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Neurologic Disease Attributed to a Pituitary Adenoma in an Alpaca
Article first published online: 31 MAY 2012
Copyright © 2012 by the American College of Veterinary Internal Medicine
Journal of Veterinary Internal Medicine
Volume 26, Issue 4, pages 1073–1077, July-August 2012
How to Cite
Gilsenan, W.F., Habecker, P.L., Coyne, T.M. and Johnson, A.L. (2012), Neurologic Disease Attributed to a Pituitary Adenoma in an Alpaca. Journal of Veterinary Internal Medicine, 26: 1073–1077. doi: 10.1111/j.1939-1676.2012.00948.x
- Issue published online: 13 JUL 2012
- Article first published online: 31 MAY 2012
- Manuscript Accepted: 18 APR 2012
- Manuscript Revised: 20 MAR 2012
- Manuscript Received: 1 DEC 2011
hematoxylin and eosin
serum biochemical analysis
A 14-year-old 80-kg castrated male Huacaya alpaca was evaluated because of a gradual onset of behavioral changes. The owner had perceived decreased feed intake and abnormal behavior during the 7 days before admission. Decreased feed intake had progressed to complete inappetence by 3 days before admission. The alpaca often was separated from the herd and was not observed to lie down on its own. No improvement was appreciated after treatment with tulathromycin before admission (dosage unknown). The alpaca was known to be vaccinated annually for rabies and clostridial diseases and was dewormed regularly (medications, dosage, and frequency unknown).
On examination, the alpaca was obtunded and somnolent. Rectal temperature was normal (38.6°C). Heart rate was increased at 92 beats/min and respiratory rate was normal at 16 breaths/min. The alpaca was in good body condition. Mucous membranes were pink and capillary refill time was normal. Peripheral lymph nodes palpated normally. Appetite and gastrointestinal motility were poor. Urination and defecation were not observed during examination. The alpaca was ambulatory but had a tendency to walk compulsively and press its head and body against walls without directional preferences or circling. Cranial nerve reflexes, including menace response, were present and appeared within normal limits. Gait analysis indicated a slow pace with asymmetric hypermetria in the hindlimbs, with the left being more severely affected than the right. Spinal reflexes were difficult to assess but appeared normal. In sternal recumbency, the alpaca would lower its neck and press its nose against the ground. Initial neurologic evaluation localized disease to the prosencephalon.
Clinical laboratory tests evaluated at admission included CBC, serum biochemical analysis (SBA), fibrinogen concentration, and blood ammonia concentration. Marked leukocytosis (37,110 cells/μL; reference range, 7,500–20,900 cells/μL), neutrophilia (33,028 cells/μL; reference range, 3,130–15,254 cells/μL), and a regenerative left shift (band neutrophils, 371 cells/μL; reference range, 0–169 cells/μL) were observed on CBC. Abnormalities on SBA included hyperglycemia (281 mg/dL; reference range, 120–132 mg/dL), increased creatinine concentration (1.9 mg/dL; reference range, 1.4–1.7 mg/dL), hypophosphatemia (2.5 mg/dL; reference range, 4.9–7.2 mg/dL), hypoalbuminemia (3.3 g/dL; reference range, 3.7–4.2 g/dL), increased aspartate aminotransferase (AST) activity (365 U/L; reference range, 106–165 U/L), increased gamma-glutamyl transferase (GGT) activity (62 U/L; reference range, 5–20 U/L), and increased creatine kinase (CK) activity (2827 U/L; reference limits, 3–145 U/L). Serum fibrinogen concentration was increased (762 mg/dL; reference range, 100–500 mg/dL). Blood ammonia concentration was normal (16 μmol/L; references range, 0–30 μmol/L). An inflammatory or infectious disease process was suspected based on hyperfibrinogenemia and a leukocytosis characterized by neutrophilia with a regenerative left shift. Abnormalities on SBA were presumed to be secondary to the primary disease process. Hypophosphatemia and increased GGT activity may have been associated with a decrease in feed intake and increased serum creatinine concentration may have been associated with a decrease in water intake. Renal disease was a possible cause of hypophosphatemia, hypoalbuminemia, and increased creatinine concentration, but was considered less likely with normal serum concentrations of sodium, potassium, and chloride. Serum albumin concentration may have otherwise been decreased because of gastrointestinal loss or to an inflammatory process as a negative acute phase protein. The observed increase in muscle enzyme activity was attributed to rhabdomyolysis associated with transportation to the hospital. Hyperglycemia was presumed to be because of stress.
Lumbosacral cerebrospinal fluid collection yielded clear, colorless fluid. Fluid analysis indicated a normal nucleated cell count (3 cells/μL; reference range, 0–5 cells/μL) and total protein concentration (27 mg/dL; reference range, 0–50 mg/dL). No cytologic abnormalities were observed.
Based on history, physical examination, and laboratory results, the main differential diagnosis for neurologic signs was a space-occupying lesion. Intracranial abscess or neoplasia was considered most likely. Treatment for presumptive intracranial abscessation was initiated with ampicillin1 (22 mg/kg IV q 8 h) and sulfadimethoxine2 (55 mg/kg IV on day 1; 27.5 mg/kg IV q24h thereafter). Additional treatments included dexamethasone3 (0.1 mg/kg IV q24h) and thiamine hydrochloride4 (20 mg/kg SC q8h) to treat or prevent polioencephalomalacia. An infusion of mannitol5 (1 g/kg IV) was administered 2 hours after admission and resulted in mild but transient improvement in obtundation. A continuous rate infusion of IV crystalloid fluid6 was initiated (2.5 mL/kg/hr IV) with supplementation of dextrose5 (25 mg/mL), thiamine hydrochloride (1 mg/mL), and potassium chloride7 (20 mEq/L). Fenbendazole8 (50 mg/kg PO q24h) was added to the treatment course on day 2 because of the possibility of infection with Parelaphostrongylus tenuis.
The alpaca's neurologic status declined steadily after admission. It spent increased time in recumbency and became unable to stand or maintain sternal recumbency within 24 hours of admission. Opisthotonus was intermittently observed. An infusion of mannitol (0.5 g/kg IV) on day 2 did not result in any change in neurologic status. Because the alpaca's neurologic status continued to deteriorate despite therapy, euthanasia9 was performed on day 3 because of poor prognosis and humane concerns.
A complete postmortem examination was performed. Gross evaluation indicated the presence of an approximately 3 cm diameter peripituitary leptomeningeal mass. The mass extended dorsally and was compressing the hypothalamus, midbrain, thalamus, and cerebral hemispheres and was displacing but not compressing the optic nerve. The spinal cord was grossly normal. Mild diffuse hepatocellular lipidosis was detected and interpreted as secondary to inappetence and corticosteroid therapy. In addition, 500 mL of clear yellow to light red fluid was present in the thoracic cavity. Neither of these findings was thought to be directly related to the alpaca's primary clinical signs. There was no gross or histologic evidence of neoplasia in other organs. No lesions were observed in the thyroid or adrenal glands.
The mass was fixed in 10% neutral-buffered formalin, and representative tissue blocks were embedded in paraffin, sectioned, and stained with hematoxylin and eosin (H&E) and reticulin. Within the pars distalis there was a tumor comprised of epitheloid to spindle-shaped tumor cells with round to oval nuclei, stippled chromatin and amphophilic cytoplasm (Fig 1, Fig 2). The tumor cells were arranged in sheets with effacement of the normal lobular pituitary architecture, highlighted by diminished reticulin staining within the mass. Mitoses were rare and necrosis was not observed. The remaining uninvolved pars distalis, intermedia, and nervosa were unremarkable.
Immunohistochemical staining of the mass and normal pituitary tissue was performed to determine the nature of the adenoma. Stains used to confirm neuroendocrine origin included synaptophysin, chromogranin, and neuron-specific enolase (NSE). Neurofilament, S100, vimentin, and AE1/3 cytokeratin stains were used to characterize neuroectodermal, mesenchymal, and ectodermal elements. Hormonal markers, including prolactin, growth hormone (GH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH), were used to elucidate the endocrinologic function of the neoplasm. Synaptophysin stain was positive in the neoplastic cells and stained the pars distalis, intermedia, and nervosa. Chromogranin stain was positive in the neoplasm and pars distalis with focal, patchy staining of the pars intermedia. The NSE was positive in the neoplasm and pars distalis. The AE1/3 cytokeratin antigens were detected in sporadic cells in the neoplasm and normal pituitary tissue. The tumor cells were negative for the S100, vimentin, and neurofilament stains. The S100 immunoreactivity was detected in the pars nervosa and pars distalis. Vimentin staining was detected in the pars nervosa. No neurofilament antigens were detected in the normal pituitary tissue. The neoplasm was negative for all of the hormonal markers. The prolactin, GH, and ACTH stains showed an expected distribution in the pars distalis. The ACTH stain showed considerable background staining of the pars intermedia and pars nervosa. Lastly, the FSH, LH, and TSH stains were negative in the neoplasm and normal pars distalis.
Positive staining with synaptophysin, chromogranin, and NSE supported the diagnosis of pituitary adenoma, a tumor of neuroendocrine origin. The S100 is normally expressed in the adenohypophysis, but can be found less frequently in neoplastic tissue. The AE1/3 antibody recognizes high and low molecular weight cytokeratins, including cytokeratins 1–8, 10, 14–16, and 19, and is useful in identifying normal and neoplastic cells of epithelial origin. However, variable expression of cytokeratin polypeptides in normal and adenomatous pituitary tissue, as in the present tumor, is well-known. Vimentin is an intermediate filament expressed in mesenchymal derivatives, but its expression also is observed in glial elements and typically absent in pituitary adenomas. Neurofilament is used in diagnostic immunohistochemistry to differentiate neuronal from non-neuronal (glial) tissue.[4, 5] Neurofilament staining is largely negative in pituitary adenomas, with the exception of occasional tumor cells that exhibit nonspecific neuronal differentiation.
The morphologic and immunohistochemical features of the present adenoma were consistent with a nonfunctional chromophobe adenoma. Chromophobe adenomas may be functional, as in dogs with hyperadrenocorticism, or nonfunctional. The term more commonly used to designate nonfunctional chromophobe adenomas in neuropathology is null cell adenoma. Consistent with a null cell adenoma, the tumor was negative for all hormonal markers (Fig 3). However, absence of staining for FSH, LH, and TSH also was observed in the normal pituitary, which may reflect sampling a representative portion of pituitary without gonadotropes or thyotropes. Conversely, this absence of staining may be attributed to the inability of the antibodies to recognize nonhuman FSH, LH, and TSH. Nevertheless, overproduction of these hormones cannot be excluded, particularly because neoplasms of gonadotropic cell lines seldom manifest clinically with signs associated with hypersecretion of hormones.
Reported causes of intracranial neurologic disease in South American camelids include listeriosis, cerebrospinal nematodiasis caused by Parelaphostrongylus tenuis, polioencephalomalacia, viral encephalitides,[11-13] intracranial abscessation, and bacterial meningoencephalitis. Intracranial neoplasms, including teratoma, gemistocytic astrocytoma, histiocytic sarcoma, and meningioma, have been reported in alpacas and Bactrian camels.[16-18] Other differential diagnoses for forebrain disease in the South American camelids include extracranial disorders, such as hepatic encephalopathy and heat stress.
Pituitary gland neoplasms are common causes of intracranial neoplasia in humans, dogs, and horses, but are less frequently reported in cats.[19-21] Neoplasms of the cranial pituitary, or pars distalis, occur considerably more frequently than those of the caudal pituitary, or pars nervosa. The pars intermedia is a component of the pituitary gland that is vestigial in humans but functional in veterinary species; neoplasms of the pars intermedia have been reported in dogs and horses. The anatomy and physiology of the pituitary gland of alpacas has not been extensively studied. It has been described that its anatomy is similar to that of ruminants. Review of published literature suggests that pituitary neoplasia is very rare in ruminants.[23-28] The majority of these reports describe acidophil pituitary adenomas in sheep and goats,[23, 26, 28, 29] although chromophobe adenomas and carcinomas have been described in sheep and cattle.[24, 25, 27] Clinical signs attributed to pituitary adenomas in ruminants have included persistent hypoglycemia and central diabetes insipidus secondary to hypopituitarism, inappropriate lactation, and secondary diabetes mellitus.[23, 28, 29] Pituitary neoplasms are more typically benign adenomas rather than carcinomas, but both tumor types have the potential to invade adjacent tissues.
Morbidity associated with pituitary neoplasms, either functional or nonfunctional, can develop because of growth of the mass causing compression of adjacent structures within the cranium.[19, 20] The most commonly affected structures include the non-neoplastic regions of the pituitary gland, the hypothalamus, the thalamus, and the optic chiasm. Consequently, clinical signs relate to loss of function of the compressed structure and include hypopituitarism, diabetes insipidus, obtundation, and blindness.
Antemortem suspicion of a pituitary neoplasm would have aided in gathering additional information regarding the behavior of the mass. Computed tomography and magnetic resonance imaging have been used to diagnose pituitary masses in other species. These diagnostic modalities were considered, but financial constraints limited performing them. Serial measurements of urine specific gravity or a water deprivation test could have helped assess the function of the caudal pituitary gland and its production of antidiuretic hormone. Measurement of serum concentration of hormones produced by the cranial pituitary may have further characterized the nature of the tumor and identified subclinical pituitary abnormalities.
Further research regarding the normal anatomy and physiology of the pituitary gland of alpacas and llamas is warranted to aid in understanding the endocrinological behavior of pituitary gland neoplasms in these animals. Pituitary gland neoplasia should be considered a differential diagnosis for an alpaca presenting with blindness or clinical signs consistent with intracranial neurologic disease. The use of advanced diagnostic imaging techniques may aid in diagnosing pituitary tumors and assist in determining appropriate therapeutic interventions.
Di-Methox, Agri Laboratories Ltd, St. Joseph, MO
Agri Laboratories Ltd
Vedco, St. Joseph, MO
Hospira Inc., Lake Forest, IL
Normosol-R, Hospira Inc
Vet-One, Nova-Tech Inc., Grand Island, NE
Panacur, Intervet Inc., Millsboro, DE
Vet-One, MWI, Meridian, ID
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- 19Anterior pituitary. In: Larsen PR , Kronenberg HM , Melmed S , Polonsky KS , eds. Williams Textbook of Endocrinology, 10th ed. Philadelphia, PA: Saunders; 2003: 181–200., .
- 20Brain disease. In: Ettinger SJ , Feldman EC , eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat, 7th ed. St. Louis, MO: Saunders; 2010: 1445., .
- 21Equine endocrine and metabolic diseases. In: Smith BP , ed. Large Animal Internal Medicine, 4th ed. St. Louis, MO: Mosby-Elsevier; 2009: 1339–41..
- 22Endocrine system. In: Fowler M , ed. Medicine and Surgery of South American Camelids, 3rd ed. Ames, IA: Wiley-Blackwell Publishing; 2010: 360..
|jvim948-sup-0001-VideoS1.wmv||video/wmv||9173K||Video S1. Depiction of alpaca's obtunded mentation at admission. Windows Media Player file (.wmv). (71 seconds).|
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