Diagnosing & Treating Canine Histiocytic Disease
ACVIM 2008
Steven E. Suter, VMD, MS, PhD, DACVIM (Oncology)
Raleigh, NC, USA

Introduction

Canine histiocytic proliferative disease (HPD) is a complex spectrum of abnormalities with both benign and malignant manifestations. Diagnosing HPD can, in some cases, be quite straight forward, while in other cases it can be extremely difficult. Determining exactly what type of HPD a dog has contracted is extremely important since the prognosis and treatment of these different syndromes is markedly different. Additionally, it can be difficult to distinguish HPD from histiocytic inflammation and lymphoma using conventional histopathologic techniques. Literally dozens of "histiocytic" syndromes have been described in people, therefore, HPD remains a topic of considerable debate among human oncologists. In dogs, it is useful to separate HPD into 8 syndromes, although the true relationship between these separations is still unknown. With recent advances in the development of monoclonal antibodies against a variety of canine hematopoietic cell surface proteins (i.e., cluster designation or CD molecules), our ability to at least diagnose HPD lineages is increasing. Hopefully, as we continue to develop and apply reliable histochemical and immunochemical HPD reagents to refine our understanding of the cell of origin of these diseases, our ability to treat these diseases will improve.

Histiocytic Disease Overview

Historically, HPD has been classified as a disease of histiocytes, which are tissue based leukocytes. Histiocytes are divided into two separate phenotypic lineages, macrophages and dendritic cells. Both of these lineages originate from a common precursor in the bone marrow. Macrophages, part of the innate immune system, are mainly phagocytic cells that intracellularly digest foreign antigens and present peptides on their cell surface in association with MHC-class II molecules. Dendritic cells, on the other hand, tend to be poorly phagocytic. The main job of dendritic cells is to process and present foreign antigens to lymph node T-cells to invoke an immune response. Therefore, dendritic cells are one of many types of antigen-presenting cells (APCs). Dendritic APCs tend to co express the cell surface markers CD1a, b, c, CD11c, and MHC-class II, therefore canine HPD is a disease of Langerhans cells (Langerhans cell histiocytosis or LCH in humans). Langerhans cells (LC) are skin dendritic cells that usually contain Birbeck granules. It is important to note at this juncture that the clinical presentation, behavior, and responsiveness to therapy vary, and the exact pathogenesis of HPD is unknown. The etiology of canine HPD is also unknown.

Canine HPD Syndromes

Idiopathic Periadnexal Multinodular Granulomatous Dermatitis

Idiopathic periadnexal multinodular granulomatous dermatitis (IPMGD) is a rare disease of multiple, benign, exclusively cutaneous lesions located mostly on the head.1 There is no breed or sex predilection. This is a benign entity that is most likely an autoimmune proliferation of cells. Many lesions have been reported to regress spontaneously, although most are quite responsive to corticosteroid therapy. In some refractory cases, intermittent low-dose corticosteroid therapy is required to prevent recrudescent disease.

Histiocytomas

Histiocytomas, which are common benign tumors in young dogs, are proliferations of epidermal LC that are CD4- and Thy-1-. They do express CD1a, CD1b, CD1c, MHC-class II, CD11c, and E-cadherin.2-3 E-cadherin expression is unique to Langerhans cells (among other leukocytes) and is utilized to localize these cells in the epidermis via homotypic interaction with E-cadherin expressing keratinocytes. The incidence of these "button-like" tumors drops off markedly after 3 years of age, but histiocytomas do develop in older dogs. Most cases present with a solitary, nonpruritic, nonpainful dome-shaped nodule, or, at times, an intracutaneous plague. The majority of these nodules remain small (<2.5 cm), but they can become alopecic and ulcerated. The areas of the body most affected tend to be the head, ears, neck, and extremities, with no apparent breed or sex predilection. Histologically, histiocytomas are characterized by nonencapsulated, poorly demarcated, intracutaneous nodules with diffuse proliferations of fairly monomorphic round cells with large round to oval, indented or twisted vesicular nuclei. Mitotic figures are frequent and reactive cellular infiltrates are scant, except for the marked infiltration of CD8+ cytotoxic T cells in later stages, which correlates with the spontaneous regression seen in the majority of histiocytomas. Regional lymph nodes are rarely enlarged and, if they are, regional lymphadenopathy regresses along with the skin nodules. Once initiated, regression may occur within days, but can take up to 10 months. Shar-pei or Shar-pei mixed breed dogs are noted to develop multiple histiocytomas in various stages of growth and regression that can persist for several months4. However, eventually all masses undergo spontaneous regression5. There is one published report of widespread cutaneous histiocytomas with rapid internal spread leading to euthanasia.

Cutaneous histiocytomas spontaneously regress, therefore, therapy is rarely needed. Since regression is initiated by the infiltration of CD8+ T cells6, the administration of immunomodulatory drugs, such as steroids, is contraindicated. In cases of delayed regression or ulcerated nodules, surgery is usually curative. The prognosis for dogs with this disease is excellent.

Cutaneous and Systemic Histiocytosis (Reactive HPD)

Both cutaneous histiocytosis (CH) and systemic histiocytosis (SH) are proliferations of CD4+, Thy-1+ activated interstitial dermal Langerhans cells. Both disease entities tend to have identical cutaneous lesions which typically manifest as multiple nonpainful, nonpruritic cutaneous plaques or nodules. The cutaneous lesions, which can be found anywhere on the body, including eyes, footpads, perineum, and scrotum, can wax and wane. The distinction between CH and SH is based on the fact that SH has other organ involvement besides skin. Histologically, both CH and SH cutaneous lesions tend to focus around blood vessels and not have a periadnexal association. Morphologically, these lesions tend to be composed of a mixed cell population including histiocytes, T lymphocytes, neutrophils and, at times, plasma cells and eosinophils. These histologic features are consistent with a reactive process.

The diagnosis of CH and SH is reached via immunohistologic detection of a reactive process which is characterized by a perivascular expansion of activated dendritic APCs with admixed T lymphocytes and neutrophils. In CH, the lesions are typically limited to the skin and draining lymph nodes. CH is typically very responsive to steroids (~50% response rate), although long-term maintenance may be required.

SH was first described as a disease of primarily male Bernese mountain dogs (BMD) with a polygenic mode of inheritance7. Approximately ¼ or all tumors in BMD are reported to be either SH or MH (malignant histiocytosis-to be discussed later). In BMD, peripheral lymphadenopathy and ocular involvement (conjunctival chemosis and corneal edema) is reported with many cases of more advanced organ involvement. Therefore, in any BMD with ocular lesions, the clinician should be highly suspicious of SH. SH patients tend to be poorly responsive to steroids. Some success has been reported using Cyclosporin A or Leflunomide, although the long term treatment needed in advanced SH patients can be exorbitantly expensive. Survival durations of 2 to 48 months have been reported.8-10 The prognosis remains guarded for these patients.

Histiocytic Sarcoma

Histiocytic sarcoma (HS) is typically a rapidly growing, solitary, locally aggressive soft tissue mass most often located in close proximity to a joint. Many lesions will grow into and circumferentially around a joint. HS can also develop in other locations, such as the spleen, lung, lymph node, gastric wall, and tongue. The lesions are characterized histologically by a nonencapsulated, poorly demarcated proliferation of sheets of pleomorphic, large, individualized round cells or more densely packed spindle cells. The cells have a large amount of pale eosinophilic cytoplasm and large round to oval, indented or twisted, vesicular nuclei. Multinucleated giant cells and bizarre mitosis are common. Erythro- and leukophagocytosis can be seen with HS, but it is not a prominent feature. Immunophenotypically, HS cells express CD1c, CD11c, and although they tend to not be epitheliotropic, they do not express CD4 or Thy-1 (CD4-/Thy-1- is characteristic of epitheliotropic APCs). Therefore, the exact sub lineage of dendritic cells involved in HS is not known at this time. Flat-coated retrievers seem to be predisposed, but the disease is seen in other breeds as well, including Golden retrievers, Labrador retrievers, Rottweilers, and BMD.11-13

Treatment of HS is aimed at both local and systemic control, since metastasis to regional LNs or distant sites can occur late in the course of the disease. Complete local control of cutaneous lesions can be achieved with aggressive surgery, taking as large lateral and deep margins as possible. Joint associated HS many times can only be locally controlled with amputation. HS lesions are also considered very radiation responsive, therefore, definitive radiation can be used to treat either very large tumors in a pre-surgical setting or to treat surgical scars if margins are either inadequate or questionable. Systemic chemotherapy remains the mainstay of trying to either slow HS disease progression or combat obvious metastatic disease progression. Doxil (stealth liposomes with mannose side-chains that contain adriamycin)14, adriamycin alone, or CCNU (Lomustine) are rational drug choices. The prognosis for HS patients if lymph node involvement is found is very guarded. The prognosis may be more favorable if the tumor is removed before LN involvement has occurred.

Hemophagocytic HS has recently been described.15 The vast majority of the 17 dogs were 2.5 to 13 year old BMD, Golden retrievers, Rottweilers, and Labrador retrievers. Most dogs presented with regenerative anemia, thrombocytopenia, hypoalbuminemia, and hypocholesterolemia. Macroscopic lesions were found mainly in the spleen and liver (hepato- and/or splenomegaly), but many other organs were found to be affected at necropsy. The most consistently involved organs microscopically were spleen, liver, bone marrow, and lung, with the spleen involved in all cases. In this syndrome, the splenic histiocytes were markedly erythrophagocytic and accompanied by foci of extramedullary hematopoiesis. Cytologically, the histiocytes varied from well differentiated to atypical, with atypia more prevalent in the spleen and bone marrow. Using immunohistochemistry, the authors found these tumors arose from splenic red pulp and bone marrow macrophages, which expressed MHC-class II, and importantly, the β2 integrin CD11d. They had low or inconsistent expression of CD1 and CD11c, which are dominantly expressed by canine nonhemophagocytic HS. All dogs in this report died or were euthanized from 2 to 32 weeks (mean 7.1 weeks) after initial diagnosis, therefore, the prognosis of dogs with hemophagocytic HS is grave.

Malignant Histiocytosis

Malignant histiocytosis (MH) is essentially disseminated HS. It is characterized by an aggressive, multi-centric clinical course that rarely has skin and/or subcutis involvement. The organs most often affected include spleen, bone marrow, lung, and lymph nodes although, as the disease progresses, many other organs become infiltrated. The histopathologic and immunophenotypic features of MH are identical to HS. HS and MH are both capable of widespread dissemination, therefore, the 2 syndromes merge clinically and it is not always possible to differentiate true multi-centric MH from widespread metastasis of disseminated HS. The perception is that, once clinical signs are apparent, that both MH and disseminated HS follow a rapid clinical progression despite varied therapeutic interventions.

Because MH is usually an advanced systemic disease once clinical signs are apparent, surgery and/or radiation are usually not optional treatment modalities. Chemotherapeutics, such as Adriamycin or CCNU, have been used by a variety of groups with overall minimal success. The prognosis for patients with MH remains grave.

Splenic Histiocytic/Fibrohistiocytic Nodules

This syndrome was originally described in two case series as a diffuse or nodular histiocytic infiltration of the spleen.16,17 Golden retriever, Labrador retrievers, German shepherds, and possibly cocker spaniels were over represented. Histologically, the diffuse form is characterized by varying degrees of mitotic activity, erythrophagocytosis, giant cell formation, thrombosis, and infarction. The presence of giant cells was a strong negative prognostic indicator in the diffuse form. In the nodular form, the nodules form a continuum between splenic lymphoid nodular hyperplasia and malignant splenic stromal neoplasms (similar histologically to malignant fibrous histiocytoma or MFH). In the nodular form, the lymphoid:fibrohistiocytic ratio and mitotic index was predictive of outcome. Patients with nodules having an increased mitotic index and decreased infiltration of lymphoid cells (low lymphoid:fibrohistiocytic ratio) fared worse. In these reports, the median survival of dogs was approximately 5 months, with nearly 50% of the dogs having evidence of multi-organ involvement at necropsy.

Treatment of splenic h/f nodules is aimed mainly at local control via splenectomy. Based on the findings of an overall short median survival and multi-organ involvement, it is rational to consider systemic chemotherapy to delay the metastatic spread of the disease. Adriamycin and/or CCNU are rational choices, although there are no controlled clinical trials that prove the efficacy of these drugs in this setting.

Malignant Fibrous Histiocytoma

Malignant fibrous histiocytomas (MFH) behave biologically like fibrosarcomas and many other soft tissue sarcomas (STS), although most are reported to be high-grade tumors. These tumors are characterized as primitive, pleomorphic sarcomas that arise from an undifferentiated mesenchymal cell. Other names include giant cell fascial sarcoma, epitheloid sarcoma, malignant histiocytoma, reticulum cell sarcoma, and giant cell tumor. These neoplasms should not be confused with MH or SH. MFHs are usually firm and invasive and arise from the subcutis. Metastasis, like all soft tissue sarcomas, is linked closely to grade. Grade I tumors have an ~10% metastatic rate, Grade II tumors have an ~20% metastatic rate, while Grade III tumors have an ~50% metastatic rate. A 1996 report retrospectively reexamined 263 biopsies diagnosed originally as either MH or MFH.18 The neoplasms were histologically reclassified into 77 cases (30%) of exclusively MH, 110 cases (40%) of exclusively MFH, and 76 cases (30%) with features of both MH and MFH. Age, sex, breed dispositions, and distribution of lesions in organs were very similar between the 3 categories.

The treatment of Grade I & Grade 2 MFH is aimed mainly at local control via surgery, unless metastatic spread is suspected. If margins are dirty or suspect, definitive radiation can be used to kill residual microscopic disease. Dogs with low and intermediate grade STS enjoy a 75% 5-year survival with surgery and radiation treatment. For high grade MFH, local control should be followed with systemic chemotherapy in light of the 50% metastatic rate. Adriamycin is a rational drug choice. There are no controlled clinical trials showing that a drug such as Adriamycin will extend dogs lives in this setting.

Summary

Canine HPD represent a very diverse group of proliferations that include both benign and malignant entities. To diagnose a particular syndrome, the clinician must many times rely on a number of diagnostic criteria, including cytology, histology, and immunochemical staining. For this reason, when HPD is suspected and biopsies are taken, it may be prudent to have them performed in a facility that can process both formalin-fixed and fresh frozen samples, since many of the anti-canine leukocyte markers work only with fresh-frozen samples. Although our ability to further refine the specific lineages responsible for HPD has improved, the prognosis for dogs with the systemic variants remains very guarded. An excellent website describing canine HPD can be found in Peter Moore's website at UC Davis: http://www.histiocytosis.ucdavis.edu/

References

1.  Carpenter JL, et al. Vet Pathol 1987; 24:5.

2.  Marchal T, et al. Acta Anat 1995;153:189.

3.  Moore PF, et al. Am J Pathol 1996;148:1699.

4.  Moore PF. unpublished data. www.histiocytosis.ucdavis.edu.

5.  Bender WM, et al. J Am Vet Med 1989;184:535.

6.  Moore PF, et al. Am J Pathol 1996;148:1699.

7.  Moore PF. Vet Pathol 1984;21:554.

8.  Padgett GA, et al. J Small Anim Pract 1995;5:93.

9.  Paterson S, et al. J Small Anim Pract 1995:36;233.

10. Moore PF. Vet Pathol 1984;21:554.

11. Hayden DW, et al. Vet Pathol 1993;30:256.

12. Wellman ML, et al. JAVMA 1985;187:919.

13. Rosin A, et al. JAVMA 1986;188:1041.

14. Vail DM, et al. Cancer Chemother Pharmacol 1997;39:410.

15. Moore PF, et al. Vet Pathol 2006;43:632.

16. Spangler WL, et al. Vet Pathol 1998;35:488.

17. Spangler WL, et al. Vet Pathol 1999;36:583.

18. Kerlin RL, et al. Vet Pathol 1996;33:713.

Speaker Information
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Steven Suter, VMD, MS, PhD, DACVIM (Oncology)
Raleigh, NC


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