Canine histiocytic sarcoma complex: recent advances (Proceedings)

Canine proliferative histiocytic disorders (PHD) include nonneoplastic or nonmalignant conditions such as the benign cutaneous histiocytoma of young dogs or the cutaneous and systemic histiocytoses (reactive histiocytic diseases), and malignant proliferations including malignant fibrous histiocytoma, splenic fibrohistiocytic nodules, and histiocytic sarcoma (localized, disseminated, hemophagocytic). This conference will focus on the various forms of canine histiocytic sarcoma (HS) and provide updates on diagnosis, prognosis, and treatment.

Determining exactly what type of PHD a dog has developed is crucial because the prognosis and therapeutic approach of the different syndromes are markedly different. It can be difficult to distinguish PHD from histiocytic inflammation, lymphoma, or other round cell tumors and sarcomas with conventional histopathologic techniques. The development of various monoclonal antibodies identifying an array of canine hematopoietic cell surface proteins (CDs or cluster of differentiation molecules) helps to diagnose PHD more precisely, and our ability to diagnose, prognosticate, and treat these diseases will only improve with time and further refinements in diagnostic techniques and therapeutic options.

Histiocytic sarcoma was initially described in Bernese mountain dogs, where it is recognized as a familial disorder and recently demonstrated to have an autosomal oligogenic mode of transmission. All forms of HS have been found to be frequent in other predisposed breeds including retrievers (golden, flat coated, Labrador) and the rottweiller. Though genetics clearly play a role in certain PHD, the exact pathogenesis and etiology currently remain unknown.

The HS complex typically affects middle-age to older dogs, but may also be diagnosed in younger dogs. It is characterized by proliferation and tissue infiltration of atypical histiocytic cells that often involves multiple organs simultaneously. Canine histiocytic sarcoma may initially present as solitary tumor (localized HS – periarticular vs. other sites) or multicentric disease (disseminated HS – previously called malignant histiocytosis) but eventually widespread metastasis is observed in a majority of cases. A third form of HS, haemophagocytic HS was recently described.

CELLULAR ORIGIN

Historically, PHD have been classified as diseases of histiocytes, which are tissue-based leukocytes. Histiocytes are divided into two separate phenotypic lineages, macrophages and dendritic (antigen-presenting) cells, and are found in all tissues. Both of these lineages originate from a common CD34+ precursor in the bone marrow and, with exposure to specific cytokines and growth factors, differentiate to become cells of the monocyte/macrophage lineage or of the dendritic cell type. After differentiation, macrophages and dendritic cells still share many surface antigens and receptors for immunoglobulin and complement molecules but, despite many similarities, enough differences (morphologic, phenotypic, functional) exist to categorize them as distinct cell lineages.

Macrophages are part of the innate immune system and function mainly as phagocytic cells that can digest foreign antigens intracellularly 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 and mainly process foreign antigens and then present them to T lymphocytes to evoke a specific immune response. Therefore, dendritic cells are one of many types of professional antigen-presenting cells (APCs). Dendritic APCs typically coexpress the cell surface markers CD1a, b, c, CD11c, and MHC-class II, therefore canine HPD are diseases of Langerhans cells (skin dendritic cells).

DIAGNOSIS

Localized histiocytic sarcoma (HS) generally presents as a rapidly growing, solitary, locally invasive soft tissue mass most typically in close proximity to a large joint (stifle and elbow), often growing into and around the joint, thereby causing pain and lameness. Localized HS also may develop in other organs such as the spleen, lung, lymph node, bone, GI wall, and tongue. Disseminated HS (malignant histiocytosis) is characterized by an aggressive, multicentric clinical course that uncommonly presents skin and/or subcutis involvement. The organs most often affected include spleen, liver, bone marrow, lung, and lymph nodes and, as the disease progresses, many other organs become infiltrated. Dogs with the hemophagocytic form of HS often present with regenerative anemia, thrombocytopenia, hypoalbuminemia, and hypocholesterolemia. The most consistently involved organs microscopically were spleen (splenomegaly), liver, bone marrow, and lung, with the spleen being involved in all cases.

The typical diagnostic investigation of canine HS will involve a complete blood cell count, complete chemistry profile, urinalysis, 3-view chest radiographs, and abdominal ultrasound. For localized HS that may be treated surgically or with radiation therapy, advanced imaging (CT scan or MRI) may occasionally be indicated. Cytology may help in the diagnostic investigation of HS, but a definitive diagnosis generally requires histopathology with immunohistochemistry and/or flow cytometry of cellular samples, using various immunomarkers.

Localized and disseminated forms of HS present identical histopathological features, and are typically characterized by a nonencapsulated, poorly demarcated proliferation of sheets of pleomorphic, large, individualized round cells, or more densely packed bundles of plump spindle cells. The neoplastic cells have a large amount of pale eosinophilic cytoplasm and large round to oval, indented or twisted, vesicular nuclei. Large, round to stellate multinucleated giant cells are typically present. The mitotic rate is usually high and bizarre (abnormal) mitoses are commonly observed. Erythro- and leukophagocytosis can be present in HS, but it is not a prominent feature, except with the hemophagocytic form where marked erythrophagocytosis is observed and often accompanied by foci of extramedullary hematopoiesis.

Immunophenotypically, HS cells (localized or disseminated forms) express CD1c, CD11c, but are negative for CD4 and Thy-1. Therefore, the exact sub lineage of dendritic cells involved in HS is not known at this time. In the hemophagocytic variant, the histiocytes may be well differentiated or atypical, with atypia more prevalent in the spleen and bone marrow. These tumors arise from splenic red pulp and bone marrow macrophages, which express MHC-class II and the 2 integrin CD11d. However, they have low or inconsistent expression of CD1 and CD11c, which are dominantly expressed by canine nonhemophagocytic HS cells.

TREATMENT AND PROGNOSIS

Relatively little information is available regarding the treatment of canine histiocytic sarcomas. Historically the prognosis of disseminated HS (malignant histiocytosis) in dogs was known to be poor to grave, without much to offer therapeutically.

However, a recent study demonstrated some therapeutic efficacy with lomustine (CCNU) chemotherapy, an oral alkylator of the nitrosourea family, with a therapeutic response rate approaching 50%. In that study, lomustine was most frequently administered at a dosage of 60-75 mg/m2 every 3-4 weeks. The median survival time for all 59 dogs in this study was 106 days. Dogs that responded to therapy (partial or complete responses) had a median survival time approaching 6 months (172 days), compared to a median of 60 days for non responders. Interestingly, all 3 dogs treated with minimal residual disease following surgery lived more than 14 months.

There are a few reports of therapeutic responses to treatment with doxorubicin, liposome-encapsulated doxorubicin, or paclitaxel. The most commonly used of these agents remains doxorubicin, at standard dosage of 30 mg/m2 IV q21d, but the efficacy with the native form of that drug may not be as high as with the more expensive liposome-encapsulated version (Doxil). The efficacy of prednisone for histiocytic sarcoma, alone or in combination, appears to be poor. This author likes to combine lomustine and doxorubicin in an alternating protocol, every 21 days, for up to 3 or 4 6-week cycles (6 to 8 treatments) and has anecdotally seen long-term (over 6 months) responders.

Other chemotherapy agents have been anecdotally used and discussed, including dacarbazine, mitoxantrone, vincristine, vinblastine, and others. Their true efficacy in the treatment of HS remains to be documented. Novel anticancer therapies including tyrosine kinase inhibitors are under investigation for the treatment canine HS. The use of liposome-encapsulated aminobisphosphonates, a class of drugs that is known to be cytotoxic to histiocytes, is under investigation and results are awaited. The occasional cases of bone involvement with HS could be treated with intravenous pamidronate, the best studied aminobisphosphonate in dogs, in an attempt to control the osteolytic bone pain and possibly slow down local progression of the disease in the bone microenvironment.

In a study evaluating surgery as a single treatment modality, there was no improvement in survival time when compared to no treatment at all. Dogs receiving any other type of therapy (radiation, chemo, or multimodality) lived longer than dogs treated solely with palliative therapy (167 versus 17 days). These results parallel the findings of another study looking specifically at periarticular HS. In the latter study, it was found that HS was a common joint tumor, often misdiagnosed as an undifferentiated or high-grade sarcoma prior to the use of immunomarkers, and that the median survival time of dogs with HS (5.3 months) was worse than that of dogs with synovial cell sarcomas or synovial myxomas (both above 30 months). It is important to notice that periarticular HS generally requires amputation for local control, as the tumor is very invasive in the joint capsule and surrounding tissues.

With localized HS that is otherwise negative on complete clinical staging, the recommended approach is to obtain local control with surgical removal (ex: amputation, splenectomy, lymphadenectomy, lung lobectomy, etc.) and then follow-up with systemic therapy since 70 to 90% of dogs with localized HS will go on to develop metastasis. Two studies recently looked at the survival times of dogs with localized HS (at diagnosis) treated with surgery and adjuvant chemotherapy. One of these studies was recently published and evaluated 16 dogs with localized HS treated with surgery followed by adjuvant lomustine chemotherapy, and reported a median survival time of 568 days. The other study has yet to be published, but demonstrated that dogs with localized HS that are not periarticular have a shorter median survival time (128 days) than those with periarticular disease (391 days). Not surprisingly, this study also showed that dogs with periarticular HS that do not have detectable metastasis at diagnosis live longer than those with measurable distant disease.

A pilot study had evaluated the use of a human cytotoxic T lymphocyte acute lymphoblastic leukemia cell line (TALL-104) as treatment for canine disseminated HS, demonstrating interesting therapeutic efficacy in the treated dogs (n = 4). Sadly, insufficient data and unavailability of this cell line make this option irrelevant for the time being.

Though it currently remains anecdotal, HS lesions are generally considered to be fairly radiation responsive. Therefore, radiation therapy could be used to treat either large tumors in a pre-surgical (cytoreductive) setting, to treat surgical scars if margins are either inadequate or questionable, or to treat inoperable tumors in a palliative fashion (decreased pain, bruising, etc.).

All dogs diagnosed with hemophagocytic HS in the published study died or were euthanized from 2 to 32 weeks (mean 7.1 weeks) following diagnosis. Therefore, the prognosis of dogs with hemophagocytic HS is considered poor to grave. Studies evaluating systemic or multimodal therapy for this variant of HS remains to be done, but the agents shown to have some efficacy with the other variants of HS may be considered in the meantime.

Palliative therapy is essential with canine HS, as with other cancers. Pain control is especially crucial, and should rely on multimodal analgesic therapy. For inoperable localized HS causing moderate to severe pain, an analgesic approach combining palliative radiation, an NSAID, an opioid, and one or more adjuvant analgesic drug is recommended. Corticosteroids may be used in lieu of NSAID, but it is important to know that HS is generally not considered to be responsive to corticotherapy. However, certain immune-mediated complications of HS may benefit from treatment with this therapeutic class. Nausea or vomiting should be treated when present or suspected. Supportive therapy with blood products should be employed when indicated.

SUMMARY

Canine HPDs represent a diverse group of proliferations that include both benign and malignant entities. Multiple diagnostic criteria are required to diagnose a specific disease, including cytology, histology, and the use of immunochemical markers. Research efforts are still directed towards improving the diagnostic accuracy and identification of the cell of origin for each HPD, and genetic defects leading to the disease which could eventually lead to breakthroughs in genetic therapy. The most aggressive form of HPD, histiocytic sarcoma, continues to carry a poor long-term prognosis though improvements in survival times have been observed in recent years with the help of retrospective clinical studies. Prospective clinical research to identify improved systemic treatments for the disease continues to be of utmost importance.