AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

March 2017

N-N10

 

Signalment (JPC 2131282):  112-week-old male Fischer 344 rat

 

HISTORY:  None.

 

HISTOPATHOLOGIC DESCRIPTION:   Cerebellum and brainstem:  Extending from the meninges and compressing the cerebellum and brainstem is an unencapsulated, well circumscribed, moderately cellular neoplasm composed of polygonal to spindle cells, exhibiting two cell morphologies, and generally arranged in sheets and occasional streams supported on a scant fibrovascular stroma.  The majority of the neoplastic cell population is composed of large polygonal to spindle cells with indistinct cell borders, abundant cytoplasm with numerous fine eosinophilic granules, and round to oval vesiculate nuclei with 1-2 distinct nucleoli.  Fewer neoplastic cells are smaller and more spindloid with indistinct cell borders, a scant to moderate amount of pale eosinophilic cytoplasm, and oval nuclei with dense chromatin and indistinct nucleoli.  The mitotic count is less than 1 per 10 HPF.  There are few hemosiderin-laden macrophages, primarily at the periphery of the neoplasm.  Within the underlying, compressed neuropil there is spongiosis with scattered hemorrhage.  The 4th ventricle is expanded up to 2mm (hydrocephalus).

 

MORPHOLOGIC DIAGNOSIS:  Cerebellum and brainstem: Granular cell meningioma, Fischer 344 rat, rodent.

 

SYNONYMS:  Granular cell tumor; Granular cell myoblastoma

 

GENERAL DISCUSSION: 

·         Occur over cerebral convexity, neurohypophysis, spinal nerve roots of dogs

·         Granular cell tumors (GCT) are rare in animals; most commonly occur in the  dog (tongue), horse (lung), and rat (meninges and distal female reproductive tract); also reported incats, birds, ferrets, and a rabbit 

·         Conflicting data regarding cell of orgin:

o   2013 Tox Path paper suggest GCTs in rats originate from a subset of macrophages associated with the meninges

o   A second Tox Path study suggests meningeal cells of neural crest origin and/or that all rat meningeal tumors might be related and derived from an arachnoidal cell precursor

o   Some researchers believe GCTs in the rat uterus are often incorrectly classified and are actually metrial gland proliferation

·         Most GCTs in other species are thought to be of neuroectodermal origin (specifically Schwann cell)Most are benign andrarely metastasize; may be locally invasive

·         In the rat, GCTs are the most common primary CNS tumor; most common in Sprague-Dawley, F344, Wistar, BN/Bi and Osborne Mendel rat strains

·         In the horse, GCT are the most common primary lung tumor 

 

TYPICAL GROSS FINDINGS: 

·         May occur in single or multiple nodules; small, white to tan, lobular, well circumscribed, poorly encapsulated, expansile neoplasm of meninges covering the superficial cerebellum, cerebrum, in the longitudinal cerebral fissure, or beneath the brain stem

·         Tumor size averages < 3 mm in diameter; can be up to 10 mm

·         Frequently compresses adjacent tissue; non invasive

 

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

·         Sheets and lobules of large, round, densely packed polygonal cells with abundant cytoplasm containing abundant tiny acidophilic granules

·         +/-  second morphology of fewer, smaller cells, with less cytoplasm and hyperchromatic nuclei

·         +/- perivascular cuffing with lymphocytes

 

ULTRASTRUCTURAL FINDINGS: 

·         GCT cells contain numerous membrane-bound phagolysosomes (secondary lysosomes with fragmented organelles) which peripheralize the nucleus (granularity of the cytoplasm is due to the lysosomes); there is a paucity of normal cytoplasmic organelles

 

ADDITIONAL DIAGNOSTIC TESTS: 

Special stains

·         PAS positive cytoplasmic granules that arediastase resistant, and alcian blue positive

·         Differing reports for granules staining with Luxol’s fast blue  

Immunohistochemistry:  (Conflicting reports regarding IHC are common)

·         Positive for vimentin (per JKP)

·         Positive for ubiquitin (per Meuten)

·         Negative for synaptophysin and GFAP (per JKP)

·         Positive for RCA-1 and Iba-1- microglial markers (per Tox Path articles)

·         +/- immunopositivity to cytokeratin, NSE, S-100

Cytology:

·         Monotonous population of cells with abundant amounts of pink to purple/magenta cytoplasmic granular material

 

DIFFERENTIAL DIAGNOSIS: 

For histologic findings in the rat:

·         Meningothelial meningioma with a granular cell component

·         Meningeal sarcoma:  Subclassified into fibrosarcomas or spindle cell sarcomas based on degree of cellular differentiation; these frequently invade the surrounding brain parenchyma unlike GCTs

·         Gemistocytic astrocytoma:  Neoplastic astrocytes have abundant eosinophilic cytoplasm and no PAS positive granules; these are invasive tumors and are GFAP and S-100 positive

Forhistologic findings in other species: (Ultrastructural and immunohistochemical properties are sufficient for differentiating granular cell tumors from oncocytomas and rhabdomyomas /sarcomas)

·         Oncocytoma:  Numerous usually enlarged mitochondria on EM; not positive with muscle immunohistochemical markers

·         Rhabdomyoma /sarcomas:  EM features are numerous mitochondria and Z lines; positive for myoglobin and desmin

 

For gross findings in the rat:

·         Pituitary adenoma:  Common in Sprague-Dawley and Wistar rats; usually pars distalis origin and prolactin producing

·         Pineocytoma:  Very rare in rats, at surface of brain compressing adjacent mesencephalon

 

COMPARATIVE PATHOLOGY: 

·         Dog:  Usually benign; occurs most often in the oral cavity, especially the tongue

·         Horse:  Most common primary lung tumor in the horse; occurs only in the lung; masses are typically associated with bronchi and may bulge into the lumen

·         Cat:  Reported in the tongue, vulva, and palate

·         Mouse:  Infrequent; found in the meninges, uterus, and subcutaneous tissue

·         Rabbit:  Single report of a testicular granular cell tumor

·         Humans:  Occurs in skin of the penis and scrotum;  most GCTs are derived from specialized pituicytes in the neurohypophysis or infundibulum

 

REFERENCES: 

1.     Bertrand L, Mukaratirwa A, Bradley A. Incidence of spontaneous central nervous system tumors in CD-1 mice and Sprague-Dawley, Han-Wister, and Wistar rats use din carcinogenicity studies. Toxicol Pathol. 2014;42(8):1168-73.

2.     Cantile C, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed.  Philadelphia, PA: Saunders Elsevier; 2016:397-398.

3.     Caswell JL, Williams KJ. Respiratory system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. Philadelphia, PA: Saunders Elsevier; 2016:498.

4.     Irizarry-Rovira AR, Lennox AM, Ramos-Vara JA. Granular cell tumor in the testis of a rabbit: Cytologic, histologic, immunohistochemical, and electron microscopic characterization. Vet Pathol. 2008;45:73-77.

5.     Koestern A, Higgins RJ. Tumors of the nervous system. In: Meuten DJ, ed. Tumors in Domestic Animals. 4th ed. Ames, IA: Iowa State Press; 2002:723-724.

6.     Mandara MT, Ricci G, Sforna M. A cerebral granular cell tumor in a cat. Vet Pathol. 2006;43:797-800.

7.     Markovits JE, Sahota PS.  Granular cell lesions in the distal female reproductive tract of aged Sprague-Dawley rats.  Vet Pathol. 2000;37:439-448.

8.     Meuten DJ. Tumors in Domestic Animals. 5th Ed. Wiley; 2017: 870-872.

9.     Mishra S, Kent M, Haley A, Platt S, Sakamoto K. Atypical meningeal granular cell tumor in a dog. J of Vet Diagn Invest. 2012;24(1):192-197.

10.  Misumori K, Stefanski SA, Maronpot RR. Nervous system. In: Jones TC, Mohr U, Hunt RD, eds.  Benign and Malignant Neoplasms, Meninges, Rat. Springer-Verlag, Berlin,GE. 1988:108-117.

11.  Miyajima R, Hasegawa K, Yasui Y, et. al. Nine cases of granular cell tumors in B6C3F1 mice. J Vet Med Sci. 2001;63:449-452.

12.  Picut CA, Swanson CL, Parker RF, Scully KL, Parker GA. The metrial gland in the rat and its similarities to granular cell tumors. Toxicol Pathol. 2009;37:474-480.

13.  Suzuki S, Uchida K, Jarda T, Nibe K, Yamashita O, Ono K, Nakayama H. The origin and role of autophagy in the formation of cytoplasmic granules in canine lingual granular cell tumors. Vet Pathol. 2015; 52(3): 456-64.

14.  Veit AC, Painter JT, Miller RA, et al. Characterization of uterine granular cell tumors in B6C3F1 mice: a histomorphologic, immunohistochemical, and ultrastructural study. Vet Pathol. 2008;45:654-662.

 

 


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