Ex) Article Title, Author, Keywords
pISSN 1598-298X
eISSN 2384-0749
Ex) Article Title, Author, Keywords
J Vet Clin 2023; 40(1): 62-67
https://doi.org/10.17555/jvc.2023.40.1.62
Published online February 28, 2023
Ji-Seon Yoon1 , Hyeona Bae2
, Hee-Chun Lee2
, Dong-In Jung2
, Sang-Ki Kim3
, Dae Young Kim4,*
, DoHyeon Yu2,*
Correspondence to:*kimdy@missouri.edu (Dae Young Kim), yudh@gnu.ac.kr (DoHyeon Yu)
†Ji-Seon Yoon and Hyeona Bae contributed equally to this work.
Copyright © The Korean Society of Veterinary Clinics.
J Vet Clin 40(4): 321 (2023)
https://doi.org/10.17555/jvc.2023.40.4.321
Paraneoplastic hypereosinophilia, characterized by the infiltration of eosinophils into systemic organs, has rarely been reported in dogs with intestinal lymphoma. A 12-year-old spayed female Maltese with eosinophilia in the peripheral blood and ascites was found to have muscular layer thickening in the small intestine. Histologically, there was transmural infiltration of small to intermediate sized neoplastic lymphocytes that were immunohistochemically CD3-/CD79a-. PCR for antigen receptor rearrangement demonstrated clonal T cell receptor gene population. A moderate number of eosinophils were present along with neoplastic lymphocytes in the small intestine, and eosinophil infiltration was also noted in the abdominal lymph nodes and spleen. The present case reports intestinal T-cell lymphoma with generalized paraneoplastic hypereosinophilia. Clinicians should be aware that hypereosinophilia can be found in the organs, body cavity fluid, and peripheral blood of dogs with intestinal lymphoma.
Keywords: T-cell, lymphoma, eosinophil, paraneoplastic syndrome, dogs.
Gastrointestinal lymphoma is uncommon in dogs representing approximately 5-7% of all canine lymphomas. Most intestinal lymphomas are T-cell in origin and can present as a solitary lesion or as a multifocal or diffuse disease (2). Most alimentary lymphomas in dogs present with progressive clinical signs, including vomiting, diarrhea, weight loss, anorexia, and lethargy. For the diagnosis of alimentary lymphoma, histopathology is needed in addition to ultrasonographic examination of the gastrointestinal tract (4).
Paraneoplastic syndromes are defined as systemic disorders affected by cytokine hormones owing to the presence of tumor cells or an immune response against the tumor. In dogs with lymphoma, paraneoplastic syndrome includes hypercalcemia, monoclonal gammopathy, hypoglycemia, polycythemia, immune-mediated diseases, and eosinophilia (15). Among them, paraneoplastic hypereosinophilia, which shows infiltration of eosinophils in systemic organs such as the peripheral blood, has rarely been reported in dogs with alimentary lymphoma (7). Here, we describe a canine case of intestinal T-cell lymphoma with generalized paraneoplastic hypereosinophilia. Eosinophilic infiltration was confirmed in the small intestine along with neoplastic T lymphocytes and was also observed in the lymph nodes, peritoneal effusion, spleen, and peripheral blood.
A 12-year-old spayed female Maltese presented with chronic vomiting, diarrhea, and weight loss for a month. There was no history of drug use related to chief complaints, and medications (pimobendan, spironolactone) were regularly prescribed for underlying cardiovascular disease. The vital signs of the dog show, a body temperature of 39.2°C, a heart rate of 140/min, a respiratory rate of 48/min, and a 3/9 body condition score. No remarkable finding in the physical examination was observed. Abdominal ultrasonography revealed thickening of the intestinal wall of the muscular layer and enlarged mesenteric lymph nodes. Mild coarse echotexture and ill-defined small hypoechoic foci were present in the splenic parenchyma, and abdominal effusion was also observed (Fig. 1). Intestinal lymphoma with splenic metastasis was a major differential diagnosis, and cytologic evaluation via ultrasound-guided fine-needle-aspiration (FNA), and laboratory tests were performed.
A blood test revealed leukocytosis (20.01 × 103/μL; reference range, 5.05-16.76 × 103/μL) with neutrophilia (15.57 × 103/μL; reference range, 2.95-11.64 × 103/μL) and eosinophilia (2.42 × 103/μL; reference range, 0.06-1.23 × 103/μL) and hyperlactatemia (3.9 mmol/L; reference range, 0.5-2.5 mmol/L). There were no remarkable findings other than abnormal leukogram in the blood test. Aspirated cells from the small intestinal wall, identified by Diff-Quik staining, were predominantly small round cells, indicating intestinal lymphoma (Fig. 2A). Eosinophils were occasionally observed in the aspirates, and abdominal fluid revealed remarkable eosinophil-predominance (approximately 75% of the nucleated cells), with 23.5% of degenerate neutrophils and 1.5% of lymphocytes out of 97.85 × 103/μL total nucleated cells (Fig. 2B). FNA from the hypoechoic foci of the spleen showed eosinophilic infiltration composed of 63.4% eosinophils, 31.5% neutrophils, 4.7% lymphocytes, and 0.4% monocytes. FNA of the mesenteric lymph nodes revealed 57% eosinophils, 35.5% neutrophils, 5.5% lymphocytes, and 2% monocytes. Peripheral eosinophilia (3.48 × 103/μL; reference range: 0.06-1.23 × 103/μL) with mature neutrophilia (15.05 × 103/μL; reference range: 2.95-11.64 × 103/μL) was remarkable (Fig. 3A). Flow cytometric analysis (10) of peripheral blood showed that most lymphocytes were CD3+/CD5+/CD21–/CD45+ (Fig. 3B).
Since rod-shaped bacteria (
Interestingly, moderate numbers of scattered eosinophils were also noted along with neoplastic round cells in the small intestine (Fig. 4C). Eosinophilic infiltration was confirmed in the peripheral blood, mesenteric lymph node, spleen, and peritoneal effusion, and the present case was diagnosed as intestinal T-cell lymphoma accompanied by generalized eosinophilic infiltration, which has rarely been reported in dogs with alimentary lymphoma. Bacterial peritonitis was managed with antibiotics, and eventually, the bacterial culture was negative 1 month after the initial presentation. Because peritonitis was identified, metronomic chemotherapy with cyclophosphamide (Alkyloxan Tab., JW Pharmaceutical, Seoul, Korea) 15 mg/kg q 24 h PO was maintained until the infection was completely resolved. After confirming the negative result in the culture, conventional chemotherapy was started with the UW-19 protocol in the consideration of the owner’s compliance. However, the dog died immediately after the initiation of chemotherapy due to recurrence of intestinal rupture.
Eosinophilia is characterized by an increase in the total eosinophil count in the blood or tissue. In dogs, allergic diseases, such as inflammatory bowel disease, pulmonary diseases, and parasitic diseases, are mostly associated with eosinophilia (6). In the present case, eosinophilic infiltration was observed along with intestinal T-cell lymphoma in this dog, although neither allergic disease nor parasitic disease was observed. Generalized hypereosinophilia as a paraneoplastic syndrome of lymphoma has been rarely reported in dogs, including multicentric B-cell lymphoma (1), splenic B-cell lymphoma, (12) spinal T-cell lymphoma (8), and intestinal T-cell lymphoma (7). It has also been reported in other neoplasms in dogs, including canine cutaneous and visceral mast cell disease, pericardial leiomyosarcoma, anaplastic mammary carcinoma, and oral fibrosarcoma (3). Among the above reports of canine lymphomas, spinal T-cell lymphoma showed eosinophilic infiltration in the spine, cerebrospinal fluid, liver, spleen, and peripheral blood. In one case of intestinal T-cell lymphoma, eosinophilic infiltration was observed in the intestinal wall, peripheral blood, and bone marrow. The present case also showed generalized eosinophilic infiltration in the lymph nodes, peritoneal effusion, spleen, and peripheral blood.
In humans, paraneoplastic hypereosinophilia has been reported in T-cell lymphoproliferative disorders, including Hodgkin lymphoma (3). Although the pathogenesis of hypereosinophilia associated with neoplasia has not been fully elucidated, it has been suggested that cytokines produced by neoplastic T lymphocytes might induce eosinophilia (9). Cytokines such as IL-3, IL-5, and granulocyte–macrophage colony-stimulating factor inhibit eosinophil apoptosis and have specific receptors on eosinophils, resulting in eosinophilia (8,9). Therefore, investigation of the expression of these cytokines in dogs with paraneoplastic eosinophilia might provide a better understanding of eosinophilia associated with T-cell lymphoma.
It has been reported that paraneoplastic eosinophilia is associated with the prognosis of neoplasm (11). The degree of eosinophilia might be related to increased neoplastic cells, as large numbers of neoplastic cells induce excessive cytokine production and increase eosinophil counts. Similarly, hypereosinophilia in primary cutaneous T-cell lymphoma in humans indicates poor prognosis (11). In dogs with T-cell lymphoma, it is unclear whether paraneoplastic eosinophilia can affect disease prognosis, as only a few cases have been reported. Two dogs with paraneoplastic eosinophilia associated with T-cell lymphoma were euthanized because of a poor response to chemotherapy. In the present case, the patient died of bacterial peritonitis due to recurrence of intestinal rupture. Future large-scale studies of paraneoplastic eosinophilia in dogs with lymphoma will provide additional information on the effect of eosinophilia on disease prognosis.
In this case, the lymphoma cells were negative for anti-CD3 antibody. In a retrospective study of 82 cases of canine lymphoma (5), 9 cases were negative for both CD3 and CD79a, and more than 80% of them were intermediate to high grade malignancy. Since CD3 is expressed on the surface membrane as the T cells mature from prothymocytes, loss of surface CD3 can be observed in a blastic phase of the neoplasia (14). Further study of the T-cell differentiation and maturation in dogs should be studied. In addition, it is necessary to check the expression of other T-cell markers such as CD5, CD4, and CD8, because the possibility of aberrant-type lymphoma that is positive for T-cell markers other than CD3 must be considered. In a previous study of human, there was a case in which surface CD3-/CD8+ ‘atypical’ aberrant T-cells were confirmed on histopathology of intestinal lesions in refractory celiac disease patients who had progressed to small cell enteropathy associated T-cell lymphoma (13). Further immunohistochemical studies of aberrant-type lymphoma should be performed in the future.
Chemotherapy was started as soon as recovery from the infection, but the dog eventually expired for peritonitis and sepsis due to a rupture of the intestinal segments. A necropsy was not performed, and the exact cause of death could not be determined. However, the intestinal wall tissue was fragile and brittle due to the extensive infiltration of tumor cells, and it can be speculated that tissue healing might be difficult after surgery.
This report describes a rare case of paraneoplastic hypereosinophilia involving multiple organs in a dog with intestinal T-cell lymphoma. Generalized hypereosinophilia should be considered as a paraneoplastic complication in dogs with lymphoma.
This research was supported 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.
J Vet Clin 2023; 40(1): 62-67
Published online February 28, 2023 https://doi.org/10.17555/jvc.2023.40.1.62
Copyright © The Korean Society of Veterinary Clinics.
Ji-Seon Yoon1 , Hyeona Bae2
, Hee-Chun Lee2
, Dong-In Jung2
, Sang-Ki Kim3
, Dae Young Kim4,*
, DoHyeon Yu2,*
1College of Veterinary Medicine, Jeonbuk National University, Iksan 54596, Korea
2College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea
3College of Industrial Science, Kongju National University, Yesan 32439, Korea
4College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA
Correspondence to:*kimdy@missouri.edu (Dae Young Kim), yudh@gnu.ac.kr (DoHyeon Yu)
†Ji-Seon Yoon and Hyeona Bae contributed equally to this work.
This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
J Vet Clin 40(4): 321 (2023)
https://doi.org/10.17555/jvc.2023.40.4.321
Paraneoplastic hypereosinophilia, characterized by the infiltration of eosinophils into systemic organs, has rarely been reported in dogs with intestinal lymphoma. A 12-year-old spayed female Maltese with eosinophilia in the peripheral blood and ascites was found to have muscular layer thickening in the small intestine. Histologically, there was transmural infiltration of small to intermediate sized neoplastic lymphocytes that were immunohistochemically CD3-/CD79a-. PCR for antigen receptor rearrangement demonstrated clonal T cell receptor gene population. A moderate number of eosinophils were present along with neoplastic lymphocytes in the small intestine, and eosinophil infiltration was also noted in the abdominal lymph nodes and spleen. The present case reports intestinal T-cell lymphoma with generalized paraneoplastic hypereosinophilia. Clinicians should be aware that hypereosinophilia can be found in the organs, body cavity fluid, and peripheral blood of dogs with intestinal lymphoma.
Keywords: T-cell, lymphoma, eosinophil, paraneoplastic syndrome, dogs.
Gastrointestinal lymphoma is uncommon in dogs representing approximately 5-7% of all canine lymphomas. Most intestinal lymphomas are T-cell in origin and can present as a solitary lesion or as a multifocal or diffuse disease (2). Most alimentary lymphomas in dogs present with progressive clinical signs, including vomiting, diarrhea, weight loss, anorexia, and lethargy. For the diagnosis of alimentary lymphoma, histopathology is needed in addition to ultrasonographic examination of the gastrointestinal tract (4).
Paraneoplastic syndromes are defined as systemic disorders affected by cytokine hormones owing to the presence of tumor cells or an immune response against the tumor. In dogs with lymphoma, paraneoplastic syndrome includes hypercalcemia, monoclonal gammopathy, hypoglycemia, polycythemia, immune-mediated diseases, and eosinophilia (15). Among them, paraneoplastic hypereosinophilia, which shows infiltration of eosinophils in systemic organs such as the peripheral blood, has rarely been reported in dogs with alimentary lymphoma (7). Here, we describe a canine case of intestinal T-cell lymphoma with generalized paraneoplastic hypereosinophilia. Eosinophilic infiltration was confirmed in the small intestine along with neoplastic T lymphocytes and was also observed in the lymph nodes, peritoneal effusion, spleen, and peripheral blood.
A 12-year-old spayed female Maltese presented with chronic vomiting, diarrhea, and weight loss for a month. There was no history of drug use related to chief complaints, and medications (pimobendan, spironolactone) were regularly prescribed for underlying cardiovascular disease. The vital signs of the dog show, a body temperature of 39.2°C, a heart rate of 140/min, a respiratory rate of 48/min, and a 3/9 body condition score. No remarkable finding in the physical examination was observed. Abdominal ultrasonography revealed thickening of the intestinal wall of the muscular layer and enlarged mesenteric lymph nodes. Mild coarse echotexture and ill-defined small hypoechoic foci were present in the splenic parenchyma, and abdominal effusion was also observed (Fig. 1). Intestinal lymphoma with splenic metastasis was a major differential diagnosis, and cytologic evaluation via ultrasound-guided fine-needle-aspiration (FNA), and laboratory tests were performed.
A blood test revealed leukocytosis (20.01 × 103/μL; reference range, 5.05-16.76 × 103/μL) with neutrophilia (15.57 × 103/μL; reference range, 2.95-11.64 × 103/μL) and eosinophilia (2.42 × 103/μL; reference range, 0.06-1.23 × 103/μL) and hyperlactatemia (3.9 mmol/L; reference range, 0.5-2.5 mmol/L). There were no remarkable findings other than abnormal leukogram in the blood test. Aspirated cells from the small intestinal wall, identified by Diff-Quik staining, were predominantly small round cells, indicating intestinal lymphoma (Fig. 2A). Eosinophils were occasionally observed in the aspirates, and abdominal fluid revealed remarkable eosinophil-predominance (approximately 75% of the nucleated cells), with 23.5% of degenerate neutrophils and 1.5% of lymphocytes out of 97.85 × 103/μL total nucleated cells (Fig. 2B). FNA from the hypoechoic foci of the spleen showed eosinophilic infiltration composed of 63.4% eosinophils, 31.5% neutrophils, 4.7% lymphocytes, and 0.4% monocytes. FNA of the mesenteric lymph nodes revealed 57% eosinophils, 35.5% neutrophils, 5.5% lymphocytes, and 2% monocytes. Peripheral eosinophilia (3.48 × 103/μL; reference range: 0.06-1.23 × 103/μL) with mature neutrophilia (15.05 × 103/μL; reference range: 2.95-11.64 × 103/μL) was remarkable (Fig. 3A). Flow cytometric analysis (10) of peripheral blood showed that most lymphocytes were CD3+/CD5+/CD21–/CD45+ (Fig. 3B).
Since rod-shaped bacteria (
Interestingly, moderate numbers of scattered eosinophils were also noted along with neoplastic round cells in the small intestine (Fig. 4C). Eosinophilic infiltration was confirmed in the peripheral blood, mesenteric lymph node, spleen, and peritoneal effusion, and the present case was diagnosed as intestinal T-cell lymphoma accompanied by generalized eosinophilic infiltration, which has rarely been reported in dogs with alimentary lymphoma. Bacterial peritonitis was managed with antibiotics, and eventually, the bacterial culture was negative 1 month after the initial presentation. Because peritonitis was identified, metronomic chemotherapy with cyclophosphamide (Alkyloxan Tab., JW Pharmaceutical, Seoul, Korea) 15 mg/kg q 24 h PO was maintained until the infection was completely resolved. After confirming the negative result in the culture, conventional chemotherapy was started with the UW-19 protocol in the consideration of the owner’s compliance. However, the dog died immediately after the initiation of chemotherapy due to recurrence of intestinal rupture.
Eosinophilia is characterized by an increase in the total eosinophil count in the blood or tissue. In dogs, allergic diseases, such as inflammatory bowel disease, pulmonary diseases, and parasitic diseases, are mostly associated with eosinophilia (6). In the present case, eosinophilic infiltration was observed along with intestinal T-cell lymphoma in this dog, although neither allergic disease nor parasitic disease was observed. Generalized hypereosinophilia as a paraneoplastic syndrome of lymphoma has been rarely reported in dogs, including multicentric B-cell lymphoma (1), splenic B-cell lymphoma, (12) spinal T-cell lymphoma (8), and intestinal T-cell lymphoma (7). It has also been reported in other neoplasms in dogs, including canine cutaneous and visceral mast cell disease, pericardial leiomyosarcoma, anaplastic mammary carcinoma, and oral fibrosarcoma (3). Among the above reports of canine lymphomas, spinal T-cell lymphoma showed eosinophilic infiltration in the spine, cerebrospinal fluid, liver, spleen, and peripheral blood. In one case of intestinal T-cell lymphoma, eosinophilic infiltration was observed in the intestinal wall, peripheral blood, and bone marrow. The present case also showed generalized eosinophilic infiltration in the lymph nodes, peritoneal effusion, spleen, and peripheral blood.
In humans, paraneoplastic hypereosinophilia has been reported in T-cell lymphoproliferative disorders, including Hodgkin lymphoma (3). Although the pathogenesis of hypereosinophilia associated with neoplasia has not been fully elucidated, it has been suggested that cytokines produced by neoplastic T lymphocytes might induce eosinophilia (9). Cytokines such as IL-3, IL-5, and granulocyte–macrophage colony-stimulating factor inhibit eosinophil apoptosis and have specific receptors on eosinophils, resulting in eosinophilia (8,9). Therefore, investigation of the expression of these cytokines in dogs with paraneoplastic eosinophilia might provide a better understanding of eosinophilia associated with T-cell lymphoma.
It has been reported that paraneoplastic eosinophilia is associated with the prognosis of neoplasm (11). The degree of eosinophilia might be related to increased neoplastic cells, as large numbers of neoplastic cells induce excessive cytokine production and increase eosinophil counts. Similarly, hypereosinophilia in primary cutaneous T-cell lymphoma in humans indicates poor prognosis (11). In dogs with T-cell lymphoma, it is unclear whether paraneoplastic eosinophilia can affect disease prognosis, as only a few cases have been reported. Two dogs with paraneoplastic eosinophilia associated with T-cell lymphoma were euthanized because of a poor response to chemotherapy. In the present case, the patient died of bacterial peritonitis due to recurrence of intestinal rupture. Future large-scale studies of paraneoplastic eosinophilia in dogs with lymphoma will provide additional information on the effect of eosinophilia on disease prognosis.
In this case, the lymphoma cells were negative for anti-CD3 antibody. In a retrospective study of 82 cases of canine lymphoma (5), 9 cases were negative for both CD3 and CD79a, and more than 80% of them were intermediate to high grade malignancy. Since CD3 is expressed on the surface membrane as the T cells mature from prothymocytes, loss of surface CD3 can be observed in a blastic phase of the neoplasia (14). Further study of the T-cell differentiation and maturation in dogs should be studied. In addition, it is necessary to check the expression of other T-cell markers such as CD5, CD4, and CD8, because the possibility of aberrant-type lymphoma that is positive for T-cell markers other than CD3 must be considered. In a previous study of human, there was a case in which surface CD3-/CD8+ ‘atypical’ aberrant T-cells were confirmed on histopathology of intestinal lesions in refractory celiac disease patients who had progressed to small cell enteropathy associated T-cell lymphoma (13). Further immunohistochemical studies of aberrant-type lymphoma should be performed in the future.
Chemotherapy was started as soon as recovery from the infection, but the dog eventually expired for peritonitis and sepsis due to a rupture of the intestinal segments. A necropsy was not performed, and the exact cause of death could not be determined. However, the intestinal wall tissue was fragile and brittle due to the extensive infiltration of tumor cells, and it can be speculated that tissue healing might be difficult after surgery.
This report describes a rare case of paraneoplastic hypereosinophilia involving multiple organs in a dog with intestinal T-cell lymphoma. Generalized hypereosinophilia should be considered as a paraneoplastic complication in dogs with lymphoma.
This research was supported 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.