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Pathology in Practice
Figure 1—Photographs of the head (A) and a sagittal section (B) through the skull of a Jersey cow that developed 3 subcutaneous masses on the head over a period of several months and was euthanized. The first mass developed at the site of SC injection of ceftiofur crystalline-free acid, which was administered for treatment of endometritis. In panel A, an ulcerated, subcutaneous mass is present over the left lateral parietal region. In panel B, a variegated, yellow and red extradural mass has obliterated the parietal bone, invaded the cranial vault, and compressed the brain.
History
Clinical and Gross Findings
Ten days after calving, a 2-year-old registered Jersey cow was treated for endometritis with ceftiofur crystallinefree acida injected SC at the base of the left ear. A month later, a small swelling was present at the injection site. The swelling continued to grow over the next several weeks. A presumptive diagnosis of an abscess or granuloma was made, and the mass was lanced and drained. Two months after initial treatment, a second small mass near the base of the left horn and a third mass in the center of the forehead were observed. The masses did not seem to be connected. The cow continued to eat and produce milk throughout the clinical course of the disease. Approximately 3 months after identification of the initial mass, the cow was submitted for euthanasia and necropsy because of the rapidly increasing size of the latter 2 masses.
Postmortem radiographic views of the skull revealed an approximately 11.5 X 17.3 X 8.7-cm multilobular, interconnected, expansile mass that deformed the left parietal and occipital bones and contained multiple foci of bone thinning and lysis. The expansile mass was poorly mineralized with ill-defined margins and a long zone of transition, consistent with aggressive bone changes. A portion of the poorly mineralized expansile mass extended into the calvarium. Severe soft tissue swelling was associated with the mass, caudal and medial to the left ear canal. The cow was in adequate nutritional condition with adequate body fat stores. Lesions were confined to the head. A fluctuant, multilobulated, subcutaneous, ulcerated 25- to 30-cm-diameter mass, extending from the caudal portion of the left orbit to the occiput, was centered at the site of the left horn base and extended slightly over the midline (Figure 1). The mass had eroded the calvarial bone and left orbit. At the level of the dorsolateral aspect of the mesencephalon, an approximately 5-cm-diameter, solid, botryoid portion of the mass compressed but did not invade the cerebrum. The mass remained distinctly extradural and was composed of solid tan to yellow tissue with large areas of necrosis containing thick, white fluid.
This report was submitted by Kristin M. Patton, DVM, PhD; Reid Tyson, DVM; Louise Castelanelli, DVM; and Howard B. Gelberg, DVM, PhD; from the Department of Biomedical Sciences and the Veterinary Diagnostic Laboratory (Patton, Gelberg) and the Department of Clinical Sciences (Tyson), College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331; and Pioneer Veterinary Hospital, 801 Main Ave, Tillamook, OR 97141 (Castelanelli). Dr. Patton’s present address is Battelle, 1425 Plain-City-Georgesville Rd, West Jefferson, OH 43162. Dr. Tyson’s present address is Department of Small Animal Clinical Sciences, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061. Address correspondence to Dr. Gelberg (howard.gelberg@oregonstate. edu). JAVMA, Vol 244, No. 3, February 1, 2014
Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page → Vet Med Today: Pathology in Practice
287
Histopathologic Findings Sections of the subcutaneous mass were stained with H&E and with immunohistochemical stains for chromogranin A, glial fibrillary acid protein, neuron-specific enolase, synaptophysin, S-100, and vimentin.b The mass consisted of broad, poorly organized, coalescing, highly cellular lobules formed by sheets of large, densely packed, anaplastic, round to polyhedral to spindloid cells punctuated by large lakes of necrotic tissue. In scattered foci, the cells formed small packets outlined by a delicate fibrovascular stroma. Occasional perivascular pseudorosettes were present. The cells had moderate amounts of poorly defined, granular to vacuolated cytoplasm and very large, pleomorphic, round, oval or indented nuclei with ruffled nuclear membranes. Chromatin was granular and dispersed, and there were single to multiple, sometimes prominent nucleoli (Figure 2). There were 0 to 2 mitoses/400X field. Results of immunohistochemical staining for chromogranin A, synaptophysin, and neuron-specific enolase were negative. The neoplastic cells were positive for vimentin (Figure 3) and S-100 (Figure 4) and were occasionally positive for glial fibrillary acid protein (Figure 5).
tumors is based on their location, histologic features, and immunohistochemical staining properties. Such tumors may be difficult to classify beyond the designation of PNET because of their lack of reactivity to neuronal markers. In cattle, a variety of these embryonal tumor types have been described, including ependymoblastomas, medulloblastomas, neuroblastomas, ganglioneuroblastomas, and glioblastomas.4,10–14 Undifferentiated PNETs in the spinal cord and cerebrum of young cattle have also been recently reported.6,7 Similar to cases of PNET in humans, PNET with ependymal differentiation has developed in bovids that were 6 and 18 months old.11,12 The increasing incidence of PNETs in cattle, as reported in the veterinary medical
Morphologic Diagnosis and Case Summary Morphologic diagnosis and case summary: primitive neuroectodermal tumor (PNET) with ependymal differentiation in a cow. Comments Integumentary and subcutaneous neoplasia of cattle, including papilloma virus–associated cutaneous fibropapillomas and squamous cell carcinomas associated with solar radiation in whitefaced cattle, are common.1 Less common neoplastic conditions include peripheral nerve sheath tumors (eg, Schwannomas, neurofibromas, and neurilemomas)2–5 that may develop as nodular or varicose thickenings along nerve tracks or nerve roots.5 Primitive neuroectodermal tumors are a family of neoplasms that develop in human infants and children6 but have rarely been reported in cattle.4,7,8 They are formed from primitive neuroepithelial cells with a common embryonic appearance and are thought to develop from a multipotent stem cell capable of differentiation into neuronal, glial, and possibly mesenchymal cell lines.6 Primitive neuroectodermal tumor types include a variety of embryonal neoplasms, such as medulloblastomas, ependymoblastomas, neuroblastomas, and ganglioneuroblastomas as well as tumors classified as PNET with neuronal differentiation, PNET with ependymal cell differentiation, and PNET with glial differentiation.2,9 The specific classification of these 288
Vet Med Today: Pathology in Practice
Figure 2—Photomicrograph of a section of the multilobular, interconnected, expansile subcutaneous cranial mass in the Jersey cow in Figure 1. Neoplastic cells have moderate amounts of poorly defined, granular to vacuolated cytoplasm and very large, pleomorphic, round, oval or indented nuclei with ruffled nuclear membranes. The cells are divided into packets by a delicate fibrovascular stroma. H&E stain; bar = 50 µm.
Figure 3—Photomicrograph of a section of the subcutaneous cranial mass in the Jersey cow in Figure 1. Notice the strong cytoplasmic immunostaining for vimentin. Immunohistochemical stain; bar = 50 µm. JAVMA, Vol 244, No. 3, February 1, 2014
of pharmacokinetic studies16,17 provide additional evidence that SC injection of ceftiofur crystalline-free acida is well tolerated in cattle with minimal, transient inflammation. Immunohistochemical characterization is paramount for classification of PNETs. These tumors are of stem cell linage and are unique in their clinical signs and morphology. The exact cell of origin is often difficult to establish. a. EXCEDE, Ceftiofur crystalline free acid sterile suspension, Pfizer Pharmacia & Upjohn Co, New York, NY. b. Envision, Dako, Carpinteria, Calif.
References 1. Harris AM, Ginn PE. Integumentary system. In: Zachary JF, McGavin MD, eds. Pathological basis of veterinary disease. 5th ed. St Louis: Elsevier, 2012;1012–1015. 2. Koestner A, Higgins RJ. Tumors of the nervous system. In: Meuten DJ, ed. Tumors in domestic Figure 4—Photomicrograph of a section of the subcutaneous cranial mass in the animals. 4th ed. Ames, Iowa: Iowa State Press, Jersey cow in Figure 1. Notice the strong nuclear and cytoplasmic immunostain2002;714–716. ing for S-100. Immunohistochemical stain; bar = 50 µm. 3. Omi K, Kitano Y, Agawa H, et al. An immunohistochemical study of peripheral neuroblastoma, ganglioneuroblastoma, anaplastic ganglioma, schwannoma and neurofibroma in cattle. J Comp Pathol 1994;111:1–14. 4. Uchida K, Murakami T, Tometsuka T, et al. Peripheral neuroblastoma and primitive neuroectodermal tumor in Japanese black cattle. J Vet Med Sci 1998;60:871–875. 5. Zachary J. Nervous system. In: Zachary JF, McGavin MD, eds. Pathological basis of veterinary disease. 4th ed. St Louis: Elsevier, 2012;835–839. 6. Wippold FJ II, Perry A. Neuropathology for the neuroradiologist: rosettes and pseudorosettes. AJNR Am J Neuroradiol 2006;27:488–492. 7. Berrocal A, Montgomery DL, Mackie JT, et al. Primitive neuroectodermal tumor in the spinal cord of a Brahman crossbred calf. Vet Pathol 2005;42:834–836. 8. Lucas M-N, Nguyen F, Abadie J, et al. Cerebral primitive neuroectodermal tumor in a heifer. J Comp Pathol 2003;128:195–198. 9. Summers BA, Cummings JF, de Lahunta A. Tumors of the central nervous system. In: Veterinary neuropathology. St Louis: Mosby Year Book Inc, 1995;378–379. Figure 5—Photomicrograph of a section of the subcutaneous cranial mass in the Jersey cow in Figure 1. Notice the strong cytoplasmic immunostaining for 10. Haynes JS, Leininger JR. Malignant neuroblastoma in a cow. Vet Pathol 1984;21:610–612. glial fibrillary acid protein. Immunohistochemical stain. 11. Miyoshi N, Matsumoto M, Kawaguchi H, et al. Ependymoblastoma in a Japanese black heifer. J Vet Med Sci 2009;71:1393–1395. 12. Saunders GK. Ependymoblastoma in a dairy calf. Vet Pathol literature, is likely attributable to an increasing frequency 1984;21:528–529. of immunotyping of tumors in cattle. 13. Steinberg H, Peek SF, Nelson KM. Neuroblastoma with neuronal In the cow of the present report, the relationship of the differentiation in the spinal cord in an Aberdeen Angus heifer initial mass with the site of antimicrobial injection was likely calf. Vet Pathol 2006;43:193–197. incidental. Drug insert information on the safety of SC admin14. Ulrich R, Stan AC, Koch A, et al. Expression of brain-derived neua istration of ceftiofur crystalline-free acid at the base of the ear rotrophic factor and tropomysin-related kinase-B in a bovine jejuwas reviewed.15 Ceftiofur crystalline-free acida was adminisnal nodular ganglioneuroblastoma. Vet Pathol 2008;45:355–360. tered SC to 2,926 beef cattle for comparison of its pharmaco15. EXCEDE (ceftiofur crystalline free acid) sterile suspension [package insert]. New York: Pfizer Pharmacia & Upjohn Co, 2009. kinetics via 2 sites of administration (either the base of the ear 16. Hibbard B, Robb EJ, Apley MD, et al. Feedlot performance of or the middle third of the ear). Local tolerance of the SC injecsteers treated concurrently with ceftiofur crystalline-free acid tion was excellent, with no postinjection problems (excessive subcutaneously in the posterior aspect of the ear and a growthbleeding or leak back) in 99.8% of cattle. The drug insert inpromoting implant. Vet Ther 2002;3:252–261. formation reports that on days 28 and 56 after injection, 97.8% 17. Hibbard B, Robb EJ, Chester ST Jr, et al. Dose determination and 98.9% of the cattle had no observable swelling at the injecand confirmation for ceftiofur crystalline-free acid administration site.15 Similar findings following ceftiofur crystalline-free tion in the posterior aspect of the ear for control and treatment of bovine respiratory disease. Vet Ther 2002;3:22–30. acid administration in dairy cattle have been reported.1 Results JAVMA, Vol 244, No. 3, February 1, 2014
Vet Med Today: Pathology in Practice
289
Pathology in Practice
Figure 1—Photographs of the head (A) and a sagittal section (B) through the skull of a Jersey cow that developed 3 subcutaneous masses on the head over a period of several months and was euthanized. The first mass developed at the site of SC injection of ceftiofur crystalline-free acid, which was administered for treatment of endometritis. In panel A, an ulcerated, subcutaneous mass is present over the left lateral parietal region. In panel B, a variegated, yellow and red extradural mass has obliterated the parietal bone, invaded the cranial vault, and compressed the brain.
History
Clinical and Gross Findings
Ten days after calving, a 2-year-old registered Jersey cow was treated for endometritis with ceftiofur crystallinefree acida injected SC at the base of the left ear. A month later, a small swelling was present at the injection site. The swelling continued to grow over the next several weeks. A presumptive diagnosis of an abscess or granuloma was made, and the mass was lanced and drained. Two months after initial treatment, a second small mass near the base of the left horn and a third mass in the center of the forehead were observed. The masses did not seem to be connected. The cow continued to eat and produce milk throughout the clinical course of the disease. Approximately 3 months after identification of the initial mass, the cow was submitted for euthanasia and necropsy because of the rapidly increasing size of the latter 2 masses.
Postmortem radiographic views of the skull revealed an approximately 11.5 X 17.3 X 8.7-cm multilobular, interconnected, expansile mass that deformed the left parietal and occipital bones and contained multiple foci of bone thinning and lysis. The expansile mass was poorly mineralized with ill-defined margins and a long zone of transition, consistent with aggressive bone changes. A portion of the poorly mineralized expansile mass extended into the calvarium. Severe soft tissue swelling was associated with the mass, caudal and medial to the left ear canal. The cow was in adequate nutritional condition with adequate body fat stores. Lesions were confined to the head. A fluctuant, multilobulated, subcutaneous, ulcerated 25- to 30-cm-diameter mass, extending from the caudal portion of the left orbit to the occiput, was centered at the site of the left horn base and extended slightly over the midline (Figure 1). The mass had eroded the calvarial bone and left orbit. At the level of the dorsolateral aspect of the mesencephalon, an approximately 5-cm-diameter, solid, botryoid portion of the mass compressed but did not invade the cerebrum. The mass remained distinctly extradural and was composed of solid tan to yellow tissue with large areas of necrosis containing thick, white fluid.
This report was submitted by Kristin M. Patton, DVM, PhD; Reid Tyson, DVM; Louise Castelanelli, DVM; and Howard B. Gelberg, DVM, PhD; from the Department of Biomedical Sciences and the Veterinary Diagnostic Laboratory (Patton, Gelberg) and the Department of Clinical Sciences (Tyson), College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331; and Pioneer Veterinary Hospital, 801 Main Ave, Tillamook, OR 97141 (Castelanelli). Dr. Patton’s present address is Battelle, 1425 Plain-City-Georgesville Rd, West Jefferson, OH 43162. Dr. Tyson’s present address is Department of Small Animal Clinical Sciences, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061. Address correspondence to Dr. Gelberg (howard.gelberg@oregonstate. edu). JAVMA, Vol 244, No. 3, February 1, 2014
Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page → Vet Med Today: Pathology in Practice
287
Histopathologic Findings Sections of the subcutaneous mass were stained with H&E and with immunohistochemical stains for chromogranin A, glial fibrillary acid protein, neuron-specific enolase, synaptophysin, S-100, and vimentin.b The mass consisted of broad, poorly organized, coalescing, highly cellular lobules formed by sheets of large, densely packed, anaplastic, round to polyhedral to spindloid cells punctuated by large lakes of necrotic tissue. In scattered foci, the cells formed small packets outlined by a delicate fibrovascular stroma. Occasional perivascular pseudorosettes were present. The cells had moderate amounts of poorly defined, granular to vacuolated cytoplasm and very large, pleomorphic, round, oval or indented nuclei with ruffled nuclear membranes. Chromatin was granular and dispersed, and there were single to multiple, sometimes prominent nucleoli (Figure 2). There were 0 to 2 mitoses/400X field. Results of immunohistochemical staining for chromogranin A, synaptophysin, and neuron-specific enolase were negative. The neoplastic cells were positive for vimentin (Figure 3) and S-100 (Figure 4) and were occasionally positive for glial fibrillary acid protein (Figure 5).
tumors is based on their location, histologic features, and immunohistochemical staining properties. Such tumors may be difficult to classify beyond the designation of PNET because of their lack of reactivity to neuronal markers. In cattle, a variety of these embryonal tumor types have been described, including ependymoblastomas, medulloblastomas, neuroblastomas, ganglioneuroblastomas, and glioblastomas.4,10–14 Undifferentiated PNETs in the spinal cord and cerebrum of young cattle have also been recently reported.6,7 Similar to cases of PNET in humans, PNET with ependymal differentiation has developed in bovids that were 6 and 18 months old.11,12 The increasing incidence of PNETs in cattle, as reported in the veterinary medical
Morphologic Diagnosis and Case Summary Morphologic diagnosis and case summary: primitive neuroectodermal tumor (PNET) with ependymal differentiation in a cow. Comments Integumentary and subcutaneous neoplasia of cattle, including papilloma virus–associated cutaneous fibropapillomas and squamous cell carcinomas associated with solar radiation in whitefaced cattle, are common.1 Less common neoplastic conditions include peripheral nerve sheath tumors (eg, Schwannomas, neurofibromas, and neurilemomas)2–5 that may develop as nodular or varicose thickenings along nerve tracks or nerve roots.5 Primitive neuroectodermal tumors are a family of neoplasms that develop in human infants and children6 but have rarely been reported in cattle.4,7,8 They are formed from primitive neuroepithelial cells with a common embryonic appearance and are thought to develop from a multipotent stem cell capable of differentiation into neuronal, glial, and possibly mesenchymal cell lines.6 Primitive neuroectodermal tumor types include a variety of embryonal neoplasms, such as medulloblastomas, ependymoblastomas, neuroblastomas, and ganglioneuroblastomas as well as tumors classified as PNET with neuronal differentiation, PNET with ependymal cell differentiation, and PNET with glial differentiation.2,9 The specific classification of these 288
Vet Med Today: Pathology in Practice
Figure 2—Photomicrograph of a section of the multilobular, interconnected, expansile subcutaneous cranial mass in the Jersey cow in Figure 1. Neoplastic cells have moderate amounts of poorly defined, granular to vacuolated cytoplasm and very large, pleomorphic, round, oval or indented nuclei with ruffled nuclear membranes. The cells are divided into packets by a delicate fibrovascular stroma. H&E stain; bar = 50 µm.
Figure 3—Photomicrograph of a section of the subcutaneous cranial mass in the Jersey cow in Figure 1. Notice the strong cytoplasmic immunostaining for vimentin. Immunohistochemical stain; bar = 50 µm. JAVMA, Vol 244, No. 3, February 1, 2014
of pharmacokinetic studies16,17 provide additional evidence that SC injection of ceftiofur crystalline-free acida is well tolerated in cattle with minimal, transient inflammation. Immunohistochemical characterization is paramount for classification of PNETs. These tumors are of stem cell linage and are unique in their clinical signs and morphology. The exact cell of origin is often difficult to establish. a. EXCEDE, Ceftiofur crystalline free acid sterile suspension, Pfizer Pharmacia & Upjohn Co, New York, NY. b. Envision, Dako, Carpinteria, Calif.
References 1. Harris AM, Ginn PE. Integumentary system. In: Zachary JF, McGavin MD, eds. Pathological basis of veterinary disease. 5th ed. St Louis: Elsevier, 2012;1012–1015. 2. Koestner A, Higgins RJ. Tumors of the nervous system. In: Meuten DJ, ed. Tumors in domestic Figure 4—Photomicrograph of a section of the subcutaneous cranial mass in the animals. 4th ed. Ames, Iowa: Iowa State Press, Jersey cow in Figure 1. Notice the strong nuclear and cytoplasmic immunostain2002;714–716. ing for S-100. Immunohistochemical stain; bar = 50 µm. 3. Omi K, Kitano Y, Agawa H, et al. An immunohistochemical study of peripheral neuroblastoma, ganglioneuroblastoma, anaplastic ganglioma, schwannoma and neurofibroma in cattle. J Comp Pathol 1994;111:1–14. 4. Uchida K, Murakami T, Tometsuka T, et al. Peripheral neuroblastoma and primitive neuroectodermal tumor in Japanese black cattle. J Vet Med Sci 1998;60:871–875. 5. Zachary J. Nervous system. In: Zachary JF, McGavin MD, eds. Pathological basis of veterinary disease. 4th ed. St Louis: Elsevier, 2012;835–839. 6. Wippold FJ II, Perry A. Neuropathology for the neuroradiologist: rosettes and pseudorosettes. AJNR Am J Neuroradiol 2006;27:488–492. 7. Berrocal A, Montgomery DL, Mackie JT, et al. Primitive neuroectodermal tumor in the spinal cord of a Brahman crossbred calf. Vet Pathol 2005;42:834–836. 8. Lucas M-N, Nguyen F, Abadie J, et al. Cerebral primitive neuroectodermal tumor in a heifer. J Comp Pathol 2003;128:195–198. 9. Summers BA, Cummings JF, de Lahunta A. Tumors of the central nervous system. In: Veterinary neuropathology. St Louis: Mosby Year Book Inc, 1995;378–379. Figure 5—Photomicrograph of a section of the subcutaneous cranial mass in the Jersey cow in Figure 1. Notice the strong cytoplasmic immunostaining for 10. Haynes JS, Leininger JR. Malignant neuroblastoma in a cow. Vet Pathol 1984;21:610–612. glial fibrillary acid protein. Immunohistochemical stain. 11. Miyoshi N, Matsumoto M, Kawaguchi H, et al. Ependymoblastoma in a Japanese black heifer. J Vet Med Sci 2009;71:1393–1395. 12. Saunders GK. Ependymoblastoma in a dairy calf. Vet Pathol literature, is likely attributable to an increasing frequency 1984;21:528–529. of immunotyping of tumors in cattle. 13. Steinberg H, Peek SF, Nelson KM. Neuroblastoma with neuronal In the cow of the present report, the relationship of the differentiation in the spinal cord in an Aberdeen Angus heifer initial mass with the site of antimicrobial injection was likely calf. Vet Pathol 2006;43:193–197. incidental. Drug insert information on the safety of SC admin14. Ulrich R, Stan AC, Koch A, et al. Expression of brain-derived neua istration of ceftiofur crystalline-free acid at the base of the ear rotrophic factor and tropomysin-related kinase-B in a bovine jejuwas reviewed.15 Ceftiofur crystalline-free acida was adminisnal nodular ganglioneuroblastoma. Vet Pathol 2008;45:355–360. tered SC to 2,926 beef cattle for comparison of its pharmaco15. EXCEDE (ceftiofur crystalline free acid) sterile suspension [package insert]. New York: Pfizer Pharmacia & Upjohn Co, 2009. kinetics via 2 sites of administration (either the base of the ear 16. Hibbard B, Robb EJ, Apley MD, et al. Feedlot performance of or the middle third of the ear). Local tolerance of the SC injecsteers treated concurrently with ceftiofur crystalline-free acid tion was excellent, with no postinjection problems (excessive subcutaneously in the posterior aspect of the ear and a growthbleeding or leak back) in 99.8% of cattle. The drug insert inpromoting implant. Vet Ther 2002;3:252–261. formation reports that on days 28 and 56 after injection, 97.8% 17. Hibbard B, Robb EJ, Chester ST Jr, et al. Dose determination and 98.9% of the cattle had no observable swelling at the injecand confirmation for ceftiofur crystalline-free acid administration site.15 Similar findings following ceftiofur crystalline-free tion in the posterior aspect of the ear for control and treatment of bovine respiratory disease. Vet Ther 2002;3:22–30. acid administration in dairy cattle have been reported.1 Results JAVMA, Vol 244, No. 3, February 1, 2014
Vet Med Today: Pathology in Practice
289
