeds.23 A sex predilection has not been identified.21

Most dogs with localized histiocytic sarcoma present with a rapidly growing, localized soft tissue mass.18 The limbs are most commonly affected,1 with the tumor site close to a joint because the tumor cells originate from dendritic cells in the synovial lining.20 Primary lesions can also develop from the stomach,24 spleen, liver, lungs, pancreas, or central nervous system.25-27 Most dogs are middle-aged to older, with overrepresentation by flat-coated retrievers,22 rottweilers, and golden retrievers.18 Presenting complaints secondary to local invasion of the primary tumor are often nonspecific (anorexia, weight loss, lethargy) unless they are related to the organ systems involved. These system-related signs often include lameness and swelling of the affected limb (musculocutaneous), coughing and dyspnea (respiratory), or seizures and paralysis (neurologic).3 Localized histiocytic sarcoma is highly metastatic, with metastasis documented in 91% of cases at necropsy.20

Despite age distributions and breed predilections (Bernese mountain dogs, retrievers, and rottweilers) similar to that of the localized form, disseminated histiocytic sarcoma most often affects the spleen, liver, lungs, bone marrow, and lymph nodes.1 In one study, 85% of dogs with histiocytic sarcoma presented with visceral involvement.21 Nonspecific clinical signs predominate, and widespread involvement is frequently noted at presentation.1 Common clinicopathologic abnormalities identified at diagnosis include anemia (29%), thrombocytopenia (22%), hypoalbuminemia (27%), and mild to moderate liver enzyme activity elevations (34%), reflecting the widespread nature of this disease.21 Less commonly reported abnormalities include neutrophilia, hypercalcemia, and hyperglobulinemia (< 10% to 20% of cases).21,28

Hyperferritinemia. Hyperferritinemia, which has been identified in people with malignant histiocytosis,29,30 was reported in a dog with disseminated histiocytic sarcoma.31 Ferritin is an iron storage protein found in low concentrations in normal serum.32 Ferritin production by neoplastic cells is thought to be the pathogenesis of hyperferritinemia in disseminated histiocytic sarcoma,32 and serum ferritin concentrations have been investigated as a marker of disease activity.33 Although all dogs with histiocytic tumors had mildly to markedly elevated serum ferritin in this study, ferritin concentrations above the reference range were found in dogs with hemolytic anemia, hemolymphatic neoplasia, inflammation, and hepatic disease.33 Hyperferritinemia alone cannot distinguish among these diseases.33 However, if hyperferritinemia is present at diagnosis, it may be a useful marker of disease remission and progression, warranting additional prospective studies.

Pathogenesis

The etiopathology of localized and disseminated histiocytic sarcomas is unknown, but the clearly defined canine breed predilections point toward a genetic or molecular mechanism.34 The ras family of oncogenes regulates several intracellular growth-promoting pathways, and ras oncogenes are mutated, leading to protein overexpression in up to 30% of human cancers.35 A member of the ras oncogene family, c-N-ras, was investigated in Bernese mountain dogs, and no activating mutations were found to explain the prevalence of histiocytic sarcoma in this breed.36 Dysregulation of other receptor tyrosine kinase (RTK) signaling pathways—kit/stem-cell factor (SCF), Flt3/Flt3 ligand (Flt3L), and Met/hepatocyte growth factor (HGF)—have been investigated in established histiocytic sarcoma cell lines and histiocytic tumor samples for their potential role in the malignant transformation of dendritic cells.34 While all cell lines and tumor samples expressed messenger RNA encoding the receptors and their respective ligands, none of the samples expressed gene mutations in regions known to frequently undergo mutations in other human and canine neoplasms.34 Furthermore, inhibition of signaling by an RTK inhibitor, SU11654, did not result in growth inhibition in vitro. That indicates that these pathways are not critical to histiocytic sarcoma cell survival and proliferation, and the use of RTK targeted therapy in the clinical setting is unlikely to be beneficial in treating histiocytic sarcomas.34

Diagnosis

Histiocytic sarcoma is diagnosed based on signalment along with clinical findings and is confirmed by cytologic and histologic examination. On cytologic examination, samples from organs or effusions of dogs with disseminated histiocytic sarcoma are typically highly cellular.28 Neoplastic cells (discrete mononuclear cells) are pleomorphic, demonstrating marked anisocytosis and anisokaryosis, abundant vacuolated granular cytoplasm, and bizarre mitotic figures (Figures 5A & 5B).28 In some cases, phagocytosis of red and white blood cells is a prominent feature.

Figure 5A. A fine-needle aspirate of a cutaneous histiocytic sarcoma in a dog. Note the marked anisocytosis, anisokaryosis, bizarre-shaped nuclei, and prominent nucleoli. One plasma cell is also present (arrow) (Wright-Giemsa, 500X). (Photo courtesy of Dr. Elizabeth Little, DACVP.), 5B. A fine-needle aspirate of a cutaneous histiocytic sarcoma in a dog. Note the pleomorphic cells, vacuolated cytoplasm, and large size compared with the neutrophil (arrow) (Wright-Giemsa, 500X). (Photo courtesy of Dr. Elizabeth Little, DACVP.)

Histologic evaluation reveals diffuse infiltration of tissues by atypical histiocytes with abundant granular cytoplasm and prominent nucleoli. Similar to cytologic samples, erythrophagocytosis, leukocytophagy, and numerous bizarre mitotic figures can be noted. The neoplastic cells are commonly arranged in sheets.28

Localized and disseminated histiocytic sarcomas are derived from dendritic cells,1 which can be confirmed by immunohistochemistry. Tumor cells uniformly express CD1b, CD1c, CD11c, CD18, CD45 (indicative of leukocyte origin), and MHC II. Low concentrations of E-cadherin and CD4-Thy1 expression differentiate localized and disseminated histiocytic sarcoma from histiocytomas and reactive histiocytosis, respectively.1 In addition, histiocytic sarcoma tumor samples are uniformly positive for lysozyme and negative for cytokeratin expression, distinguishing them from neoplasms of epithelial origin.28 Immunohistochemistr y to detect cyclooxygenase -2 expression (often overexpressed in a variety of human sarcomas)37 found strong staining in only one out of 20 tumor samples tested.38

Figure 6. A right lateral thoracic radiograph of a 4.5-year-old castrated male Bernese mountain dog with disseminated histiocytic sarcoma. Nodular and alveolar soft tissue pulmonary infiltrates and increased opacity in the regions of the cranial mediastinal and tracheobronchial lymph nodes are present, consistent with marked enlargement of these lymph nodes. (Radiographic interpretation courtesy of Dr. Justin Goggin, DACVR.)

Clinical staging

Complete clinical staging with radio graphs of the abdomen, thorax, limbs, and axial skeleton combined with abdominal and thoracic ultrasonography is valuable for evaluating the extent of the disease. The most common thoracic radiographic abnormalities in dogs with disseminated histiocytic sarcoma are sternal, bronchial, hilar, or mediastinal lymphadenopathy and generalized thymic enlargement.23,39 Pulmonary changes (consolidation, nodular opacities, diffuse pulmonary infiltrates) (Figures 6, 7A, & 7B) and pleural effusion have also been noted.23,39 Abdominal abnormalities are nonspecific and include hepatomegaly,23,39 splenomegaly,23,39 splenic masses (Figure 8),23 abdominal lymphadenopathy,23 and ascites.39 Aggressive soft tissue lesions may lead to regional osteolysis; however, survey spinal radiographs are typically normal in dogs presenting with neurologic deficits. Myelography may reveal intradural lesions or extradural compressive lesions in dogs with neurologic manifestations.23

Figure 7A & 7B. Left lateral (7A) and ventrodorsal (7B) radiographs of a 12-year-old intact male golden retriever with disseminated histiocytic sarcoma. A soft tissue opaque nodule is present in the right middle lung lobe (arrows), and more ill-defined, irregularly shaped soft tissue infiltrates are present in the lung caudal to the nodule. (Radiographic interpretation courtesy of Dr. Justin Goggin, DACVR.)

The ultrasonographic features of canine disseminated histiocytic sarcoma are nonspecific, with most abnormalities reported in the spleen and liver.40 The kidneys, adrenal glands, pancreas, ovaries, and gastrointestinal tract may be affected as well. Well-defined hypoechoic nodules in the spleen (Figure 9) associated with disseminated histiocytic sarcoma are similar to those seen with lymphoma, extramedullary hematopoiesis, abscessation, and lymphoid hyperplasia.40 Liver involvement is less consistent, and lesions of variable echogenicity (Figure 10) contribute to generalized hepatomegaly.40 Although the ultrasonographic appearance of disseminated histiocytic sarcoma is not unique, ultrasonography is useful in guiding fine-needle aspiration to aid in diagnosis.

Figure 8. A lateral abdominal radiograph of an 11-year-old neutered male mixed-breed dog with histiocytic sarcoma of the spleen. Note the smoothly marginated, spherical mass (arrow) arising in the midventral abdomen, consistent with a splenic mass. Serosal detail is good, consistent with a lack of peritoneal fluid. (Radiographic interpretation courtesy of Dr. Justin Goggin, DACVR.)

Treatment and prognosis

Malignancies of histiocytic origin are aggressive and uniformly fatal, with most dogs dying of local tumor recurrence or widespread metastatic disease.1,20-22,41-45 For dogs with localized tumors, a median survival time of five months was reported with aggressive surgical excision (amputation) alone; most dogs succumbed to metastatic disease.20

Figure 9. An abdominal ultrasonogram from a 3.5-year-old spayed female Bernese mountain dog with disseminated histiocytic sarcoma. Note the 1.4-cm mass in the tail of the spleen and the moderate amount of abdominal effusion. (Photo courtesy of Dr. Rebecca Green, DACVIM [internal medicine].)

T cell therapy. One small study in four dogs with disseminated histiocytic sarcoma (one dog with advanced disease and three with disease confined to the skin and regional lymph nodes) reported successful treatment after the administration of gamma-irradiated human leukemic T cell line, TALL-104, which possesses tumoricidal activity in a non-MHC-restricted fashion without lysing cells of normal tissue.46 Three dogs achieved a complete response, and one dog achieved two separate partial responses. None of the dogs developed visceral disease during the follow-up period of nine to 22 months.46 Although TALL-104 cells (which are not available for commercial use at this time) appeared to be a promising therapeutic modality for treating canine disseminated histiocytic sarcoma, these results should be interpreted with caution given the small size of the study population and the fact that the atypical lesion distribution (confined to the skin and lymph nodes) in 75% of the cases is a seldomly described presentation of disseminated histiocytic sarcoma.

Figure 10. An abdominal ultrasonogram of the liver of the same dog as in Figure 9. The liver is mottled, and multiple 1- to 3-cm nodules of mixed echogenicity are present throughout the parenchyma. (Photo courtesy of Dr. Rebecca Green, DACVIM [internal medicine].)

Lomustine. The evaluation of lomustine (chlorethyl-cyclohexol-nitrosourea [CCNU]) in 59 dogs with histiocytic sarcoma documented a 46% response rate, although this response was short, with a median remission of 85 days in the dogs that responded.21 Univariate analysis revealed that anemia, hypoalbuminemia, splenic involvement, and thrombocytopenia at diagnosis were as poor prognostic indicators for survival (Table 2). The median survival time in dogs presenting with poor prognostic factors was less than one month vs. five and a half months for dogs presenting without clinicopathologic abnormalities.21 The overall median survival time of 106 days is not surprising given the aggressive nature of this disease. However, three dogs with microscopic residual disease were treated with lomustine: One dog died at 568 days from original diagnosis while the others were alive at the conclusion of the study and were censored from the survival analysis at 433 and 884 days.21 Referral to an oncologist or internist is necessary for lomustine therapy.

Table 2: Prognostic Factors for Canine Histiocytic Sarcoma

Combination therapy. A similar study examined the prognosis for morphologically (but not immunohistologically) confirmed histiocytic sarcoma in flat-coated retrievers treated with various combinations of surgery, chemotherapy (lomustine or doxorubicin hydrochloride), radiation therapy, and corticosteroids.22 In dogs in which a response could be evaluated, there was a 94% response rate (68% complete response; 26% partial response) after palliative radiation therapy and a 67% response rate (42% complete response; 25% partial response) to lomustine.22 The overall median survival time for all 37 dogs was 123 days.

Pretreatment indicators of decreased survival (Table 2) were the presence of distant metastasis or metastasis of any kind.22 Treatment with radiation therapy or chemotherapy was a strong predictor of increased survival (median survival time of dogs not receiving radiation and chemotherapy was 60 and 34 days, respectively). Dogs receiving any therapy lived significantly longer than dogs receiving only palliative therapy (median survival time = 17 days) consisting of analgesics and corticosteroids. Dogs treated with a combination of radiation therapy and lomustine enjoyed the longest survival times.

Similarities among canine and human histiocytoses

Overall recommendations. The combined results of these recent studies21,22 suggest that dogs treated aggressively with multimodality therapy early in the disease course before marked laboratory abnormalities are noted may fare better than those that are treated after presenting with widespread disease dissemination. Nonspecific clinical signs of illness in at-risk breeds should prompt diagnostic testing and facilitate the early detection and treatment of histiocytic sarcoma.

HEMOPHAGOCYTIC HISTIOCYTIC SARCOMA

A distinct subtype of histiocytic sarcoma characterized by hemophagocytosis and Coombs' negative regenerative anemia has recently been described.47 Hemophagocytic histiocytic sarcoma shares many characteristics with localized and disseminated histiocytic sarcoma such as identical breed representation (Bernese mountain dogs, retrievers, and rottweilers), presenting clinical signs (lethargy, inappetence, weight loss, and pale mucous membranes), affected organ systems (spleen, liver, bone marrow, and lungs), and an aggressive clinical course. However, unlike localized and disseminated histiocytic sarcoma, which arises from proliferating interstitial dendritic cells, hemophagocytic histiocytic sarcoma is the first identified canine proliferative disorder of splenic red pulp and bone marrow macrophages.47 Immunohistochemical analysis from histologic specimens confirms splenic macrophage origin (positive expression of CD11d) and argues against dendritic cell origin (CD1c and CD11c negative).47

Multiorgan involvement typical of other canine histiocytic diseases combined with the unique characteristic of hemophagocytosis and regenerative anemia distinguishes hemophagocytic histiocytic sarcoma as its own clinical entity. Other clinicopathologic findings include thrombocytopenia, hypoalbuminemia, and hypocholesterolemia in 88%, 94%, and 69% of the cases, respectively. Disease progression is rapid, with a reported mean survival time from diagnosis until death of seven weeks.47 As treatment-related survival data for hemophagocytic histiocytic sarcoma are not currently available, we recommend treating with chemotherapeutic agents that possess known efficacy against localized and disseminated histiocytic sarcoma.21 Given the current research focus on the ever-elusive canine histiocytic disease complex, further clinical study of this newly defined canine histiocytic syndrome is anticipated.

SUMMARY

The canine histiocytic diseases represent a complex of diseases originating from myeloid dendritic cells.3 Although originating from a common precursor, the benign and malignant counterparts of the histiocytic disease spectrum are vastly different in biologic behavior, recommended treatment, and prognosis. Recognizing the breed and age predilections for this spectrum of clinical diseases is paramount to identifying cases that require a diagnostic work-up. Immunohistochemical analysis is beneficial in solidifying an accurate diagnosis so that appropriate therapy can be instituted promptly, as aggressive early treatment can improve survival times in dogs with histiocytic sarcoma. Recent retrospective analyses have shown promise for combination therapy, including radiation therapy and chemotherapy to treat histiocytic sarcoma. Controlled, prospective studies are warranted to determine the appropriate treatment of histiocytic sarcoma.

Rebecca E. Risbon, VMD

Craig A. Clifford, DVM, MS, DACVIM (oncology)

Red Bank Veterinary Hospital

197 Hance Ave.

Tinton Falls, NJ 07724

Katherine Skorupski, DVM, DACVIM (oncology)

Department of Surgical and Radiological Sciences

School of Veterinary Medicine

University of California

Davis, CA 95616

REFERENCES

1. Affolter VK, Moore PF. Localized and disseminated histiocytic sarcoma of dendritic cell origin in dogs. Vet Pathol 2002;39:74-83.

2. Withrow SJ, Vail D. Histiocytic diseases. In: Small animal clinical oncology. 4th ed. St. Louis, Mo: Saunders Elsevier, 2007;814-823.

3. Moore PF. The histiocytic disease complex, in Proceedings. Am Coll Vet Intern Med Annu Mtg, 2004.

4. Morris JS, McInnes EF, Bostock DE, et al. Immunohistochemical and histopathologic features of 14 malignant fibrous histiocytomas from Flat-Coated Retrievers. Vet Pathol 2002;39:473-479.

5. Kerlin RL, Hendrick MJ. Malignant fibrous histiocytoma and malignant histiocytosis in the dog—convergent or divergent phenotypic differentiation? Vet Pathol 1996;33:713-716.

6. Affolter VK, Moore PF. Canine cutaneous and systemic histiocytosis: reactive histiocytosis of dermal dendritic cells. Am J Dermatopathol 2000;22:40-48.

7. Moore PF, Schrenzel MD, Affolter VK, et al. Canine cutaneous histiocytoma is an epidermotropic Langerhans cell histiocytosis that expressed CD1 and specific beta 2-integrin molecules. Am J Pathol 1996;148:1699-1708.

8. Hayden DW, Waters DJ, Burke BA, et al. Disseminated malignant histiocytosis in a golden retriever: clinicopathologic, ultrastructural, and immunohistochemical findings. Vet Pathol 1993;30:256-264.

9. PF Moore, Affolter VK, Olivry T, et al. The use of immunological reagents in defining the pathogenesis of canine skin disease involving proliferation of leukocytes. In: Kwochka KW, Wilemse T, von Tscharner C, eds. Advances in veterinary dermatology. Oxford: Butterworth-Heinemann , 1998;77-94.

10. Cline MJ. Histiocytes and histiocytosis. Blood 1994;84:2840-2853.

11. Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000;18:767-811.

12. Vail DM, Withrow SJ. Tumors of the skin and subcutaneous tissues. In: Withrow S, MacEwen E, eds. Small animal clinical oncology. 3rd ed. Philadelphia, Pa: WB Saunders Co, 2001;248-249.

13. Scott DW, Miller WH, Griffin CE. Neoplastic and non-neoplastic tumors. In: Muller and Kirk's small animal dermatology. 6th ed. Philadelphia, Pa: WB Saunders Co, 2001;1346-1357.

14. Bender WM, Muller GH. Multiple, resolving, cutaneous histiocytoma in a dog. J Am Vet Med Assoc 1989;194:535-537.

15. LeBlanc C, LeBland A. Cytologic diagnosis and treatment of common round cell tumors, in Proceedings. Am Coll Vet Intern Med, 2006.

16. Moore PF. Canine histiocytosis. School of Veterinary Medicine, University of California, Davis, Calif. Available at: www.histiocytosis.ucdavis.edu.

17. Nagata M, Hirata M, Ishida T, et al. Progressive Langerhans' cell histiocytosis in a puppy. Vet Dermatol 2000;11:241-246.

18. Bonagura JD, ed. Canine cutaneous histiocytic diseases. In: Kirk's current veterinary therapy XIII small animal practice. Philadelphia, Pa: WB Saunders Co, 2000;588-591.

19. DeHeer HL, Grindem CB. Histiocytic disorders. In: Jain NC, ed. Schalms veterinary hematology. 4th ed. Philadelphia, Pa: Lea & Febiger, 1986;696-702.

20. Craig LE, Julian ME, Ferracone JD. The diagnosis and prognosis of synovial tumors in dogs: 35 cases. Vet Pathol 2002;39:66-73.

21. Skorupski KA, Clifford CA, Paoloni MC, et al. CCNU for the treatment of dogs with histiocytic sarcoma. J Vet Intern Med 2007;21:121-126.

22. Fidel J, Schiller I, Hauser B, et al. Histiocytic sarcomas in flat-coated retrievers: a summary of 37 cases (November 1998-March 2005). Vet Comp Oncol 2006;4:63-74.

23. Shaiken LC, Evans SM, Goldschmidt MH. Radiographic findings in canine malignant histiocytosis. Vet Radiol 1991;32:237-242.

24. Fant P, Caldin M, Furlanello T, et al. Primary gastric histiocytic sarcoma in a dog—a case report. J Vet Med A Physiol Pathol Clin Med 2004;51:358-364.

25. Snyder JM, Shofer FS, Van Winkle TJ, et al. Canine intracranial primary neoplasia: 173 cases (1986-2003). J Vet Intern Med 2006;20:669-675.

26. Uchida K, Morozumi M, Yamaguchi R, et al. Diffuse leptomeningeal malignant histiocytosis in the brain and spinal cord of a Tibetan Terrier. Vet Pathol 2001;38:219-222.

27. Chandra AM, Ginn PE. Primary malignant histiocytosis of the brain in a dog. J Comp Pathol 1999;121:77-82.

28. Brown DE, Thrall MA, Getzy DM, et al. Cytology of canine malignant histiocytosis. Vet Clin Pathol 1994;23:118-123.

29. Matzner Y, Konijn AM, Hershko C. Serum ferritin in hematologic malignancies. Am J Hematol 1980;9:13-22.

30. Lukina EA, Levina AA, Mokeeva RA, et al. The diagnostic significance of serum ferritin indices in patients with malignant and reactive histiocytosis. Br J Haematol 1993;83:326-329.

31. Newlands CE, Houston DM, Vasconcelos DY. Hyperferritinemia associated with malignant histiocytosis in a dog. J Am Vet Med Assoc 1994;205:849-851.

32. Smith JE. Iron metabolism in dogs and cats. Compend Contin Educ Pract Vet 1992;14:39-43.

33. Friedrichs K, Andrews G, Thomas C, et al. Evaluation of serum ferritin as a marker for malignant histiocytic tumors, in Proceedings. Am Soc Vet Clin Pathol 37th Annu Meeting, 2002.

34. Zavodovskaya R, Liao AT, Jones CR, et al. Evaluation of dysregulation of the receptor tyrosine kinases Kit, Flt3, and Met in histiocytic sarcomas of dogs. Am J Vet Res 2006;67:633-641.

35. Tannock IF, Hill RP, Bristow RG, et al. Oncogenes and tumor suppressor genes. In: The basic science of oncology. 4th ed. New York: McGraw-Hill Companies Inc, 2005;123-141.

36. Madewell BR, Pazzi KA, Gumerlock PH. A search for activating N-ras mutations in malignant histiocytosis of the Bernese Mountain dog. Comp Haematol Int 1992;2:103-105.

37. Dickens DS, Kozielski R, Khan J, et al. Cyclooxygenase-2 expression in pediatric sarcomas. Pediatr Dev Pathol 2002;5:356-364.

38. Heller DA, Clifford CA, Goldschmidt MH, et al. Assessment of cyclooxygenase-2 expression in canine hemangiosarcoma, histiocytic sarcoma, and mast cell tumor. Vet Pathol 2005;42:350-353.

39. Schmidt ML, Rutteman GR, van Niel MH, et al. Clinical and radiographic manifestations of canine malignant histiocytosis. Vet Q 1993;15:117-120.

40. Ramirez S, Douglass JP, Robertson ID. Ultrasonographic features of canine abdominal malignant histiocytosis. Vet Radiol Ultrasound 2002;43:167-170.

41. Uno Y, Momoi Y, Watari T, et al. Malignant histiocytosis with multiple skin lesions in a dog. J Vet Med Sci 1993;55:1059-1061.

42. Rosin A, Moore P, Dubielzig R. Malignant histiocytosis in Bernese Mountain dogs. J Am Vet Med Assoc 1986;188:1041-1045.

43. Hirasa K, Baba E, Kotani T. Hemolytic anemia induced by malignant histiocytosis. Canine Pract 1984;11:46-48.

44. Ramsey IK, McKay JS, Rudorf H, et al. Malignant histiocytosis in three Bernese mountain dogs. Vet Rec 1996;138:440-444.

45. Kohn B, Arnold P, Kaser-Hotz B, et al. Malignant histiocytosis of the dog: 26 cases (1989-1992). Kleintierpraxis 1993;38:409-424.

46. Visonneau S, Cesano A, Tran T, et al. Successful treatment of canine malignant histiocytosis with the human major histocompatibility complex nonrestricted cytotoxic T-cell line TALL-104. Clin Canc Res 1997;3:1789-1797.

47. Moore PF, Affolter VK, Vernau W. Canine hemophagocytic histiocytic sarcoma: a proliferative disorder of CD11d+ macrophages. Vet Pathol 2006;43:632-645.