JPC SYSTEMIC PATHOLOGY
Signalment (JPC 1948327): Adult Holstein cow
HISTORY: This cow was treated for toxic mastitis and recumbency. There was no improvement over a 5 day period. Cervical nerves were firm and 4 to 5 cm in diameter. The brachial plexus was thickened. The cervicothoracic ganglia were 6.0 x 6.0 x 8.0 cm, firm, and white. Intercostal nerves were thickened with multiple 2 to 3 cm nodules. The vagus nerve was 4 cm in diameter and epicardial nerves were prominent. The celiac ganglion was 15 cm in diameter.
HISTOPATHOLOGIC DESCRIPTION: Brachial plexus (per contributor): Expanding the perineurium and displacing adjacent nerve fibers is an up to 1.5 cm diameter, well circumscribed, densely cellular, expansile neoplasm composed of spindle cells arranged in a storiform pattern supported by a fine fibrovascular stroma. Neoplastic cells form variably dense, short, interlacing streams and bundles, and occasionally whorl around blood vessels. Neoplastic cells have indistinct borders, a small amount of microvacuolated, eosinophilic fibrillar cytoplasm, and an oval to elongate vesiculate nucleus with 1 to 2 variably distinct nucleoli. The mitotic count is less than 1 per 10 HPF and there is scattered single-cell necrosis. Multifocally, there are low numbers of lymphocytes, neutrophils, and macrophages scattered throughout the neoplasm and concentrated around blood vessels where they are admixed with fibrin and small amounts of necrotic debris.
MORPHOLOGIC DIAGNOSIS: Brachial plexus (per contributor): Peripheral nerve sheath tumor, Holstein, bovine.
SYNONYMS: Bovine neurofibromatosis; neurofibroma or neurofibrosarcoma; Schwannoma or malignant Schwannoma; neurilemmoma
· In humans, peripheral nerve sheath tumors (PNSTs) are subclassified as neurofibroma or Schwannoma based on the presumed cell of origin; Schwann cells are also known as neurolemmal cells
· In domestic animals, there is no universally agreed upon classification system for PNSTs and they are "lumped" or "split" depending on the preference of the educational institution; the principal cell is probably of Schwann or perineural origin
· "Benign PNST of the skin and subcutis" (typically “lumped” into the classification of soft tissue sarcoma) is common in dogs and is discussed elsewhere
· Benign PNST resembling Schwannoma in humans is extremely rare in dogs and cats but is often seen in cattle as an incidental finding at the time of slaughter
· Because PNST in cattle affects multiple nerves, the condition is commonly called neurofibromatosis, but this should not be confused with neurofibromatosis (NF) in humans, which is a distinct clinical entity with two subtypes (NF1 and NF2)
· The bovine neoplasm occurs most often in mature animals, and occasionally calves
· Malignant PNST is most commonly seen in dogs (rarely in cats) and usually involves the brachial or lumbar plexus; the most commonly affected cranial nerve in dogs is cranial nerve V (trigeminal nerve); it can also involve any of the spinal nerve roots
· Equine PNSTs are most common on the eyelids
· PNST is uncommon in other domestic and laboratory animal species
· Unknown – a neu oncogene point mutation has been reported in malignant Schwannomas and malignant PNSTs in several domestic species
TYPICAL CLINICAL FINDINGS:
· Often an incidental gross finding at slaughter
TYPICAL GROSS FINDINGS:
· The bovine neoplasm often involves the brachial plexus and intercostal nerves; additionally, autonomic nerves of the liver, heart (epicardial plexus), mediastinum, and thorax can be affected; in cattle, the most commonly affected cranial nerve is cranial nerve VIII (vestibulocochlear nerve); the skin is involved infrequently
· Olfactory and optic nerves are NOT affected because they do not have Schwann cells
· Nerves are thickened, firm, whitish gray, and may have yellow to gray nodules
· Ganglia may be enlarged and appear lobulated on cut section
TYPICAL LIGHT MICROSCOPIC FINDINGS:
· Neoplastic spindle cells are arranged in a storiform pattern with bundles, palisades, and whorls; the hallmark of PNSTs in humans is the classic Antoni A pattern with Verocay bodies; this is rare in tumors of domestic species
· The Antoni A pattern is characterized by elongate cells arranged in short interlacing streams and bundles in areas of moderate to high cellularity within a scant eosinophilic matrix
· The Antoni B pattern is characterized by elongate cells arranged in a loose meshwork in less densely cellular areas within abundant myxomatous matrix
· Verocay bodies are characterized by stacked parallel rows of elongate cells with palisading nuclei (nuclear regimentation) and anuclear eosinophilic fibrillar material
· Cartilaginous and osseous metaplasia occurs infrequently
· Schwann cells: continuous basal lamina with type IV collagen, 10 nm diameter intermediate filaments and pinocytotic vesicles, and extracellular long-spaced collagen ("Luse" bodies)
ADDITIONAL DIAGNOSTIC TESTS:
· PNSTs may be positive for vimentin, glial fibrillary acidic protein (GFAP), laminin and collagen IV
· Benign PNSTs are generally positive for vimentin and S-100, while anaplastic or heterogenous malignant PNSTs tend to be negative for S-100
For histologic findings:
· Fibroma/fibrosarcoma: Lack palisades and whorls, have more pronounced collagenous stroma
· Leiomyoma/leiomyosarcoma: Lack palisades and whorls, elongate nuclei with blunt ("cigar-shaped") ends
Tumor in bovine heart (gross):
· Myocardial adenomatoid tumor- in the left ventricular myocardium, adjacent to the epicardium, and composed of epithelioid cells that formed cords and tubules, and were immunoreactive for pan-cytokeratins, cytokeratin 5/6, vimentin, calretinin, Wilms' tumor 1 suppressor gene, and CD30 antigen
· PNST of the skin and subcutis (hemangiopericytoma) is common; typically classified as soft tissue sarcoma
· Malignant PNST is most commonly seen in dogs
· There is a recent report of a primary splenic PNST in a dog
· Acoustic Schwannoma (involving cranial nerve VIII) has been reported in a dog
· A recent report of cutaneous PNST in dogs showed relatively consistent expression of vimentin, laminin, PGP 9.5, and NSE as well as variable expression of S-100 and collagen IV
· Olig-2 and nerve growth factor receptor (NGFR) may be useful in separating malignant PNST from perivascular wall tumors
· Schwannomas are the most common primary cardiac tumor
· Spontaneous intraocular and orbital malignant Schwannomas have been reported, but are extremely rare
· A spontaneous uterine cervical tumor in a Fischer 344 rat was recently reported with cell populations that included both benign and malignant PNSTs; the benign PNST cells were identified as having a myofibroblastic origin
· Damselfish neurofibromatosis
· Bicolored damselfish develop multiple cutaneous neurofibromas
· A viral etiology is likely
· Used as animal model for human neurofibromatosis 1 (NF1)
· Lake trout
· Identified but etiology unknown
· Used as a model for malignant peripheral nerve sheath tumors
· Cat: PNSTs most frequently occur on the head, neck, and distal limbs; can involve skin, subcutis, skeletal muscle, and/or mucous membranes; malignant PNST is rare in cats
· Horses: Reported in horses as young as 3 years of age; equine PNSTs are most common on the eyelids
· Report of a primary PNST localized to the parotid gland exhibiting characteristics of a benign Schwannoma
· S-100 is not useful in classification of PNSTs in horses
· Recent study suggests PNSTs or sarcoids in horses should be classified as soft tissue sarcomas with nerve sheath tumor histomorphology
· Piglets: Neuroma development following tail docking
· Traumatic neuromas are defined as non-neoplastic proliferations of epineurial, perineurial and endoneurial connective tissue, Schwann cells and regenerating cells representing attempts at regeneration
· Single case reports in a goat, an African pygmy hedgehog, and a grizzly bear
· SCID mice are used as an animal model for human neurofibromatosis
· Humans: Neurofibromatosis type 1 (NF1, von Recklinghausen's disease) is a common, multisystemic genetic growth disorder; an analogous disease with multiple subtypes of neurofibromas, as seen in humans, has been recently described in dogs, horses and a chicken
· Tasmanian devil: Devil facial tumor disease (DFTD) is a transmissible neoplasm that is a peripheral nerve sheath neoplasm of Schwann cell origin; periaxin was confirmed as the most sensitive and specific marker, labeling the majority of DFTD cells in 100% of primary DFTD tumors and DFTD metastases
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