Introduction

Histiocytic sarcoma (HS) is a malignant neoplasm of histiocytes, which are antigen presenting cells of the monocyte/macrophage or dendritic cell lineage. Histiocytic sarcomas exhibit variable positive expression of markers that include CD18, CD1, CD11b, and CD11c, Clinically, CD18, CD204, and Iba-1 are commonly used to definitively diagnose HS through immunohistochemistry on tissue biopsies. The disease can manifest as 3 clinically diverse forms: Disseminated HS, Localized HS, and Hemophagocytic HS. The Disseminated and Localized forms of the disease are considered to be of dendritic cell origin, but their clinical presentation, behavior, and response to treatment vary significantly. The Disseminated form is characterized as being essentially multicentric disease, with relatively poor response to chemotherapy and uniformly fatal outcome. The Localized form is characterized by the identification of a primary tumor, with frequent regional lymph node metastasis. With local and systemic treatment, typical survival rates for the Localized form are significantly longer when compared to the Disseminated, with a minority of dogs surviving for years. The Hemophagocytic form of the disease is considered to be of specific macrophage origin, and typically presents with significant clinical signs of red blood cell destruction, thrombocytopenia, and disseminated disease in the bone marrow, spleen, liver, and other organs. This form of HS is very challenging to definitively diagnose ante-mortem, and limited information exist about effective treatment strategies.

What is a Histiocyte?

Histiocyte is a type of an immune cell (leukocyte) that is part of the mononuclear/phagocytic system. Histiocytes are responsible for recognizing foreign antigens, phagocytizing them, and presenting them to the adaptive immune system. Histiocytes originate from the bone marrow and via the blood circulation home in various organs, where they differentiate. They may have different names depending on the organ they settle. In these organs, histiocytes can have different morphology, and express different markers. As such, there is currently not complete agreement on which cells are actually histiocytes, and which are not. The cells typically referred to as histiocytes in veterinary medicine are macrophages, dendritic cells, and Langerhans cells.

Histiocytic diseases can be divided in neoplastic diseases (Histiocytic Sarcoma complex), and non-neoplastic diseases. The focus of this workshop will be the Histiocytic Sarcoma complex (HS), with the understanding that in clinical practice, there is some overlap between HS and some of the non-neoplastic histiocytic disorders.

Histiocytic Sarcoma is a Cancer of the Immune System

The term HS is clearly a misnomer: This is a cancer of the immune system (a round cell tumor), and not of mesenchymal origin (a sarcoma). The understanding of this misnomer is important of the diagnostic work up and staging of patients with the disease, as well as their management. It is also foundational in for the diagnostic immunohistochemistry to be ordered, as frequently in standard histopathology HS can be indistinguishable from High Grade Soft Tissue Sarcomas. Furthermore, HS’s origin from the innate immune system can explain several paraneoplastic syndromes observed in patients diagnosed with the disease, such as fever, lethargy, severe regenerating anemia, or thrombocytopenia.

Current Classification

The disease is characterized by proliferation of pleiomorphic histiocytic cells in multiple organs. Neoplastic infiltrates are most often found in the spleen, liver, lung, bone marrow and lymph nodes, while atypical sites include ocular and central nervous system. HS may present as localized tumor or disseminated disease, but eventually widespread metastasis occurs with a frequently fatal outcome. Three distinct forms of the disease have been recognized based on the cellular origin of the tumor and the clinical manifestation of the disease: Disseminated HS (DHS), Localized HS (LHS), and Hemophagocytic HS (HHS). The HHS is immunophenotypically-distinct and carries a particularly grave prognosis. The remaining cases of canine HS appear to arise from interstitial dendritic antigen presenting cells (DAPCs) and exhibit variable clinical behavior. Localized and disseminated forms of HS present with identical histopathological features and manifest as poorly demarcated masses composed of pleomorphic, large, individualized round cells, or densely packed bundles of plump spindle cells. The HS immunophenotype is consistent with that of DAPCs, indicating that interstitial, white pulp splenic DAPCs, or other DAPCs may be the originators of these tumors.

Disseminated HS

The DHS typically presents as a multicentric disease, with multiple lymph node involvement, presence of organ metastasis, and many times skin nodules. Clinical signs may be absent, but frequently paraneoplastic fever, lethargy, anorexia, and difficulty breathing are noted. The duration of clinical signs before diagnosis has been reported to be about 17 days. The disease progression appears to be rapid although chemotherapy can prolong survival.

Localized HS

LHS is characterized by the clear identification of a primary tumor, frequently accompanied by regional lymph node metastasis, or distant organ metastasis. The primary tumor is more commonly associated with an appendicular joint (periarticular HS, aka PAHS), but any other anatomic localization is possible (skin, lung, spleen). Clinical signs may be absent and if present, they are typically are associated with anatomic location of the primary tumor (i.e., lameness).

The duration of clinical signs before diagnosis has been reported to be between 1–3 months. The treatment of choice typically includes surgical resection of the primary tumor followed by chemotherapy. Radiation therapy has been used sporadically in place of surgery to target the primary tumor and appears to achieve similar outcomes.

Hemophagocytic HS

HHS is the least studied and most challenging form of HS. Most dogs present through the Emergency Service with splenic masses/splenomegaly, significant regenerative anemia, thrombocytopenia, and in poor physical condition. Frequently, due to their unstable condition, limited diagnostics are performed, as the thrombocytopenia makes aspirates of internal organs risky. In the single paper describing the disease, multiple organs were affected (spleen liver, bone marrow, kidneys), and the mean survival was 7 weeks (no median reported).

Diagnostic and Disease Management Challenges

There are several diagnostic challenges for HS, including definitively diagnosing the disease, accurately classifying the disease, and deciding on the optimal treatment plan. First, in order to definitely diagnose HS in the dog, immunohistochemistry (IHC) is required, which presents a real diagnostic hurdle when a tissue biopsy is not feasible. In cases where FNAs and cytology is the only diagnostic sampling method available, one can be suspicious of the disease, but will not be certain. In addition, without IHC, the HHS cannot be distinguished from DHS or autoimmune diseases. Many dogs diagnosed with HHS have serious clinical signs and biochemical abnormalities associated with hemophagocytosis and bone marrow infiltration, but these are not pathognomonic for the disease. Furthermore, absence of these signs does not exclude HHS from the diagnosis. Finally, a diagnostic challenge lays in the classification between DHS and LHS. Frequently, LHS is characterized by a clearly identifiable primary, but it is not uncommon to have not only concurrent lymph node metastasis, but also distant metastasis to organs such as lungs, liver, or spleen. These cases are challenging to accurately classify, as they approach very closely the clinical presentation of DHS.

The management of HS is extremely challenging. The first hurdle arises from the aforementioned diagnostic challenges: It is hard to treat effectively what is not diagnosed accurately. Second, a large proportion of the published literature for the treatment of HS in the dogs is retrospective, histopathology and IHC is not universally employed, thus weakening the reported results.

The most commonly used therapeutic modality for the treatment of HS is chemotherapy, with lomustine-based protocols used typically as first choice. Use of other chemotherapeutics has been reported with variable outcomes, which do not appear to significantly change the course of the disease. Surgery seems to have a role in selected cases of LHS, even in the presence or regional lymph node metastasis. Radiation therapy is probably underutilized in the treatment of HS, although there is evidence of HS responding at least temporarily to coarse fractionation treatment schemes.

Therapeutic Approaches

Treatment for dogs diagnosed with HS consisting of surgery, radiation, chemotherapy, or a combination, appears to improve survival outcome, when compared to palliative therapy. Currently, chemotherapy appears to be the most commonly used treatment modality for dogs diagnosed with HS. Lomustine has a response rate of 30–50% and is being used as first line treatment as single agent, or in combination with surgery or radiation therapy. Dogs diagnosed with DHS and treated with chemotherapy have expected median survival between 3–6 months, with virtually all of them succumbing to the disease. Dogs diagnosed with LHS and treated with adequate local therapy (surgery, radiation) and chemotherapy have expected median survival over 1 year, and reported as high as 19 months in the absence of lymph node metastasis. Despite the relatively longer survival, most of the patients still die due to the disease. The outcomes for dogs diagnosed with HHS appear to be dismal, but it is unclear whether this is a confounding effect of their clinical condition on diagnosis, or due to a more aggressive course of the disease. Concurrent use of corticosteroids in the treatment of HS can be controversial, as their use has been linked with shorter survival times.

Epilogue - Or How to Spot HS

Histiocytic Sarcoma is a relatively rare cancer, but it appears to be more common than we thought. The development of new IHC markers for the disease, as well the discovery of molecular targets that can be used for the diagnosis or development of therapeutics is likely to allow us to recognize the true incidence of HS in dogs. Increased number of research publications do increase clinician awareness for the disease, as well as its divergent clinical course. Finally, it is well understood that while there are breeds predisposed to the disease, HS can afflict dogs of any breed.