JPC SYSTEMIC PATHOLOGY
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 bands of fibrous connective tissue. Neoplastic cells exhibit multiple histomorphologies. Neuroblastic cells predominate, and are round to elongate and arranged in vague streams and solidly cellular nodules on a fibrovascular stroma to eosinophilic finely fibrillar material (neural tissue). Blastemal cells often palisade along blood vessels (pseudorosettes) or areas of eosinophilic fibrillar neural tissue. Cells have indistinct cell borders, scant eosinophilic fibrillar cytoplasm, and round to ovoid hyperchromatic nuclei with finely-stippled chromatin and indistinct nucleoli. 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 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. There is mild anisocytosis and anisokaryosis, and the mitotic count in this population is less than 1 per 10 HPF. Well-differentiated ganglion cells have an eccentric nucleus with abundant cytoplasm and Nissl substance, whereas less well-differentiated cells have a high nuclear to cytoplasmic ratio and are sometimes binucleated. Admixed with and separating islands of blastemal and glanglion cells there are vague, poorly-discernible bundles of neurofibrils, reminiscent of peripheral nerves. There is multifocal hemorrhage, fibrin, edema, and necrosis. Within the thick fibrous septa between lobules, there are many hemosiderin-laden macrophages, admixed with extracellular hematoidin pigment, hemorrhage, and rare multinucleated giant cells.
MORPHOLOGIC DIAGNOSIS: Retroperitoneal mass (per contributor): Ganglioneuroblastoma, Samoyed, canine.
· Neuroblastic tumors of the peripheral nervous system (PNS) are rare in humans, domestic animals (i.e. dogs, cats, cattle, horses, pigs), and laboratory animals
· Thought to originate from a neural crest stem cell, thus accounting for a wide spectrum of morphologic variants
· Ganglioneuroblastoma is intermediate in the spectrum between the relatively benign ganglioneuroma and the undifferentiated neuroblastoma
TYPICAL CLINICAL FINDINGS:
· Often an incidental finding
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, retropleural or retroperitoneal space
· Can be multicentric or solitary
· Generally large, gray, fleshy, firm, poorly-circumscribed, multilobular masses
· +/- areas of necrosis, hemorrhage
TYPICAL LIGHT MICROSCOPIC FINDINGS:
· Consists of (1) a neuroblastic component, (2) individual multipolar ganglion cells at various degrees of differentiation, and (3) a mature Schwannian stromal component:
· Neuroblastic component:
· Primitive, small, rounded cells that resemble lymphocytes with hyperchromatic nuclei and scant cytoplasm
· May form pseudorosettes or rosettes
· Present in distinct macroscopic nodules (nodular ganglioneuroblastoma) or multiple microscopic foci (intermixed ganglioneuroblastoma)
· Ganglion component:
· Vary in maturational stage:
· Mature forms: Large, eccentric, vesicular nucleus, Nissl substance
· Immature forms: Higher nuclear:cytoplasmic ratio, may be binucleate
· Interspersed throughout the tumor or in small aggregates
· Schwannian component:
· Schwann cells, nerve fascicles
· Mature Schwannian stroma
· Background consists of tangled, nonmyelinated nerve fibers and fibroblast-like collagen-producing cells, prominent fibrous connective tissue stroma
· Satellite cells are not prominent
· In adrenal medulla can differentiate into two cell lines: Pheochromocytoma and ganglioneuroma
· Numerous cytoplasmic dense core neurosecretory granules
· Stacks of rough endoplasmic reticulum
· Bundles of neurofilament-containing nonmyelinated nerve fibers
ADDITIONAL DIAGNOSTIC TESTS:
· Neuronal cells (neuroblasts, ganglion cells): Neurofilament (NF) and neuron-specific enolase (NSE) positive; glial fibrillary acidic protein (GFAP) and cytokeratin negative
· Ganglion cells: Positive for synaptophysin and chromogranin A
· Recent report of a nodular ganglioneuroblastoma in the jejunum of an ox:
· Neuroblastic cells were reportedly S-100 positive but NF negative
· Ganglion cells were positive for NF, NSE, CGA, brain-derived neurotrophic factor (BDNF), and tropomyosin-related kinase-B (Trk-B)
· Schwann cells are S-100 positive; fibroblasts are vimentin positive
Other neuroblastic tumors of the PNS:
· Less primitive / more differentiated than ganglioneuroblastoma
· Nests of large ganglion cells in varying degrees of differentiation, Schwann cells and nerve fibers; lacks the neuroblastic component of ganglioneuroblastoma
· Common sites include neuraxis, autonomic and cranial nerve ganglia, and adrenal medulla
· Benign behavior; low mitotic rate
· Counterpart in the CNS is the gangliocytoma
· More primitive / less differentiated than ganglioneuroblastoma
· Sheets of poorly-defined cells round cells with deeply-basophilic, round nuclei and scant cytoplasm; lacks ganglion cells
· Occasionally form pseudorosettes or rosettes
· Can occur in any part of CNS, and is more common (albeit still rare) in CNS than PNS
· In PNS, sites include adrenal medulla and sympathetic ganglia
· May metastasize (local lymph nodes and liver)
Neuronal and mixed neuronal glial tumors of the CNS:
· Gangliocytoma: Extremely rare; predilection for cerebellum; morphology as for the ganglioneuroma of the PNS; NSE and synaptophysin positive
· Ganglioglioma: Rare; composed of neoplastic neuronal and neoplastic GFAP-positive astrocytic cells
· Olfactory neuroblastoma (esthesioneuroblastoma):
· Rare neoplasm arising from olfactory neuroepithelium, residual neural crest cells, or local components of the dispersed neuroendocrine system
· Most are reported in dogs and cats; arise in ethmoturbinate region and may penetrate the cribriform plate and infiltrate the cerebral cortex
· Histomorphology as described for neuroblastoma, above
· May be confused with lymphoma or undifferentiated carcinoma if important diagnostic features (i.e. palisades around blood vessels and rosette and/or pseudorosette formation) are not present
· Stain for both neuronal and epithelial immunohistochemical markers (e.g. NSE and cytokeratin)
· In cats, feline leukemia virus has been identified in association with olfactory neuroblastoma, but causal role has not been established
Embryonal tumors of the CNS:
· Medulloblastoma (cerebellar primitive neuroectodermal tumor [PNET]): Rare; mostly reported in young dogs and calves; thought to arise from undifferentiated precursors of the cerebellar cortex; classic “carrot-shaped” cells that form perivascular palisades and pseudorosettes; termed “PNET” rather than medulloblastoma when present in sites other than the cerebellum; NSE and synaptophysin positive, +/- GFAP positivity
· Neuroblastoma: As described above; rare; similar to medulloblastoma but cells are round rather than “carrot-shaped” and are GFAP negative
· Thoracolumbar spinal tumor of young dogs (spinal nephroblastoma): Solitary intradural, extramedullary neoplasm in young, large-breed dogs (males, German shepherd dogs overrepresented); occurs between 10th thoracic and 2nd lumbar segment; originates from renal primordium; consists of blastemal, mesenchymal, and epithelial components forming primitive glomeruli, abortive tubules, and a loose spindle-cell stroma; stains positive for cytokeratin and negative for glial and neuronal markers
· Pineal tumors: Benign pineocytoma; malignant pineoblastoma; rare; reported in horses, cattle, and dogs; diagnosis depends on site of tumor and replacement of pineal body
· WISTAR and F344 Rats: Adrenal medullary neuroblastomas are rarely seen but are often associated with pheochromocytomas (these are termed complex pheochromocytomas); may be hamartomatous malformations
· SD Rats: Ganglioneuromas of the thyroid gland, unrelated to treatment or sex, occurred at an incidence of 7.2% in SD rats during a two-year carcinogenicity bioassay; tumors had coincidental C-cell proliferations within the same or in the contralateral lobe and were composed of large ganglion cells and/or neuronal precursors in a matrix of neurites and Schwann cells; the tumors were reported to react positively for calcitonin, S100 protein, and NFP
· Furthermore, there were single cases described in the pituitary gland of an SD-derived rat and an aged F344 rat
· Hamster: Ganglioneuroma may occur as a spontaneous neoplasm
· B6C3F1 mouse: Shown to arise from the trigeminal ganglion
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