JPC SYSTEMIC PATHOLOGY
Signalment (JPC #1849481): 5-year-old female Afghan hound
HISTORY: This dog was stuporous, depressed and unable to walk for 5 days prior to death. Dysphagia was noted for 4 days before death. At necropsy, a spherical mass approximately 1 cm in diameter occupied the third ventricle, displacing adjacent brain tissue. The lateral ventricles were expanded.
HISTOPATHOLOGIC DESCRIPTION: Brain, thalamus and third ventricle: Arising from the choroid plexus, filling the third ventricle and compressing and invading the adjacent neuropil is a 7mm diameter, unencapsulated, expansile neoplasm composed of columnar cells 1-3 cell layers thick, forming numerous arborizing papillary projections supported by a moderately dense fibrovascular stroma. Neoplastic cells have indistinct borders and a moderate amount of granular eosinophilic cytoplasm. Nuclei are round to oval with finely stippled chromatin and 1 variably distinct magenta nucleolus. Mitoses average 1/10 HPFs. There is moderate anisokaryosis. Multifocally the stroma is mildly expanded by clear space (edema), hemorrhage, and fibrin, with rare lymphocytes, plasma cells, and hemosiderin-laden macrophages. Between neoplastic papillary projections, there are many lamellated pale basophilic concretions up to 100 um in diameter (psammoma bodies). The adjacent neuropil is vacuolated and disorganized with mild gliosis, occasional reactive astrocytes, numerous small caliber blood vessels lined by plump reactive endothelium, and perivascular hemorrhage.
MORPHOLOGIC DIAGNOSIS: Brain, third ventricle: Choroid plexus papilloma, Afghan hound, canine.
· Choroid plexus epithelial cells are specialized ependymal cells that secrete CSF from their microvillar brush border and serve as part of the blood-CSF barrier via specialized tight junctions (zonulae occludenes)
· Choroid plexus tumors (CPTs) are derived from the neuroepithelium of the choroid plexus
· Uncommon in dogs (10% of primary intracranial CNS tumors), rare in horses and oxen, and very rare in other species
· Golden retrievers may be overrepresented
· Usually seen in middle-aged to older dogs
· Usually in the fourth ventricle but can be in third and lateral ventricles
· Obstructive hydrocephalus is a common complication
· The World Health Organization (WHO) classifies human choroid plexus tumors (CPTs) into 3 different grades (a similar scheme is has recently been suggested in dogs):
· Choroid plexus papilloma (CPP, grade I)
· Atypical choroid plexus papilloma (atypical CPP, grade II)
· Choroid plexus carcinoma (CPC, grade III)
· A recent study found that many canine CPTs contain multifocal, localized areas with a switch from membranous (normal) to cytoplasmic/nuclear (aberrant) expression of E-cadherin
· Decreased or aberrant expression of E-cadherin may remove the regulatory effect of contact inhibition on proliferation, thus allowing an escape from growth control signals resulting in unrestricted replication of tumor cells; however, this finding did not correlate with tumor metastasis and so it is probably not useful for grading/prognosis of CPTs
· Mitotic index, cell density, and multilayering of papillae are the main significant, histologic markers of malignancy for grading CPTs in dogs
· Intraventricular spread within ventricular system and subarachnoid space may not be indicators of malignancy
TYPICAL CLINICAL FINDINGS:
· CNS signs - spastic tetraparesis, positional nystagmus, head tilt, vomiting, seizures
· CSF may be bloody or contain increased protein, neoplastic cells are not usually evident
· CPC usually has a higher CSF protein concentration than CPP
TYPICAL GROSS FINDINGS:
· Well-defined, grayish white to red, granular or cauliflower-like masses that grow into the ventricle, cerebellopontine angle, or surrounding neural parenchyma
· Hydrocephalus (due to CSF obstruction), brain swelling or hemorrhage may occur
TYPICAL LIGHT MICROSCOPIC FINDINGS:
· Choroid plexus papilloma (grade I; CPP): Regularly arborizing exophytic masses lined by a single layer of uniform cuboidal to columnar epithelium; mitoses are rare; mild anisokaryosis may be evident
· Atypical choroid plexus papilloma (grade II; atypical CPP): Intermediate grade between CPP and CPC; not universally recognized in dogs; atypical CPP may exhibit increased cellular density, nuclear pleomorphism, higher mitotic activity(≥2 per 10 HPF), and areas of solid growth
· Choroid plexus carcinoma (grade III; CPC): Piling up of epithelium, invasion of adjacent neuropil, and/or anaplastic features (nuclear atypia, loss of architecture, transition to cellular sheets, increased mitotic rate (>5 per 10 HPF), necrosis)
· All CPT grades may metastasize throughout the ventricular system or subarachnoid space with implantation in the ependymal or meninges respectively; even histologically benign CPP can behave as aggressive carcinomas with widespread metastasis
· There is frequent mineralization and formation of psammoma bodies
· Juxtaluminal tight junctions, microvilli, and apical ciliary basal bodies (but cilia are rare)
· Lateral cell surfaces lack interdigitations
· Cells rest on a continuous basal lamina
ADDITIONAL DIAGNOSTIC TESTS:
· Vimentin positive; often positive for cytokeratin; GFAP variable (recent study found that 55% are GFAP positive); laminin positive; S-100 protein negative
· E-cadherin positive (this can help differentiate from ependymoma which is E-cadherin negative)
· E-cadherin expression not significantly different for different grades
· N-cadherin strongly positive in normal choroid plexus and grade I tumors; weak staining in high grade CPT
· Doublecortin (marker of highly invasive brain tumors): Negative
· Ki-67 expression may be increased in higher tumors
· Kir7.1 can distinguish CPT from other primary brain tumors and cerebral metastatic carcinoma
· Ependymoma: May occur within ventricles; neoplastic cells form true rosettes on a scant fibrillar stroma; lack papillary projections
· Metastatic adenocarcinoma/carcinoma: Adenocarcinoma/carcinoma metastasis to the brain is uncommon in animals
· Choroid plexus cholesteatomas in horses; most often in 4th ventricle, macrophages with cholesterol clefts
· Rarely reported in cats, goats, horses, cattle, and rats
· Recently reported in a beluga whale
1. Burger PC, Scheithauer BW. Tumors of neuroglia and choroid plexus. In: Burger PC, Scheithauer, eds. Tumors of the Central Nervous System. Fascicle 7. 4th series. Washington, DC: Armed Forces Institute of Pathology; 2007:33-208.
2. Cantile C, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:401.
3. Choi EJ, Sloma EA, Miller AD. Kir7.1 immunoreactivity in canine choroid plexus tumors. J Vet Diagn Invest. 2016; 28(4):464-468.
4. Higgins RJ, Bollen AW, Dickinson PJ, Sisó-Llonch S. Tumors of the nervous system. In: Meuten DJ, ed. Tumors in Domestic Animals. 5th ed. Ames, IA: Wiley Blackwell; 2017:853-855.
5. Frosch MP, Anthony DC, De Girolami U. The central nervous system. In: Kumar V, Abbas AK, Fausto N, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Philadelphia, PA: Elsevier Saunders; 2015:1311.
6. Koestner A, Bilzer T, Fatzer R, Schulman FY, Summers BA, Van Winkle TJ. Histological classification of tumors of the nervous system of domestic animals. In: Schulman FY, ed. World Health Organization International Histological Classification of Tumors of Domestic Animals. Vol IV, 2nd Series. Washington, DC: Armed Forces Institute of Pathology, American Registry of Pathology; 1998: 23-24.
7. Koestern A, Higgins RJ. Tumors of the nervous system. In: Meuten DJ, ed. Tumors in Domestic Animals. 4th ed. Ames, IA: Iowa State Press; 2002:709-711.
8. Lohr CV. One hundred two tumors in 100 goats (1987-2011). Vet Pathol. 2012; 50(4):668-675.
9. Miller AD, Zachary JF. Nervous system. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier Mosby; 2017:873-874.
10. Nentwig A, Higgins RJ, Francey T, Doherr M, Zurbriggen A, Oevermann A. Aberrant E-cadherin, b-catenin, and glial fibrillary acidic protein (GFAP) expression in canine choroid plexus tumors. J Vet Diagn Invest. 2012;24(1):14-22.
11. Ortloff A, Neumann J, Illanes O. Concurrent gliosarcoma and choroid plexus carcinoma in a cow. J Comp Pathol. 2017; 156:25-28.
12. Reginato A, Girolami D, et al. E-cadherin, N-cadherin expression and histologic characterization of canine choroid plexus tumors. Vet Pathol. 2016; 53(4):788-791.
13. Thomas C, Mergl J, et al. Choroid plexus papilloma in a beluga whale (Delphinapterus leucas). J Vet Diagn Invest. 2016; 28(4):461-463.
14. Westworth DR, Dickinson PJ, Vernau W, et al. Choroid plexus tumors in 56 dogs (1985-2007). J Vet Intern Med. 2008;22:1157-1165.
15. Zachary JF. Nervous system. In: McGavin MD, Zachary JF eds. Pathologic Basis of Veterinary Disease. 5th ed. St. Louis, MO: Mosby Elsevier; 2012: 773, 778, 836-837.