Medical Brief: Histiocytic Sarcoma

Medical Brief: Histiocytic Sarcoma

Histiocytic sarcomas (HS) are malignant tumors originating from interstitial dendritic cells (IDCs) derived from stem cell precursors (CD34+) of bone marrow. HS is considered part of histiocytic disorders that also include cutaneous histiocytoma and Langerhans cell histiocytosis, both originating from Langerhans dendritic cells (LDC), and reactive histiocytosis that also originate from IDCs. Another subtype of histiocytic disorder is the hemophagocytic HS (or erythrophagocytic HS) originating from macrophages. LDC, IDC or macrophages have the same stem cell precursor, although they differentiate themselves  according to which growth factors these cells are exposed to during the maturation process 1–4.

The incidence of HS is low, and represents less than 1% of all lymphoreticular tumors. It is considered a very aggressive neoplasm characterized by rapid metastasis ability and low survival rates. Because of this, HS is a challenging disease to treat and has a low treatment success rate 1,2.

According to the literature, some breeds may have a higher incidence of HS due to a genetic predisposition. These breeds are Golden Retrievers, Labrador, Rottweiler, Bernese Mountain Dog, Welsh Corgi, Flat Coated Retriever and Miniature Schnauzer 5–7. Similarly, these breeds also represent more than 50% of HS cases submitted for DNA sequencing through the FidoCure® platform (Figures 1). HS usually affect middle age to older dogs with no sex predisposition (Figure 2) 8.

Although the definitive cause of HS is still not clear, genetic predisposition and chronic inflammation have been associated with the development of the neoplasm in dogs. Chronic joint inflammation has been correlated with HS in Bernese Mountain Dogs and Rottweilers 1,9–11. The most common sites of HS involve organs such as spleen, lymph nodes, lungs, bone marrow, central nervous system, skin/subcutis and periarticular space. For hemophagocytic HS,  from macrophage lineage, the commonly primary affected organs are spleen and bone marrow and this form of HS has a very aggressive behavior 2,4,12,13. Clinical signs are generally associated with the location and extent of disease and can include lethargy, weakness, inappetence, weight loss, abdominal distension, dyspnea, coughing and lameness 1,13,14.

A definitive diagnosis can be obtained with histopathologic examination of the tumor. However, to establish the correct cellular origin or lineage, immunohistochemistry needs to be performed to differentiate neoplastic proliferation of dendritic cells from macrophages. HS can be a very aggressive neoplastic disease and cause paraneoplastic syndromes. The evaluation of a CBC and serum biochemistry should be done at diagnosis. Regenerative anemia, leukocytosis, thrombocytopenia, elevated liver enzymes, hypocholesterolemia, hypoalbuminemia, hypercalcemia and high ferritin levels, are commonly observed. A cytologic evaluation of a bone marrow aspirate may reveal neoplastic cell infiltration, especially in dogs with pancytopenia. For a full clinical staging, thoracic radiography and abdominal ultrasound should be done to investigate whether metastatic lesions are present. A CT scan and MRI may also be warranted 1,8,15. The median survival time for patients with HS can vary according to the dog's clinical condition, clinical stage and treatment, ranging from days to 1 to 2 months for  hemophagocytic HS and 4 to 13 months for other forms of HS 1,3,4,15.
The standard treatment for HS consists of both local and systemic therapy, even for localized tumors, due their aggressive metastatic potential. Surgical excision is often performed in tumors but always requires a wide margin to avoid early tumor recurrence 1.  Radiation therapy can also be recommended for the primary tumor or as adjuvant treatment in cases where the surgical margins are incomplete as this may increase  median survival time 8,16. Systemic chemotherapy with lomustine or doxorubicin, which are considered to be the most effective agents against HS, may improve survival outcomes 1,8,17,18. Bisphosphonates like liposomal clodronate and zoledronate may be another therapeutic option due their ability to deplete tumor associated macrophages (TAMs) and increase apoptosis of tumor cells when used in combination with vincristine and doxorubicin, but these effects have just been demonstrated in vitro1,19. Although corticosteroids are commonly prescribed to help control some clinical signs caused by advanced disease, their administration is associated with negative survival outcomes 1,14,20. Unfortunately, acquired chemotherapy resistance is an obstacle in HS treatment that results  in short median survival time 8,18.

The genomic evaluation of canine HS may be warranted for several reasons. Genomic information may foster a better understanding of the pathophysiology of the disease and certain genomic markers may be a predictor of aggressive biologic behavior for this tumor. In addition, certain genomic and molecular information may facilitate the recommendation and use of targeted therapies to inhibit aberrantly activated biochemical pathways. According to the literature, genetic studies involving Bernese Mountain Dogs and Flat Coated Retrievers identified mutations in tumor suppressor genes CDKN2A/B, RB1 and PTEN, suggesting their important role in HS tumorigeneses 21–23. Mutations in TP53 gene are also frequently observed in various HS, as well as mutations in PTPN11, MMP, AURKA and AURKB 22,24–28.

In the FidoCure® database, BRCA2 is the gene most commonly mutated, representing 38.56% of the canine HS samples (Figure 3). This is a tumor suppressor gene frequently mutated in human breast and ovarian cancer, with recent evidence of being mutated in sarcomas 29. PARP1, along with the BRCA2 gene, mutated in 12.81% of HS, encodes a protein that is also involved in these DNA repair pathways. Mutation in the DNA repair genes can cause genomic instability and accumulation of additional mutations in malignant cells 29,30. In the FidoCure® dataset BRCA2 and PARP1 co-mutations occurred in 2 dogs (5.12%) with HS. PARP1 inhibitors, such as olaparib and niraparib, have been developed to leverage the ability of PARP1 inhibition to induce double-strand breaks in cells with BRCA 1/2 mutations, resulting in an inability to repair DNA  and inducing apoptosis in cancer cells 31–34. These drugs may represent an opportunity for treating dogs with tumors that harbour these mutations as well.

TP53 is the second most commonly mutated gene in dogs with HS in the FidoCure® database (Figures 3 and 4). TP53 is considered an important tumor suppressor gene that also acts in the DNA repair pathways. This gene encodes p53 protein that regulates gene expression by promoting apoptosis, cell cycle arrest and DNA repair. According to the literature, mutations in TP53 are present in 26.7 to 46% of canine HS samples and significantly associated with the presence of preexisting metastatic lesions 22,24,35.

In the FidoCure® database, we identified mutations in the KMT2C and KMT2D genes in 25.64% and 17.94% of dogs with HS, respectively. The gene family of KMT2 are epigenetic regulators that act as tumor suppressor in normal cells and participate in the p53 signaling pathway and mutations in these genes affect cell proliferation and the viability of cancer cells, and are associated with cancer progression. Mutations in these genes, especially in KMT2C and KMT2D, are frequent in human malignancies 36–40.

PDGFR is a tyrosine kinase receptor gene that when  overexpressed  or misregulated promotes   cell proliferation, survival and migration in many cancers 41. In canine HS samples submitted to the FidoCure® Platform, 23.07% of tumors carry at least one germline or somatic mutation in this gene. Tumors with these mutations may represent an important opportunity for the use of tyrosine kinase inhibitors. Mutations and copy number gains in this gene are seen in human HS, thusly allowing therapy with tyrosine kinase inhibitors such as imatinib, dasatinib, imatinib and masitinib 42–44. In canine HS cell lines, masitinib sensitizes tumor cells to vinblastine and dasatinib inhibits tumor growth in a xenograft mouse model of canine HS 45,46. The combination of traditional chemotherapy with tyrosine kinase inhibitors may benefit dogs with mutations in the PDGFR gene or in other tyrosine receptor genes 41.

CDKN2 genes transcribe proteins such as p16, p14 and p15, that are involved in cell regulation. Mutations in CDKN2, is another  frequent mutation, reported in approximately 46% of HS cases 23. In Bernese Mountain Dog and Flat Coated Retriever dogs, alterations on CDKN2A/B genes vary from 62.8% to 96% in HS samples of these two breeds21,22. In the FidoCure® database, CDKN2A mutations occurred in 12.82% of canine HS analyzed samples, and mutations in the CDKN2B were not analyzed.

Interestingly, mutations in the PTPN11 gene have been associated with HS development in humans and dogs. In canine HS, these mutations have been identified in 36.6 to 42.7% of Bernese Mountain Dogs and in 8.6% of other breeds of dog 25,26. Golden Retrievers also have a high prevalence of PTPN11 mutations, found in 23% of HS samples26. This gene was not in our original panel but the recent incorporation of this gene in the FidoCure® panel will give us interesting information for further analysis. This gene encodes SHP-2, a protein tyrosine phosphatase involved in cell proliferation, differentiation and migration by activating the ERK and MAPK pathways. These pathways are activated in 56.75% of canine HS and associated with a more aggressive visceral disseminated subtype 26,27. Although the frequency of mutations in KRAS and BRAF genes are low in canine HS tumors according to the literature and to the FidoCure® database, they are also related to RAS/MAPK pathway activation and represent a potential target for therapy 26,27,47.

Trametinib can inhibit the MAPK pathway and may represent an important strategy to improve treatment outcomes. This MEK inhibitor can promote cell-cycle blockage, increase apoptosis and contribute to longer survival time in human patients. The efficacy of this drug has also been demonstrated in canine HS cell lines in xenograft mouse models 44,48.

We believe that personalized cancer therapy for dogs with HS-- providing specific treatment recommendations based upon the individual genomic characteristics of each patient-- may improve the outcome for dogs with this aggressive cancer.

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