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Eosinophilic Leukemia in a Pet African Hedgehog (Atelerix albiventris)
AEMV FORUM EOSINOPHILIC LEUKEMIA IN A PET AFRICAN HEDGEHOG (ATELERIX ALBIVENTRIS) Christine T. Higbie, DVM, David Eshar, DVM, Dip. ABVP (Exotic Companion Mammal), Dip. ECZM (Small Mammal), Shambhunath Choudhary, DVM, PhD, Lisa M. Pohlman, DVM, MS, Dip. ACVP, Chanran R. Ganta, BS, MS, PhD, and Gordon Andrews, DVM, PhD, Dip. ACVP
Abstract A 2-year-old, captive, intact female African hedgehog (Atelerix albiventris) was evaluated for nonspecific clinical signs and progressive hind limb ataxia over a 1-month period. Abnormal results from a complete blood count included a mild regenerative anemia and an inflammatory leukogram with a degenerative left shift, toxic changes, and eosinophilia. Serum biochemistry analysis showed increased alkaline phosphatase and alanine transaminase levels. Whole-body radiograph images of the hedgehog revealed a thin body condition, oligodontia, and ventral lumbosacral spondylosis deformans. An abdominal ultrasonographic examination of the patient indicated that a hyperechoic mass with unknown origin was present in the caudal abdomen and moderate free fluid and a hyperechoic splenic nodule were present. A cytological examination of material collected through a fine needle aspirate of the abdominal mass was suggestive of carcinoma with marked eosinophilic inflammation. Exploratory surgery revealed a right ovarian mass and an abnormal spleen. An ovariohysterectomy and splenectomy were performed. Histopathology of the reproductive tract and spleen revealed an endometrial polyp in the uterus, a granulosa cell tumor in the right ovary, and a large number of immature eosinophils present throughout the spleen, consistent with eosinophilic leukemia. The hedgehog died 2 days following the surgical procedure. A postmortem examination of the patient revealed a mild bicavitary effusion, hepatomegaly, and a stomach ulcer. Histopathological examination of examined tissue indicated neoplastic eosinophils that encompassed 80% of the bone marrow and also infiltrated multiple glands, viscera, and associated blood vessels. The necropsy results supported the previous diagnosis of eosinophilic leukemia. Practitioners should be aware that similar clinical signs may be associated with eosinophilic leukemia in Atelerix albiventris. Copyright 2015 Elsevier Inc. All rights reserved. Key words: African hedgehog; Atelerix albiventris; eosinophilia; leukemia; neoplasia
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2-year-old, 233 g captive, intact female African hedgehog (Atelerix albiventris) with a 1-month history of vague signs of behavior change, decreased appetite, decreased activity, and progressive hind limb ataxia was evaluated by the Exotics and Zoological Medicine Service, Kansas State University Veterinary Health Center. The hedgehog was reticent to interact with its owner and also reluctant to be touched. On visual examination of the hedgehog, bilateral ataxia of the hind limbs was noted. Conscious proprioception in the hind limbs was absent, and there was a subsequent delay in movement with crossing over of the hind limbs when the hedgehog was walking. The patient’s ability to curl up was significantly weakened, and it was unable to maintain sternal recumbency.
From the Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA; and the Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA Address correspondence to: Christine T. Higbie, DVM, School of Veterinary Medicine, Louisiana State University, Skip Bertman Drive, Baton Rouge, LA 70803. E-mail:[email protected] Ó 2015 Elsevier Inc. All rights reserved. 1557-5063/15/2101-$30.00 http://dx.doi.org/10.1053/j.jepm.2015.12.012
Journal of Exotic Pet Medicine 25 (2016), pp 65–71
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The hedgehog was anesthetized with isoflurane gas at 5% in 1.5 L/min oxygen by facemask for induction, and then maintained on isoflurane gas in oxygen at 1.5% to 3% in 1.5 L/min oxygen by facemask for further examination and diagnostic testing. On physical examination, the hedgehog was given a body condition score of 2 of 5. The patient was assessed to be 5% to 7% dehydrated based on an increase in skin turgor over the back of the neck, stringy saliva in the mouth, tacky mucous membranes, and a prolonged capillary refill time42 seconds. The mandibular and prescapular lymph nodes on palpation were bilaterally prominent. A firm, 2 cm 2 cm mass was palpable in the caudal abdomen. While the hedgehog was under general anesthesia, a blood sample was obtained from the cranial vena cava for a complete blood count and plasma biochemical analysis. The complete blood count revealed a mild anemia (centrifuged hematocrit ¼ 35%; reference range: 41% to 43%)1 with marked polychromasia and 2 nucleated red blood cells per 100 white blood cells. The lymphocyte count was mildly increased (6.6 K/mL, reference range: 4.48 to 5.44 K/mL),1 and there was a severe neutropenia present (1.3 K/mL, reference range: 8.54 to 9.74 K/mL)1 with toxic neutrophilic changes. A degenerative left shift was noted (band neutrophils ¼ 2.7 K/mL, reference range: 0 K/mL, metamyelocytes ¼ 0.4 K/mL, reference range: 0 K/ mL),1 and a moderate-to-severe eosinophilia was present (1.7 K/mL, reference range: 0.14 to 0.2 K/ mL).1 Serum biochemistry analysis was unremarkable apart from an increased alkaline phosphatase (275 U/L, reference range: 20.78 to 23.38 U/L) and alanine transaminase (64 U/L, reference range: 21.49 to 25.57 U/L).1 Diagnostic imaging was performed while the hedgehog was still under general anesthesia. Whole-body, 2-view (dorsoventral and right lateral) radiographs revealed a thin body condition, oligodontia, and ventral lumbosacral spondylosis deformans. Abdominal ultrasonography revealed a round mass of mixed echogenicity in the midventral abdomen, located ventromedial to the left kidney. The mass measured 1.5 cm in height 2.1 cm in length 1.9 cm in width and had an unknown organ of origin. There was a moderate amount of echogenic free fluid in the abdominal cavity, and a hyperechoic splenic nodule was present in the dorsal portion of the head of the spleen. Ultrasound-guided fine needle aspirate of the abdominal mass was performed under general anesthesia, and cytology revealed a low amount of 6 6
intact nucleated cells. As a result, the organ of origin of the mass could not be discerned; however, a carcinoma was suspected. Marked eosinophilic inflammation was present within the neoplasm. The hedgehog received lactated Ringer’s solution (35 mL subcutaneously) and enrofloxacin (20 mg/ kg subcutaneously, Baytril; Bayer HealthCare LLC, Shawnee Mission, KS USA) before recovery from anesthesia, which occurred without complication. At the owner’s request, the hedgehog was discharged from the hospital to receive supportive care at home, before its scheduled abdominal exploratory surgery. The hedgehog was treated at home with amoxicillin and clavulanic acid (12.5 mg/kg orally, every 12 hours, Clavamox; Zoetis, Florham Park, NJ USA) and prednisolone (2.5 mg/kg orally, every 12 hours, PrednisoLONE Oral Solution; Hi-Tech Pharmacal, Amityville, NY USA), in addition to assisted feeding with canned dog food (i/d, Hill’s Pet Nutrition, Topeka, KS USA) and fruit baby food every 4 to 6 hours to improve its clinical condition in preparation for the surgical procedure. The hedgehog reportedly responded very well to the treatment regimen and had an excellent appetite for the owner. Exploratory surgery was performed 3 days following the initial presentation. Clavamox was administered orally, as prescribed, the night before surgery, and the hedgehog received meloxicam (0.3 mg/kg orally, Metacam; Boehringer Ingelheim Vetmedica, St. Joseph, MO USA) and enrofloxacin (20 mg/kg subcutaneously) on the morning of the surgical procedure. Before the surgical procedure, the patient was premedicated with midazolam (0.3 mg/kg intramuscularly) and butorphanol (0.3 mg/kg intramuscularly), and then general anesthesia was induced with 5% isoflurane gas in a 2-L/min flow of oxygen by facemask. The hedgehog was maintained (2%) on isoflurane gas in a 1.5-L/min flow of oxygen by facemask during surgery. A 24-gauge intravenous catheter was placed in the right cephalic vein and lactated Ringer’s solution with 5% dextrose was administered by continuous rate infusion (10 mL/ kg/hour) using a syringe pump throughout the surgical procedure. Given the small size of the intravenous catheter, a second intravenous catheter was placed into the left cephalic vein for backup in the event of an emergency during the anesthetic procedure. The hedgehog was maintained on a heating pad throughout the procedure, and its heart rate and rhythm were monitored using a Doppler ultrasound probe placed over the sternum.
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The ventral abdominal region was clipped and aseptically prepared for surgery. A 4-cm ventral midline approach to the midcaudal abdomen was performed. Abdominal exploration revealed the mass to be the right ovary. An ovariohysterectomy was performed using small- and medium-sized hemoclips (Hemoclip; Weck Closure Systems Research, Triangle Park, NC USA) and bipolar radiosurgery was used for hemostasis (Ellman Surgitron FFPF; Ellman International, Hewlett, NY USA) with the coagulation setting at 5. The mass was removed from the abdomen without complication using this method. The spleen was located and visually examined. Although the splenic nodule observed during the ultrasonographic examination could not be appreciated with the naked eye, the spleen appeared pale in color and mottled. The extremely friable spleen was removed using hemoclips and the bipolar radiosurgery forceps for hemostasis. No other abdominal visceral abnormalities were visualized. The abdomen was lavaged with warm, sterile 0.9% saline and then closed routinely in 3 layers. Before recovery from anesthesia, buprenorphine (0.03 mg/kg intravenously) was administered for analgesia, flumazenil (0.05 mg/kg intravenously) was provided to facilitate full recovery from anesthesia, and the intravenous catheters were removed. The hedgehog had a quick and uneventful recovery from the surgical procedure. Normal urination was noted and the patient ate a small amount of food the same night. The hedgehog defecated normally 24 hours after surgery and was discharged from the hospital at that time. The animal was prescribed enrofloxacin (20 mg/kg orally, once a day for 10 days, privately compounded by a compounding pharmacy), meloxicam (0.3 mg/kg orally, once a day for 5 days) clavamox as previously prescribed to be administered for a total of 14 days. Both enrofloxacin clavamox were prescribed to increase the spectrum of antibacterial coverage. The spleen and reproductive tract were placed in 10% formalin and submitted for histopathology. Histologically, the ovary was filled with and expanded by a densely cellular, encapsulated neoplasm composed of cells that were inclined to be arranged in nests or packets suspended in a fine fibrovascular stroma (Fig. 1). The cells were moderately pleomorphic, had distinct-to-indistinct cell borders, and moderate amounts of finely fibrillar-to-vacuolated cytoplasm. Nuclei exhibited moderate anisokaryosis, and were roundto-oval-to-polygonal with a vesicular chromatin
FIGURE 1. Photomicrograph of a granulosa cell tumor of the right ovary of the African hedgehog. The neoplasm is composed of nests and lobules of neoplastic granulosa cells suspended in a fine fibrovascular stroma. The neoplastic cells are moderately pleomorphic, have distinct-to-indistinct cell borders and moderate amounts of finely fibrillar to vacuolar cytoplasm. Hematoxylin and eosin stain. Bar ¼ 50 mm.
pattern, and contained 1 or 2 variably sized nucleoli. A total of 6 mitotic figures were counted in 10 high-power microscopic fields. Coalescing areas of coagulative necrosis accounted for approximately “two-thirds” of the cross-sectional area. Within or immediately adjacent to areas of coagulative necrosis were multiple congested blood vessels and mild multifocal areas of hemorrhage. Moderate numbers of immature eosinophils were present subjacent to the capsule. The histologic diagnosis was a granulosa cell tumor. One of the uterine horns had a benign endometrial polyp that protruded into the lumen. The core of the polyp was composed of fibrovascular connective tissue in which there were nests of endometrial glands. The polyp was covered by a single layer of columnar-topseudostratified columnar endometrial cells. The stroma of the polyp was infiltrated by moderate numbers of immature eosinophils. In the spleen, the red pulp was diffusely infiltrated and expanded by sheets of immature eosinophils (Fig. 2A). The cells had distinct cellular borders, rounded nuclei, and a moderate amount of cytoplasm composed of distinct, brightly eosinophilic granules. The mitotic rate was 5 per high-power microscopic field. There was a mild degree of anisokaryosis and anisocytosis along with mild-to-moderate diffuse extramedullary hematopoiesis in the red pulp. There were scattered lymphoid follicles and periarteriolar lymphoid sheaths, but these were subjectively decreased in number. Infiltrates of small numbers of similar eosinophils were occasionally
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FIGURE 2. Photomicrographs from the African hedgehog in this case report depicting the infiltration of the (A) spleen, (B) submandibular lymph node, (C) humeral bone marrow, and (D) lung with neoplastic eosinophils. (A) Splenic red pulp is diffusely infiltrated and expanded by sheets of immature eosinophils that have distinct cellular borders, rounded nuclei, and moderate amount of cytoplasm composed of distinct brightly eosinophilic granules. Small numbers of myeloid or erythroid precursor cells are scattered among the neoplastic eosinophils (arrows). Hematoxylin and eosin stain. Bar ¼ 20 mm. (B) The nodal structure of the lymph node is effaced by sheets of immature eosinophils. Arrows indicate remnants of a lymphoid follicle. Hematoxylin and eosin stain. Bar ¼ 50 mm. (C) The bone marrow is hypercellular and the normal hematopoietic tissue is replaced by sheets of neoplastic eosinophils. Hematoxylin and eosin stain. Bar ¼ 50 mm. (D) The interalvolar septae are expanded by infiltration of neoplastic eosinophils. Hematoxylin and eosin stain. Bar ¼ 50 mm.
present within the white pulp. The histologic interpretation of the spleen was that of eosinophilic leukemia due to the sheets of eosinophils that distorted the normal architecture of the spleen, their immature appearance, and the presence of mitotic figures within the cells. The hedgehog was reportedly acting well at home for the owner after discharge. The owner was medicating the hedgehog without issue and was also syringe-feeding the hedgehog to supplement what it ate on its own. The owner reported that the hedgehog was running on a wheel that night, despite being advised to restrict exercise until the time of a scheduled re-examination. The hedgehog was found dead in its enclosure the morning following hospital discharge (2 days postoperatively). The body was submitted for gross necropsy examination and histopathological examination of submitted tissues. Gross examination revealed an enlarged liver, enlarged submandibular lymph nodes, ulcers of the mucosa of the stomach, and 6 8
small amounts of serosanguineous fluid in both the thoracic and abdominal cavities. Histologically, the nodal structure of the submandibular lymph nodes was effaced by sheets of immature eosinophils similar to those described in the spleen (Fig. 2B). Approximately 80% of the bone marrow was effaced and replaced by similar neoplastic eosinophils with diffuse depletion of erythrocytic and platelet precursor cells (Fig. 2C). Similar neoplastic eosinophils were found diffusely within the alveolar septae of the lungs (Fig. 2D), liver, kidneys, and other lymph nodes, as well as within the blood vessels of the brain, heart, lungs, kidneys, thyroid glands, parathyroid glands, skeletal muscles, stomach, and intestines. Based on the histopathology results, a final definitive disease diagnosis of eosinophilic leukemia was determined for this hedgehog. DISCUSSION Eosinophilic leukemia (or chronic eosinophilic leukemia, CEL) is a rare neoplasm of the
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myelopoietic line, which has been described in a variety of animals and in people.2-6 Eosinophilic leukemia is characterized by the presence of blasts in the peripheral blood, morphologic abnormalities in eosinophils, immaturity of eosinophils with abnormal granulation, high myeloid:erythroid ratio, and significant anemia7,8 in the absence of an identifiable cause for eosinophilia.9 Differentiating idiopathic hypereosinophilic syndrome (IHES) and paraneoplastic hypereosinophilia from CEL can be difficult as the presentation, clinical signs, and features of these diseases frequently overlap.9-12 In people, CEL is defined as a clonal proliferation of eosinophils characterized by persistent, unexplained eosinophilia for more than 6 months at over 1500 cells/mL,13 whereas IHES is an unexplained polyclonal increase in eosinophils in which, as in CEL, increases are found in both the blood and the tissues.14 The diagnosis of CEL or IHES can be determined only after a number of infectious, inflammatory, and neoplastic diseases known to be associated with eosinophilia have been excluded.10,15 In animals, specific criteria to differentiate IHES from CEL have been proposed, such as differences in location of eosinophil infiltration, maturity of infiltrating eosinophils, and numerical ranges in leukocyte count and packed cell volume.6 Many cases of IHES and CEL do not strictly fit the criteria listed above, leading to confusion and difficulty in making an accurate diagnosis.9,10,12 Morphologically, the only criterion useful in distinguishing the 2 conditions is an increase in blast cells seen in eosinophilic leukemia,11 as was observed in this case. Special staining and flow cytometry can also be performed to help discern eosinophilic leukemia.2 Some more recent reports suggest that the separation between the 2 disorders may be artificial, and that both the conditions may represent a spectrum of the same disease.11,16 Eosinophil granules contain toxic cationic proteins, which serve as the primary mediators of cellular damage when released into tissues.15,17-19 These toxins (major basic protein, eosinophil peroxidase, eosinophil-derived neurotoxin, and eosinophil cationic protein)17-20 are responsible for increased vascular permeability, mucous secretion, and smooth muscle contraction.15 Free radicals produced by eosinophilic peroxidase and the respiratory burst oxidative pathway of the infiltrating eosinophils further enhance the damage.15,17,21 Enhanced fibrosis may result from stimulation of fibroblast proliferation and inhibition of proteoglycan degradation by
eosinophil products.22 The level of peripheral eosinophilia cannot be used to determine the extent of organ damage, as the eosinophil infiltration of tissues accompanied by the mediator release from the eosinophil granules is the cause of the resulting tissue damage.17 Flow cytometry was considered to look for cell clonality in this case but was not performed as there are no CD-specific antibodies available for hedgehogs. However, a diagnosis of eosinophilic leukemia was made in this case because of the predominance of immature eosinophils (blasts) with rounded nuclei in the bone marrow and the peripheral blood. In addition, all organs were infiltrated by immature eosinophils, and there were increased numbers of mitotic figures and atypical cells within the tissues. Lastly, neoplastic eosinophils caused effacement of the normal architecture of the organs, and both splenomegaly and hepatomegaly were noted on surgical exploration of the abdomen (splenomegaly) and on gross necropsy (hepatomegaly). It is likely that the hepatic eosinophilic infiltration observed in this hedgehog was also the cause of the increased alkaline phosphatase and alanine transaminase measured by the serum biochemistry analysis. The mainstay of treatment for IHES and CEL in people is glucocorticoids, which suppress cytokine gene transcription and inhibit cytokine-dependent eosinophil survival.15 Some patients are resistant to glucocorticoids and require treatment with hydroxyurea, vincristine, interferon-α, or cyclosporine. The use of interferon-α appears especially promising, as it promotes a shift from a Th2 cell-dependent response to a T-helper type 1 cell-dependent response.15 Other treatments such as antibodies directed against interleukin-5 are also being investigated. Neoplasia appears to be an unusually common disease condition in the aged hedgehog, and numerous types are often found concurrently within the same animal.23 The most commonly reported malignant tumor of the uterus and ovary in the hedgehog is adenosarcoma, followed by stromal sarcoma and leiomyosarcoma.23,24 Adenomas have been documented in the uterus of 8 hedgehogs,25 and single cases of adenocarcinoma, adenoleiomyosarcoma, vaginal spindle cell tumor, and ovarian granulosa cell tumor have also been described in the literature.25-28 Concurrent neoplasia has included 3 cases of mammary adenocarcinoma, 1 case of histiocytic sarcoma, and 1 case of mast cell tumor.25,28 Typical clinical signs in affected female hedgehogs with reproductive tract tumors, in order of prevalence, are
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vaginal bleeding, hematuria, and weight loss.25,28 The hedgehog in this case was concurrently diagnosed with an ovarian granulosa cell tumor and endometrial polyps. It is suspected that both of these neoplasias were incidental findings, as the hedgehog did not exhibit vaginal bleeding or hematuria, and the weight loss noted was most likely due to the generalized eosinophilic infiltration of the patient’s organ systems. The hedgehog in this case also exhibited hind limb ataxia, which could have been due to neoplasia, infarct, cardiac disease, demyelination (Wobbly Hedgehog Syndrome [WHS]), intervertebral disk disease, trauma, or toxins.29 The onset of WHS is commonly diagnosed in animals younger than 2 years of age, but can occur at any age, and is found in approximately 10% of African hedgehogs kept in North America.30 The etiology of WHS is unknown, but pedigree analyses suggest a familial tendency to develop the disease.30 One of the earliest indications of WHS is the inability of the animal to roll up, as observed in the hedgehog described in this case. The presence of infiltration of all organ systems with neoplastic eosinophils makes neoplastic infiltration of the spinal cord the most likely cause of ataxia in this case; however, concurrent neoplasia of the brain and/or spinal cord are also possibilities.31,32 Infarct development was also a strong possibility for the patient’s ataxic condition because of the fact that cationic proteins found in eosinophil granules are known to incite thrombosis.15 Cardiac disease may have resulted in the progressive hind limb ataxia, as enhanced fibrosis frequently occurs secondary to the effects of eosinophil products on tissue, and eosinophil infiltration was seen in the heart of this hedgehog. Cardiac failure secondary to myocardial fibrosis has been documented in humans with IHES and CEL,17 however, no evidence of clinical cardiac dysfunction was observed in this case. This report documents a case of concurrent, unrelated neoplasias found in a mature African hedgehog with nonspecific. Practitioners should be aware that similar clinical signs may be associated with eosinophilic leukemia in Atelerix albiventris. REFERENCES
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25. Mikaelian I, Reavill DR: Practice A: spontaneous proliferative lesions and tumors of the uterus of captive African hedgehogs (Atelerix albiventris). J Zoo Wildl Med 35: 216-220, 2004 26. Ramos-Vara JA: Soft tissue sarcomas in the African hedgehog (Atelerix albiventris): microscopic and immunohistologic study of three cases. J Vet Diagn Invest 13: 442-445, 2001 27. Raymond JT, Garner MM: Spontaneous tumors in captive African hedgehogs (Atelerix albiventris): a retrospective study. J Comp Pathol 124:128-133, 2001 28. Wellehan JFX, Southorn E, Smith DA, et al: Surgical removal of a mammary adenocarcinoma and a granulosa cell tumor in an African pygmy hedgehog. Can Vet J 44: 235-237, 2003
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Abstract A 2-year-old, captive, intact female African hedgehog (Atelerix albiventris) was evaluated for nonspecific clinical signs and progressive hind limb ataxia over a 1-month period. Abnormal results from a complete blood count included a mild regenerative anemia and an inflammatory leukogram with a degenerative left shift, toxic changes, and eosinophilia. Serum biochemistry analysis showed increased alkaline phosphatase and alanine transaminase levels. Whole-body radiograph images of the hedgehog revealed a thin body condition, oligodontia, and ventral lumbosacral spondylosis deformans. An abdominal ultrasonographic examination of the patient indicated that a hyperechoic mass with unknown origin was present in the caudal abdomen and moderate free fluid and a hyperechoic splenic nodule were present. A cytological examination of material collected through a fine needle aspirate of the abdominal mass was suggestive of carcinoma with marked eosinophilic inflammation. Exploratory surgery revealed a right ovarian mass and an abnormal spleen. An ovariohysterectomy and splenectomy were performed. Histopathology of the reproductive tract and spleen revealed an endometrial polyp in the uterus, a granulosa cell tumor in the right ovary, and a large number of immature eosinophils present throughout the spleen, consistent with eosinophilic leukemia. The hedgehog died 2 days following the surgical procedure. A postmortem examination of the patient revealed a mild bicavitary effusion, hepatomegaly, and a stomach ulcer. Histopathological examination of examined tissue indicated neoplastic eosinophils that encompassed 80% of the bone marrow and also infiltrated multiple glands, viscera, and associated blood vessels. The necropsy results supported the previous diagnosis of eosinophilic leukemia. Practitioners should be aware that similar clinical signs may be associated with eosinophilic leukemia in Atelerix albiventris. Copyright 2015 Elsevier Inc. All rights reserved. Key words: African hedgehog; Atelerix albiventris; eosinophilia; leukemia; neoplasia
A
2-year-old, 233 g captive, intact female African hedgehog (Atelerix albiventris) with a 1-month history of vague signs of behavior change, decreased appetite, decreased activity, and progressive hind limb ataxia was evaluated by the Exotics and Zoological Medicine Service, Kansas State University Veterinary Health Center. The hedgehog was reticent to interact with its owner and also reluctant to be touched. On visual examination of the hedgehog, bilateral ataxia of the hind limbs was noted. Conscious proprioception in the hind limbs was absent, and there was a subsequent delay in movement with crossing over of the hind limbs when the hedgehog was walking. The patient’s ability to curl up was significantly weakened, and it was unable to maintain sternal recumbency.
From the Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA; and the Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA Address correspondence to: Christine T. Higbie, DVM, School of Veterinary Medicine, Louisiana State University, Skip Bertman Drive, Baton Rouge, LA 70803. E-mail:[email protected] Ó 2015 Elsevier Inc. All rights reserved. 1557-5063/15/2101-$30.00 http://dx.doi.org/10.1053/j.jepm.2015.12.012
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The hedgehog was anesthetized with isoflurane gas at 5% in 1.5 L/min oxygen by facemask for induction, and then maintained on isoflurane gas in oxygen at 1.5% to 3% in 1.5 L/min oxygen by facemask for further examination and diagnostic testing. On physical examination, the hedgehog was given a body condition score of 2 of 5. The patient was assessed to be 5% to 7% dehydrated based on an increase in skin turgor over the back of the neck, stringy saliva in the mouth, tacky mucous membranes, and a prolonged capillary refill time42 seconds. The mandibular and prescapular lymph nodes on palpation were bilaterally prominent. A firm, 2 cm 2 cm mass was palpable in the caudal abdomen. While the hedgehog was under general anesthesia, a blood sample was obtained from the cranial vena cava for a complete blood count and plasma biochemical analysis. The complete blood count revealed a mild anemia (centrifuged hematocrit ¼ 35%; reference range: 41% to 43%)1 with marked polychromasia and 2 nucleated red blood cells per 100 white blood cells. The lymphocyte count was mildly increased (6.6 K/mL, reference range: 4.48 to 5.44 K/mL),1 and there was a severe neutropenia present (1.3 K/mL, reference range: 8.54 to 9.74 K/mL)1 with toxic neutrophilic changes. A degenerative left shift was noted (band neutrophils ¼ 2.7 K/mL, reference range: 0 K/mL, metamyelocytes ¼ 0.4 K/mL, reference range: 0 K/ mL),1 and a moderate-to-severe eosinophilia was present (1.7 K/mL, reference range: 0.14 to 0.2 K/ mL).1 Serum biochemistry analysis was unremarkable apart from an increased alkaline phosphatase (275 U/L, reference range: 20.78 to 23.38 U/L) and alanine transaminase (64 U/L, reference range: 21.49 to 25.57 U/L).1 Diagnostic imaging was performed while the hedgehog was still under general anesthesia. Whole-body, 2-view (dorsoventral and right lateral) radiographs revealed a thin body condition, oligodontia, and ventral lumbosacral spondylosis deformans. Abdominal ultrasonography revealed a round mass of mixed echogenicity in the midventral abdomen, located ventromedial to the left kidney. The mass measured 1.5 cm in height 2.1 cm in length 1.9 cm in width and had an unknown organ of origin. There was a moderate amount of echogenic free fluid in the abdominal cavity, and a hyperechoic splenic nodule was present in the dorsal portion of the head of the spleen. Ultrasound-guided fine needle aspirate of the abdominal mass was performed under general anesthesia, and cytology revealed a low amount of 6 6
intact nucleated cells. As a result, the organ of origin of the mass could not be discerned; however, a carcinoma was suspected. Marked eosinophilic inflammation was present within the neoplasm. The hedgehog received lactated Ringer’s solution (35 mL subcutaneously) and enrofloxacin (20 mg/ kg subcutaneously, Baytril; Bayer HealthCare LLC, Shawnee Mission, KS USA) before recovery from anesthesia, which occurred without complication. At the owner’s request, the hedgehog was discharged from the hospital to receive supportive care at home, before its scheduled abdominal exploratory surgery. The hedgehog was treated at home with amoxicillin and clavulanic acid (12.5 mg/kg orally, every 12 hours, Clavamox; Zoetis, Florham Park, NJ USA) and prednisolone (2.5 mg/kg orally, every 12 hours, PrednisoLONE Oral Solution; Hi-Tech Pharmacal, Amityville, NY USA), in addition to assisted feeding with canned dog food (i/d, Hill’s Pet Nutrition, Topeka, KS USA) and fruit baby food every 4 to 6 hours to improve its clinical condition in preparation for the surgical procedure. The hedgehog reportedly responded very well to the treatment regimen and had an excellent appetite for the owner. Exploratory surgery was performed 3 days following the initial presentation. Clavamox was administered orally, as prescribed, the night before surgery, and the hedgehog received meloxicam (0.3 mg/kg orally, Metacam; Boehringer Ingelheim Vetmedica, St. Joseph, MO USA) and enrofloxacin (20 mg/kg subcutaneously) on the morning of the surgical procedure. Before the surgical procedure, the patient was premedicated with midazolam (0.3 mg/kg intramuscularly) and butorphanol (0.3 mg/kg intramuscularly), and then general anesthesia was induced with 5% isoflurane gas in a 2-L/min flow of oxygen by facemask. The hedgehog was maintained (2%) on isoflurane gas in a 1.5-L/min flow of oxygen by facemask during surgery. A 24-gauge intravenous catheter was placed in the right cephalic vein and lactated Ringer’s solution with 5% dextrose was administered by continuous rate infusion (10 mL/ kg/hour) using a syringe pump throughout the surgical procedure. Given the small size of the intravenous catheter, a second intravenous catheter was placed into the left cephalic vein for backup in the event of an emergency during the anesthetic procedure. The hedgehog was maintained on a heating pad throughout the procedure, and its heart rate and rhythm were monitored using a Doppler ultrasound probe placed over the sternum.
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The ventral abdominal region was clipped and aseptically prepared for surgery. A 4-cm ventral midline approach to the midcaudal abdomen was performed. Abdominal exploration revealed the mass to be the right ovary. An ovariohysterectomy was performed using small- and medium-sized hemoclips (Hemoclip; Weck Closure Systems Research, Triangle Park, NC USA) and bipolar radiosurgery was used for hemostasis (Ellman Surgitron FFPF; Ellman International, Hewlett, NY USA) with the coagulation setting at 5. The mass was removed from the abdomen without complication using this method. The spleen was located and visually examined. Although the splenic nodule observed during the ultrasonographic examination could not be appreciated with the naked eye, the spleen appeared pale in color and mottled. The extremely friable spleen was removed using hemoclips and the bipolar radiosurgery forceps for hemostasis. No other abdominal visceral abnormalities were visualized. The abdomen was lavaged with warm, sterile 0.9% saline and then closed routinely in 3 layers. Before recovery from anesthesia, buprenorphine (0.03 mg/kg intravenously) was administered for analgesia, flumazenil (0.05 mg/kg intravenously) was provided to facilitate full recovery from anesthesia, and the intravenous catheters were removed. The hedgehog had a quick and uneventful recovery from the surgical procedure. Normal urination was noted and the patient ate a small amount of food the same night. The hedgehog defecated normally 24 hours after surgery and was discharged from the hospital at that time. The animal was prescribed enrofloxacin (20 mg/kg orally, once a day for 10 days, privately compounded by a compounding pharmacy), meloxicam (0.3 mg/kg orally, once a day for 5 days) clavamox as previously prescribed to be administered for a total of 14 days. Both enrofloxacin clavamox were prescribed to increase the spectrum of antibacterial coverage. The spleen and reproductive tract were placed in 10% formalin and submitted for histopathology. Histologically, the ovary was filled with and expanded by a densely cellular, encapsulated neoplasm composed of cells that were inclined to be arranged in nests or packets suspended in a fine fibrovascular stroma (Fig. 1). The cells were moderately pleomorphic, had distinct-to-indistinct cell borders, and moderate amounts of finely fibrillar-to-vacuolated cytoplasm. Nuclei exhibited moderate anisokaryosis, and were roundto-oval-to-polygonal with a vesicular chromatin
FIGURE 1. Photomicrograph of a granulosa cell tumor of the right ovary of the African hedgehog. The neoplasm is composed of nests and lobules of neoplastic granulosa cells suspended in a fine fibrovascular stroma. The neoplastic cells are moderately pleomorphic, have distinct-to-indistinct cell borders and moderate amounts of finely fibrillar to vacuolar cytoplasm. Hematoxylin and eosin stain. Bar ¼ 50 mm.
pattern, and contained 1 or 2 variably sized nucleoli. A total of 6 mitotic figures were counted in 10 high-power microscopic fields. Coalescing areas of coagulative necrosis accounted for approximately “two-thirds” of the cross-sectional area. Within or immediately adjacent to areas of coagulative necrosis were multiple congested blood vessels and mild multifocal areas of hemorrhage. Moderate numbers of immature eosinophils were present subjacent to the capsule. The histologic diagnosis was a granulosa cell tumor. One of the uterine horns had a benign endometrial polyp that protruded into the lumen. The core of the polyp was composed of fibrovascular connective tissue in which there were nests of endometrial glands. The polyp was covered by a single layer of columnar-topseudostratified columnar endometrial cells. The stroma of the polyp was infiltrated by moderate numbers of immature eosinophils. In the spleen, the red pulp was diffusely infiltrated and expanded by sheets of immature eosinophils (Fig. 2A). The cells had distinct cellular borders, rounded nuclei, and a moderate amount of cytoplasm composed of distinct, brightly eosinophilic granules. The mitotic rate was 5 per high-power microscopic field. There was a mild degree of anisokaryosis and anisocytosis along with mild-to-moderate diffuse extramedullary hematopoiesis in the red pulp. There were scattered lymphoid follicles and periarteriolar lymphoid sheaths, but these were subjectively decreased in number. Infiltrates of small numbers of similar eosinophils were occasionally
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FIGURE 2. Photomicrographs from the African hedgehog in this case report depicting the infiltration of the (A) spleen, (B) submandibular lymph node, (C) humeral bone marrow, and (D) lung with neoplastic eosinophils. (A) Splenic red pulp is diffusely infiltrated and expanded by sheets of immature eosinophils that have distinct cellular borders, rounded nuclei, and moderate amount of cytoplasm composed of distinct brightly eosinophilic granules. Small numbers of myeloid or erythroid precursor cells are scattered among the neoplastic eosinophils (arrows). Hematoxylin and eosin stain. Bar ¼ 20 mm. (B) The nodal structure of the lymph node is effaced by sheets of immature eosinophils. Arrows indicate remnants of a lymphoid follicle. Hematoxylin and eosin stain. Bar ¼ 50 mm. (C) The bone marrow is hypercellular and the normal hematopoietic tissue is replaced by sheets of neoplastic eosinophils. Hematoxylin and eosin stain. Bar ¼ 50 mm. (D) The interalvolar septae are expanded by infiltration of neoplastic eosinophils. Hematoxylin and eosin stain. Bar ¼ 50 mm.
present within the white pulp. The histologic interpretation of the spleen was that of eosinophilic leukemia due to the sheets of eosinophils that distorted the normal architecture of the spleen, their immature appearance, and the presence of mitotic figures within the cells. The hedgehog was reportedly acting well at home for the owner after discharge. The owner was medicating the hedgehog without issue and was also syringe-feeding the hedgehog to supplement what it ate on its own. The owner reported that the hedgehog was running on a wheel that night, despite being advised to restrict exercise until the time of a scheduled re-examination. The hedgehog was found dead in its enclosure the morning following hospital discharge (2 days postoperatively). The body was submitted for gross necropsy examination and histopathological examination of submitted tissues. Gross examination revealed an enlarged liver, enlarged submandibular lymph nodes, ulcers of the mucosa of the stomach, and 6 8
small amounts of serosanguineous fluid in both the thoracic and abdominal cavities. Histologically, the nodal structure of the submandibular lymph nodes was effaced by sheets of immature eosinophils similar to those described in the spleen (Fig. 2B). Approximately 80% of the bone marrow was effaced and replaced by similar neoplastic eosinophils with diffuse depletion of erythrocytic and platelet precursor cells (Fig. 2C). Similar neoplastic eosinophils were found diffusely within the alveolar septae of the lungs (Fig. 2D), liver, kidneys, and other lymph nodes, as well as within the blood vessels of the brain, heart, lungs, kidneys, thyroid glands, parathyroid glands, skeletal muscles, stomach, and intestines. Based on the histopathology results, a final definitive disease diagnosis of eosinophilic leukemia was determined for this hedgehog. DISCUSSION Eosinophilic leukemia (or chronic eosinophilic leukemia, CEL) is a rare neoplasm of the
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myelopoietic line, which has been described in a variety of animals and in people.2-6 Eosinophilic leukemia is characterized by the presence of blasts in the peripheral blood, morphologic abnormalities in eosinophils, immaturity of eosinophils with abnormal granulation, high myeloid:erythroid ratio, and significant anemia7,8 in the absence of an identifiable cause for eosinophilia.9 Differentiating idiopathic hypereosinophilic syndrome (IHES) and paraneoplastic hypereosinophilia from CEL can be difficult as the presentation, clinical signs, and features of these diseases frequently overlap.9-12 In people, CEL is defined as a clonal proliferation of eosinophils characterized by persistent, unexplained eosinophilia for more than 6 months at over 1500 cells/mL,13 whereas IHES is an unexplained polyclonal increase in eosinophils in which, as in CEL, increases are found in both the blood and the tissues.14 The diagnosis of CEL or IHES can be determined only after a number of infectious, inflammatory, and neoplastic diseases known to be associated with eosinophilia have been excluded.10,15 In animals, specific criteria to differentiate IHES from CEL have been proposed, such as differences in location of eosinophil infiltration, maturity of infiltrating eosinophils, and numerical ranges in leukocyte count and packed cell volume.6 Many cases of IHES and CEL do not strictly fit the criteria listed above, leading to confusion and difficulty in making an accurate diagnosis.9,10,12 Morphologically, the only criterion useful in distinguishing the 2 conditions is an increase in blast cells seen in eosinophilic leukemia,11 as was observed in this case. Special staining and flow cytometry can also be performed to help discern eosinophilic leukemia.2 Some more recent reports suggest that the separation between the 2 disorders may be artificial, and that both the conditions may represent a spectrum of the same disease.11,16 Eosinophil granules contain toxic cationic proteins, which serve as the primary mediators of cellular damage when released into tissues.15,17-19 These toxins (major basic protein, eosinophil peroxidase, eosinophil-derived neurotoxin, and eosinophil cationic protein)17-20 are responsible for increased vascular permeability, mucous secretion, and smooth muscle contraction.15 Free radicals produced by eosinophilic peroxidase and the respiratory burst oxidative pathway of the infiltrating eosinophils further enhance the damage.15,17,21 Enhanced fibrosis may result from stimulation of fibroblast proliferation and inhibition of proteoglycan degradation by
eosinophil products.22 The level of peripheral eosinophilia cannot be used to determine the extent of organ damage, as the eosinophil infiltration of tissues accompanied by the mediator release from the eosinophil granules is the cause of the resulting tissue damage.17 Flow cytometry was considered to look for cell clonality in this case but was not performed as there are no CD-specific antibodies available for hedgehogs. However, a diagnosis of eosinophilic leukemia was made in this case because of the predominance of immature eosinophils (blasts) with rounded nuclei in the bone marrow and the peripheral blood. In addition, all organs were infiltrated by immature eosinophils, and there were increased numbers of mitotic figures and atypical cells within the tissues. Lastly, neoplastic eosinophils caused effacement of the normal architecture of the organs, and both splenomegaly and hepatomegaly were noted on surgical exploration of the abdomen (splenomegaly) and on gross necropsy (hepatomegaly). It is likely that the hepatic eosinophilic infiltration observed in this hedgehog was also the cause of the increased alkaline phosphatase and alanine transaminase measured by the serum biochemistry analysis. The mainstay of treatment for IHES and CEL in people is glucocorticoids, which suppress cytokine gene transcription and inhibit cytokine-dependent eosinophil survival.15 Some patients are resistant to glucocorticoids and require treatment with hydroxyurea, vincristine, interferon-α, or cyclosporine. The use of interferon-α appears especially promising, as it promotes a shift from a Th2 cell-dependent response to a T-helper type 1 cell-dependent response.15 Other treatments such as antibodies directed against interleukin-5 are also being investigated. Neoplasia appears to be an unusually common disease condition in the aged hedgehog, and numerous types are often found concurrently within the same animal.23 The most commonly reported malignant tumor of the uterus and ovary in the hedgehog is adenosarcoma, followed by stromal sarcoma and leiomyosarcoma.23,24 Adenomas have been documented in the uterus of 8 hedgehogs,25 and single cases of adenocarcinoma, adenoleiomyosarcoma, vaginal spindle cell tumor, and ovarian granulosa cell tumor have also been described in the literature.25-28 Concurrent neoplasia has included 3 cases of mammary adenocarcinoma, 1 case of histiocytic sarcoma, and 1 case of mast cell tumor.25,28 Typical clinical signs in affected female hedgehogs with reproductive tract tumors, in order of prevalence, are
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vaginal bleeding, hematuria, and weight loss.25,28 The hedgehog in this case was concurrently diagnosed with an ovarian granulosa cell tumor and endometrial polyps. It is suspected that both of these neoplasias were incidental findings, as the hedgehog did not exhibit vaginal bleeding or hematuria, and the weight loss noted was most likely due to the generalized eosinophilic infiltration of the patient’s organ systems. The hedgehog in this case also exhibited hind limb ataxia, which could have been due to neoplasia, infarct, cardiac disease, demyelination (Wobbly Hedgehog Syndrome [WHS]), intervertebral disk disease, trauma, or toxins.29 The onset of WHS is commonly diagnosed in animals younger than 2 years of age, but can occur at any age, and is found in approximately 10% of African hedgehogs kept in North America.30 The etiology of WHS is unknown, but pedigree analyses suggest a familial tendency to develop the disease.30 One of the earliest indications of WHS is the inability of the animal to roll up, as observed in the hedgehog described in this case. The presence of infiltration of all organ systems with neoplastic eosinophils makes neoplastic infiltration of the spinal cord the most likely cause of ataxia in this case; however, concurrent neoplasia of the brain and/or spinal cord are also possibilities.31,32 Infarct development was also a strong possibility for the patient’s ataxic condition because of the fact that cationic proteins found in eosinophil granules are known to incite thrombosis.15 Cardiac disease may have resulted in the progressive hind limb ataxia, as enhanced fibrosis frequently occurs secondary to the effects of eosinophil products on tissue, and eosinophil infiltration was seen in the heart of this hedgehog. Cardiac failure secondary to myocardial fibrosis has been documented in humans with IHES and CEL,17 however, no evidence of clinical cardiac dysfunction was observed in this case. This report documents a case of concurrent, unrelated neoplasias found in a mature African hedgehog with nonspecific. Practitioners should be aware that similar clinical signs may be associated with eosinophilic leukemia in Atelerix albiventris. REFERENCES
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25. Mikaelian I, Reavill DR: Practice A: spontaneous proliferative lesions and tumors of the uterus of captive African hedgehogs (Atelerix albiventris). J Zoo Wildl Med 35: 216-220, 2004 26. Ramos-Vara JA: Soft tissue sarcomas in the African hedgehog (Atelerix albiventris): microscopic and immunohistologic study of three cases. J Vet Diagn Invest 13: 442-445, 2001 27. Raymond JT, Garner MM: Spontaneous tumors in captive African hedgehogs (Atelerix albiventris): a retrospective study. J Comp Pathol 124:128-133, 2001 28. Wellehan JFX, Southorn E, Smith DA, et al: Surgical removal of a mammary adenocarcinoma and a granulosa cell tumor in an African pygmy hedgehog. Can Vet J 44: 235-237, 2003
29. Ivey E, Carpenter JW: African hedgehogs, in Quesenberry KE, Carpenter JW (eds): Ferrets, Rabbits, and Rodents: Clinical Medicine and Surgery. (ed 3). Philadelphia, PA, WB Saunders Co, pp 419-421, 2012 30. Graesser D, Spraker TR, Dressen P, et al: Wobbly hedgehog syndrome in African pygmy hedgehogs (Atelerix sp.). J Exot Pet Med 15:59-65, 2006 31. Garner MM, Kiupel M: Brain tumors in African hedgehogs (Atelerix albiventris). Proceedings of the 31st Annual Conference and Expo of the Association of Avian Veterinarians, San Diego, CA, p. 65, 2010 32. Gibson CJ, Parry NMA, Jakowski RM, et al: Anaplastic astrocytoma in the spinal cord of an African pygmy hedgehog (Atelerix albiventris). Vet Pathol Online 45: 934-938, 2008
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