JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

February 2023

N-N08

 

Signalment (JPC #1843726): 2.5‑year‑old female Samoyed  

 

HISTORY: The dog was anorexic for 10 days. Exploratory surgery revealed a retroperitoneal mass that surrounded the kidney but did not invade the renal parenchyma.

 

HISTOPATHOLOGIC DESCRIPTION: Retroperitoneal mass (per contributor): Extending to all borders is a multilobulated, infiltrative, densely cellular neoplasm separated by dense, interlacing bands of fibrous connective tissue. Neoplastic cells exhibit multiple histomorphologies, including neuroblastic cells and ganglion cells admixed with areas of neurofibril morphology. Neuroblastic cells predominate, and have blastemal cell morphology characterized by small, round to elongate cells with indistinct borders, scant eosinophilic fibrillar cytoplasm, and round to ovoid, hyperchromatic nuclei with finely-stippled chromatin and indistinct nucleoli. Neuroblastic cells are arranged in indistinct streams and solidly cellular nodules, and often palisade around blood vessels (pseudorosettes) or areas of eosinophilic fibrillar neural tissue (Homer Wright rosettes) on a variable fibrovascular to eosinophilic, finely fibrillar neural stroma. Mitoses average 4 per HPF. Ganglion cells are either individualized or occur in small clusters, often on the periphery of or within nodules of blastemal cells. These cells are variably differentiated; well-differentiated ganglion cells have distinct cell borders, abundant eosinophilic cytoplasm that occasionally contains peripheralized basophilic granules (Nissl substance), round to oval, often eccentric nuclei that are either vesiculate or have finely stippled chromatin, and one to two prominent nucleoli. Less well-differentiated ganglion cells have a high nuclear to cytoplasmic ratio and are sometimes binucleated. There is mild anisocytosis and anisokaryosis, and the mitotic count in this population is less than 1 per 10 HPF. Mixed with and separating islands of blastemal and ganglion cells are indistinct bundles of neurofibrils reminiscent of peripheral nerves. There is multifocal hemorrhage, fibrin, edema, and necrosis. There are many hemosiderin-laden macrophages within the thick fibrous interlobular septa mixed with extracellular hematoidin pigment, hemorrhage, and rare multinucleated giant cells. 

 

MORPHOLOGIC DIAGNOSIS: Retroperitoneal mass (per contributor):  Ganglioneuroblastoma, Samoyed, canine.

 

GENERAL DISCUSSION:

• Neuroblastic tumors (NTs) are rare embryonal neoplasms
• Peripheral nervous system (PNS) NTs are usually located in the adrenal medulla or sympathetic ganglia (Meuten)
• PNS NTs form a continuum of histologic features based on degree of differentiation: 

• Neuroblastoma (neuroblast cells only): most primitive and most aggressive
• Ganglioneuroblastoma(ganglion cells, schwann cells, neuroblasts and nerve fibers): moderately differentiated
• Ganglioneuroma (ganglion cells, schwann cells and nerve fibers): most differentiated, relatively benign

 

PATHOGENESIS:

• Central nervous system NTs rarely occur; derived from neural epithelial cells and differentiate along neuronal lines (JKP, Meuten, Romano JVDI 2021)

 

TYPICAL CLINICAL FINDINGS:

• Occur in young animals
• Ganglioneuromas are benign, often incidental findings (Meuten)
• Neuroblastomas are malignant, with rapid spread and metastasis to lymph nodes, liver, brain, bone marrow, spleen (Meuten)
• Clinical signs depend on primary site and disease extent; often nonspecific (anorexia, lethargy)

 

TYPICAL GROSS FINDINGS:

• Most arise in the cranial or spinal nerve ganglia, adrenal medulla, or sympathetic ganglia of the autonomic nervous system in the mediastinum or retropleural or retroperitoneal space
• Multicentric or solitary
• Generally large, gray, fleshy, firm, poorly-circumscribed, multilobular masses
• +/- areas of necrosis, hemorrhage

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Three components in variable quantities depending on degree of differentiation:
  • Neuroblastic component: Primitive, small, rounded cells that resemble lymphocytes with hyperchromatic nuclei and scant cytoplasm; may form pseudorosettes or Homer-Wright rosettes
    • Predominant morphology in neuroblastoma
  • Ganglion component: Variable maturation
    • Mature forms: Large, eccentric, vesicular nucleus, Nissl substance
    • Immature forms: Higher N:C ratio, may be binucleate
    • Present in ganglioneuroblastoma or ganglioneuroma
    • Generally absent in neuroblastoma
  • Schwannian component: Schwann cells, nerve fascicles, and mature Schwannian stroma
• Background consists of tangled, nonmyelinated nerve fibers and fibroblast-like collagen-producing cells, prominent fibrous connective tissue stroma

 

ULTRASTRUCTURE:

• Numerous cytoplasmic dense core neurosecretory granules 
• Stacks of rough endoplasmic reticulum
• Bundles of neurofilament-containing nonmyelinated nerve fibers

 

ADDITIONAL DIAGNOSTIC TESTS:

• Ganglion cells: Positive for synaptophysin, chromogranin A
• Neuroblasts, ganglion cells: 

• Positive: Neurofilament (NF) and neuron-specific enolase (NSE)
• Negative: glial fibrillary acidic protein (GFAP), cytokeratin

 

DIFFERENTIAL DIAGNOSIS:

• Pheochromocytomas also arise in the adrenal medulla but have distinct histologic morphologies; pheochromocytomas may arise alongside NTs from same progenitor cell differentiating in two directions (JKP Vol 3)
• Neuroblastomas have “small blue round tumor” morphology (high N:C ratio, hyperchromatic nuclei) which may be mistaken for lymphoma
• Olfactory neuroblastomas are a distinct and unrelated entity with a similar morphology; thought to arise from different cell line – the basal progenitor cells of olfactory epithelium in the nasal cavity and on the cribriform plate
• Neuroblastomas can arise anywhere in the CNS are difficult to distinguish from medulloblastomas

 

COMPARATIVE PATHOLOGY:

• NTs are documented in humans, dogs, cats, cattle, horses, pigs, birds, and laboratory animals
• Cattle: Ganglioneuromas often contain melanin
• Humans: Neuroblastomas are the most common neoplasm of childhood, (Arenas-Gamboa JCP 2014); usually diagnosed in patients < 5 years old (Romano JVDI 2021)

 

REFERENCES:  

1. Arenas-Gamboa AM, Tanabe M, Edwards J, Storts R. Peripheral neuroblastomas in dogs: A case series. J Comp Pathol. 2014;150: 362-365.
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: Elsevier; 2016:401-402.
3. Higgins RJ, Bollen AW, Dickinson PJ, Siso-Llonch S. Tumors of the nervous system. In: Meuten DJ, ed. Tumors in Domestic Animals. 5th ed. Ames, IA: Iowa State Press; 2017:856-858.
4. Miller AD, Porter BF. Nervous System. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022: 954-955.
5. Miller MA. Endocrine System. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:795.
6. Romano AM, Frank CB. Olfactory ganglioneuroblastoma in a dog: case report and literature review. J Vet Diagn Invest. 2021; 33(5): 1013-1017.
7. Rosol TJ, Grone A. Endocrine Glands. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA: Elsevier; 2016:353-354.
8. Schmidt RE, Reavill DR, Phalen DN Pathology of Pet and Aviary Birds. 2^nd ed. Ames, IO: Wiley-Blackwell. 2015; 170, 232, 234-235

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