Mammary tumors are among the most common malignant neoplasms in female dogs. Hematological, biochemical, or hemostatic abnormalities may appear as paraneoplastic syndrome in canine mammary gland tumor (4). In general, hemostatic dysfunction was observed in half of dogs diagnosed with neoplasia (7): the majority of hemostatic dysfunctions in tumor are hypercoagulable. In tumors with metastasis, hypocoagulable states are observed, and it can be observed only in malignant tumors when compared to benign tumors (6). The burst of coagulation activities in a hypercoagulable state can lead to a hypocoagulable state; thus, prolonged periods of malignancy and metastasis can lead to excessive consumption of platelets and coagulation factors, resulting in hemorrhage referred to as disseminated intravascular coagulation (DIC) (2). DIC is a serious, life-threatening complication in which excessive intravascular coagulation leads to diffuse microthrombosis and the subsequent failure of multiple organs. The incidence of DIC was 12.2% in 164 dogs with malignant solid tumors such as hemangiosarcoma, mammary gland carcinoma, and pulmonary adenocarcinoma. Among mammary gland carcinomas, 28.5% presented with DIC, which was significantly higher than that of other malignancies (9). Herein, we report the case of a dog with mammary gland carcinoma and subsequent coagulopathy.

A 16-year-old spayed female miniature Schnauzer was referred to the Gyeongsang Animal Medical Center for bilateral epistaxis and bilateral hindlimb swelling (Fig. 1). Epistaxis began a few days after mastectomy and persisted intermittently for several days. Bilateral hindlimb swelling occurred one month after mastectomy, accompanied by non-weight-bearing lameness, swelling, erythema, and pain. Trauma, musculoskeletal diseases, infection, and immune-mediated diseases should be considered as differential diagnosis list for bilateral hindlimb swelling, but those are less likely to be a main cause based on the history, prior radiography and unresonsiveness to antibiotics. Presenting not only hindlimb swelling but also generalized inflammatory response from the abdomen to the inner thigh after mastectomy, coagulopathy or lymphatic emboli caused by mammary gland tumor was considered first.

Figure 1. Photographs of the physical examination. (A) Bilateral epistaxis, (B) hindlimbs showing edema and redness, and (C) ventral abdomen showing erythema and ecchymoses.

The owner noticed a mammary gland mass several years prior, and a total mastectomy was performed at local veterinary clinics two months prior to administration. Preoperative computed tomography (CT) performed at a local veterinary clinic identified the extent of tumor invasion and metastasis. Irregular-shaped, various-sized, and heterogeneous contrast-enhanced multiple nodules were revealed in the mammary gland at the level of the 2nd to 5th teat bilaterally with mineral attenuating materials. Enlarged right inguinal and right axillary lymph nodes were also identified (Fig. 2). Intermediate-grade (grade II) solid carcinoma was diagnosed at that time (Fig. 3).

Figure 2. Sagittal (A) and transverse postcontrast CT images at the level of 4th teat (B), right axillary (C), and right inguinal lymph nodes (D) in a dog with a mammary gland tumor. The variably sized and heterogeneous contrast-enhanced multiple modules were identified at the level of the 2nd to 5th teat with mineral attenuating materials (A, B: arrows). Enlarged right axillary and right inguinal lymph nodes were identified (C, D: arrowheads).

Figure 3. Histopathological findings of mammary gland tumor. Poorly-demarcated infiltrative multinodular mass composed of large polyhedral neoplastic epithelial cells in solid sheets and some acini and small islands at the periphery was found in the subcutis (H&E stain, original magnification × 100) (A). The tumor cells have round to oval vesicular nuclei with moderate to marked pleomorphism, coarsely clumped and marginated chromatins, multiple nuclei, and eosinophilic cytoplasm (H&E stain, original magnification × 200) (B). The mitoses are common in 2 to 3 per 400 × field.

On presentation, the dog showed erythema and pain around the mammary gland lesion, hindlimbs, and generalized subcutaneous ecchymoses in the abdominal region (Fig. 1). Vital signs, such as heart rate, respiratory rate, rectal temperature, and blood pressure, were normal. In terms of coagulopathy, laboratory examination and diagnostic imaging were performed to check for underlying diseases, such as tumors, and to differentiate them from other causes. Coagulation profile tests such as fibrinogen concentration, prothrombin time (PT), activated partial thromboplastin time (aPTT) and thromboelastography (TEG) were performed to demonstrate coagulopathy associated with epistaxis and subcutaneous ecchymoses.

Complete blood count (CBC) with manual blood film examination revealed mild thrombocytopenia (145 × 10³/μL [reference interval, 148-484 × 10³/μL]), and stress leukogram: leukocytosis (20.04 × 10³/μL [reference interval, 5.05-16.76 × 10³/μL]) with neutrophilia (17.5 × 10³/μL [reference interval, 2.95-11.64 × 10³/μL]), and monocytosis (1.14 × 10³/μL [reference interval, 0.16-1.12 × 10³/μL]).

The coagulation profile demonstrated delayed PT (>100 s [reference interval, 11-17 s]), aPTT (>300 s [reference interval, 75-105 s]), and hypofibrinogenemia (47.6 mg/dL [reference interval, 200-400 mg/dL]). TEG showed a remarkable hypocoagulable pattern of a slow clot rate (prolonged K and low alpha angle) and decreased clot strength (low MA) (Fig. 4).

Figure 4. Thromboelastography (TEG) showing a hypocoagulable state. Prolonged K time, decreased alpha angle, and a low maximal amplitude, indicating decreased fibrinogen level, procoagulant factors, and clot strength.

Inflammatory mammary carcinoma (IMC) was strongly suspected based on the clinical data, and DIC in canine mammary gland tumors was diagnosed. However, the owner did not consent to a secondary biopsy for IMC and elected palliative therapy with oral administration of firocoxib 5 mg/kg (twice a day). The dog died one month after diagnosis and necropsy was not performed.

The prognosis of canine mammary gland carcinomas varies, as described above. In human medicine, hematological changes are considered important determinants of prognosis in patients with neoplasms (10). Similarly, paraneoplastic changes in the blood, including anemia, leukocytosis, erythrocytosis, thrombocytopenia, hyperglobulinemia, hyperviscosity syndrome, and coagulopathy, can be prognostic factors in veterinary medicine (1). Coagulopathy, in which the blood’s ability to clot is impaired, occasionally covers thrombotic states (5) as a paraneoplastic syndrome. Progressive consumption coagulopathy in DIC is a life-threatening syndrome characterized by uncontrolled activated coagulation as a complication secondary to other diseases. In a previous study, 67% of mammary carcinomas showed hemostatic abnormalities, and the likelihood and frequency increased in stages III and IV (12). Diagnosis is based on the presence of an underlying disease, typical clinical symptoms such as bleeding, organ dysfunction related to microvascular thrombosis, and assessment of laboratory parameters (platelet count, PT, fibrinogen concentration, and fibrin/fibrinogen degradation products) (11). DIC is present in 12.2% of patients with malignant neoplasia (9), and it occurs most frequently in hemangiosarcoma, followed by mammary adenocarcinoma (particularly inflammatory mammary carcinoma) and pulmonary adenocarcinoma. This dog had mammary gland carcinoma as an underlying disease and epistaxis and generalized ecchymoses as clinical symptoms. Ultimately, thrombocytopenia, delayed PT/aPTT, hypofibrinogenemia, and a hypocoagulable pattern in TEG supported the dog as a hypocoagulable state of DIC, which is the final status of the disease.

Although a final histopathological confirmation was not performed, mammary gland carcinoma might have progressed to IMC in this case. IMC is a clinicopathological entity that is diagnosed based on a combination of clinical features and confirmed by histopathology. To diagnose IMC, physical examination should show erythema, heat, edema, peau d'orange, wheals, and ridging of the skin appearing on more than 1/3 of the breast skin with a medical history of rapid onset (<3 months) and a negative result for bacterial infection (10). Considering the physical examination of inflammatory reactions, such as erythema, heat, and pain around the mammary gland, we presume that the patient has a high possibility of IMC (10). IMC is an uncommon, highly malignant form of mammary tumor (3). Among various histopathological classifications of mammary gland carcinoma, IMC has the worst prognosis that most dogs survive no longer than one month regardless of the type of treatment (8). Coagulopathy is a clinical paraneoplastic syndrome, and its incidence is higher in IMC, metastatic tumors, and tumor necrosis than in other mammary gland tumors (8,13). Coagulopathy is a negative prognostic factor in that the only factors significantly associated with survival time are the use of medical treatments such as piroxicam and chemotherapeutic drugs (8).

Mammary gland tumors are the most common tumors in female dogs and are frequently encountered clinically. As observed in this case, veterinarians should be aware that hemostatic dysfunction can lead to a worse prognosis in canine mammary gland tumors. It is essential to assess coagulation tests for a better understanding of the disease status and planning treatments.

This case shows hemostatic dysfunction as a paraneoplastic syndrome in a dog with mammary gland carcinoma. It is essential to assess coagulation tests for a better understanding of the disease status and planning treatments in canine mammary gland tumors.

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2017R1D1A1B03034904) (2020R1C1C1008675), and by Korea Institute of Planning and Evaluation for Technology in Food, Agriculture and Forestry (IPET) through Companion Animal Life Cycle Industry Technology Development Program, funded by Ministry of Agriculture, Food and Rural Affairs (MAFRA) (322092-04-1-HD030).

The authors have no conflicting interests.