JPC SYSTEMIC PATHOLOGY
CARDIOVASCULAR SYSTEM
April 2022
C-N03

Signalment (JPC #4087576):  Adult female Angus cow

 

HISTORY:  This cow was one of 18 head in a 300-acre paddock. She had calved the day prior to her death, and the calf nursed. A few hours after calving, the cow laid down in sternal recumbency, but was bright and alert. She was found dead the following morning.

 

HISTOPATHOLOGIC DESCRIPTION:  Heart:  Comprising 80% of the section, expanding the myocardium, separating and replacing normal cardiac myocytes, and extending to the cut margins is a well circumscribed, expansile, multilobulated, moderately cellular neoplasm composed of spindle cells arranged predominantly in closely packed areas (Antoni A pattern) forming short, interlacing streams and bundles and few indistinct whorls separated by a small amount of collagenous matrix, and are rarely arranged more loosely, with neoplastic cells more widely separated and surrounded by a pale, loose, eosinophilic matrix (Antoni B-like pattern).  There are thin, clear clefts partially separating neoplastic cells. Neoplastic cells have often indistinct cell borders, scant eosinophilic fibrillar cytoplasm, and an oval to elongate nucleus with finely stippled chromatin and 1 to 2 variably distinct nucleoli. The mitotic count is less than 1 per 2.37mm^2.  There is scattered single cell necrosis, and a large, geographic area of hyaline change that contains scant scattered necrotic debris.  Adjacent to the neoplasm, compressed cardiomyocytes are occasionally shrunken (atrophy) or have hypereosinophilic sarcoplasm and a pyknotic nucleus (necrosis). Cardiomyocytes are often separated by increased clear space (edema) with few scattered lymphocytes, plasma cells, and macrophages.  Rarely, multifocal cardiomyocytes contain intrasarcoplasmic, 50-70um diameter protozoal cysts which have a thin 2um eosinophilic capsule and are filled with many crescent shaped 4-8um bradyzoites.

 

MORPHOLOGIC DIAGNOSIS:  1. Heart:  Peripheral nerve sheath tumor, ox (Bos Taurus), bovine.

2. Heart, myocardium: Sarcocysts, multifocal.

 

SYNONYMS:  Bovine neurofibromatosis; neurofibroma or neurofibrosarcoma; Schwannoma or malignant Schwannoma; neurilemmoma

 

GENERAL DISCUSSION: 

• Peripheral nerve sheath tumors (PNSTs) occur in cranial and spinal nerves of the peripheral nervous system
• In humans, PNSTs are subclassified as neurofibroma or Schwannoma based on the presumed cell of origin; Schwann cells are also known as neurilemmal 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 author or institution; the principal cell is likely of Schwann or perineural origin
• There are three distinct types of nerve sheath tumors: Schwannomas (Schwann cell origin), perineuriomas (perineurial cell origin), and neurofibromas (include elements from Schwann cells and fibroblasts); all three can undergo malignant transformation resulting in malignant nerve sheath tumors
• "Benign PNST of the skin and subcutis" (typically “lumped” into the classification of soft tissue sarcoma) is common in dogs and is discussed elsewhere (I-N13)
• Benign PNSTs resembling human schwannoma occur in dogs, are rare in cats and horses, and are commonly seen in cattle as incidental findings
• PNST in cattle:
  • Commonly called neurofibromatosis (a unique form of neurofibroma in cows) because it affects multiple nerves (8^th cranial nerve, brachial plexus, intercostal nerves, and the autonomic nerves of the liver, heart, mediastinum, and thorax); different from human neurofibromatosis (NF) which is a distinct clinical entity with two subtypes (NF1 and NF2)
  • Occurs most often in mature animals, and occasionally calves
  • Can occur as isolated or multiple benign neoplasms of peripheral nerves
• Malignant PNST (anaplastic and invasive) 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
• PNSTs are reported in the testis mostly as individual cases

 

PATHOGENESIS:

• 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
• Cranial nerve origin: Unilateral muscle atrophy and Horner’s syndrome
• Secondary inappropriate erythrocytosis due to increased Epo (erythropoietin) production; unrelated to hypoxia

 

TYPICAL GROSS FINDINGS:

• In cattle, often involves the brachial plexus and intercostal nerves; may affect the autonomic nerves of the liver, heart (epicardial plexus), mediastinum, and thorax; 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
• Heart: Single or multiple, round or nodular masses, either on the epicardial surface or within the myocardium
• Nerves (nerve trunks, nerve roots): Nodular or varicose thickenings, firm, or soft gelatinous whitish gray mass, and may have yellow to gray nodules
• Ganglia may be enlarged and appear lobulated on cut section
• May form mass inside the dura mater, may extend through a vertebral foramen
• Malignant peripheral nerve sheath tumors are invasive; metastasis to the lung and other organs

 

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 (Verocay bodies are rare in tumors of domestic species)
• Schwannomas have two morphologic patterns
  • Antoni A pattern: monomorphic spindle shaped cells arranged in sheets, fascicles, bands, herring bones, whorls short interlacing streams and bundles in areas of moderate to high cellularity; poorly defined eosinophilic cytoplasm, pointed basophilic nuclei commonly arranged in a Verocay body pattern, and variable amounts of a collagenous matrix
    • Verocay bodies: stacked parallel rows of elongate cells with palisading nuclei (nuclear regimentation) and anuclear eosinophilic fibrillar material;
  • Antoni B pattern: spindle cells with inconspicuous cytoplasm arranged in a loose meshwork in less densely cellular areas within abundant myxomatous matrix (often microcystic)
• Hyalinized stroma (per PBVD) and the absence of nerve fibers
• Cartilaginous and osseous metaplasia occurs infrequently
• Perineuriomas: tight, concentric whorls of perineurial cells surround a central axon
• Neurofibromas: elongated spindle cells with poorly defined pale eosinophilic, tapering, wavy, or buckled nuclei, and numerous small nerve fibers (which are not present in schwannomas); +/- mast cells; prominent fibromyxoid to myxoid matrix (myxoid neurofibroma) or prominent collagen (collagenous neurofibroma)
• Malignant peripheral nerve sheath tumors: closely packed cells with oval or elongate nuclei arranged in interlacing streams; not supported reticulin or collagen

 

ADDITIONAL DIAGNOSTIC TESTS:

Immunohistochemistry:

• PNSTs: Immunoreactive for laminin and type IV collagen (highlight the basal lamina produced by the neoplastic Schwann cells); may be positive for vimentin, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), CNPase, S-100
  • Perineuriomas: Neurofilament proteins (NFP) often highlight the central axon; laminin highlight the spindle cell population
  • Neurofibromas: Immunoreactive for laminin (basal lamina) or S-100 (Schwann cell component)
• Malignant PNSTs: stain strongly for vimentin, variable intensity immunoreactivity for S-100, GFAP, nerve growth factor receptor, myoglobin; negative for alpha-smooth muscle actin (vs. hemangiopericytomas)

 

DIFFERENTIAL DIAGNOSIS:

For histologic findings:

• Fibroma/fibrosarcomas: Lack palisades and whorls, have more pronounced collagenous stroma
• Leiomyoma/leiomyosarcomas: Lack palisades and whorls, elongate nuclei with blunt ("cigar-shaped") ends

Tumor in bovine heart (gross):

• Lymphoma
• Myocardial epithelial inclusions (C-M08): mass in the left ventricular subendocardial myocardium, composed of epithelioid cells that form cords and tubules, immunoreactive for pan-cytokeratins, cytokeratin 5/6, vimentin, calretinin, Wilms' tumor 1 suppressor gene, CD30 (suggests mesothelial origin)

 

COMPARATIVE PATHOLOGY:

• Canine
  • PNSTs:
    • PNST of the skin and subcutis is common in dogs (I-N13); histologically difficult to differentiate from hemangiopericytoma/perivascular wall tumor (PWT), typically lumped together and classified as “soft tissue sarcoma” and graded based on degree of necrosis, mitotic count, and degree of differentiation
      • PWTs are immunoreactive to nerve growth factor receptor (NGFR and Olig2) and have weaker immunoreactivity to S100 when compared to MPNSTs (Suzuki et al., Vet Pathol. 2014); this may be useful in differentiating these two diagnoses
    • A report of cutaneous PNST showed immunoreactivity to vimentin, laminin, PGP 9.5, and NSE, and variable immunoreactivity to S-100 and collagen IV
    • Schwannomas in dogs most commonly occur in the 5th cranial nerve or spinal roots (posterior cervical–anterior thoracic roots of the brachial plexus and their extensions and roots at the thoracic and lumbar levels)
    • Infrequent mammary tumor (Alonso-Diez et al., Vet Pathol. 2019)
    • There is a report of a primary splenic PNST
    • Acoustic Schwannoma (involving cranial nerve VIII) has been reported
    • Ocular Schwannomas (spindle cell tumors of blue-eyed dogs)
      • Typically arise in the iris and extend to the ciliary body and are nonpigmented; may not form a recognizable mass
      • Metastasis can occur, but rare
• MPNSTs:
  • MPNST is most commonly seen in dogs
  • Case report in the urinary bladder trigone (Lee et al., J Comp Pathol 2020); grossly homogenous, grey to tan, with focal areas of pigmentation (on cut surface), pedunculated mass; strong immunoreactivity for S100 and vimentin
  • Case series of four cases of a melanotic variant; affected young female dogs from 3 months to 3 years old; multicentric, intradural, intra- and extraparenchymal, infiltrative neoplasms with a predilection for the spinal cord; microscopically similar to PNST with prominent cytoplasmic melanin highlighted by Fontana-Masson stain; immunoreactive for S-100, vimentin, melan A; immunonegative for GFAP and periaxin; TEM (one case) identified cytoplasmic pre-melanosomes and melanosomes (Warren et al., J Comp Pathol 2020)
  • Case report: concomitant malignant pulmonary PNST and benign cutaneous PNST; both neoplasms were immunopositive for vimentin, GFAP, S100; MPNST should be included as a differential for primary malignant pulmonary neoplasms in dogs (Silva et al., J Comp Pathol2017)
  • Case report: Cutaneous neurofibromas accompanied a constellations of proliferative and neoplastic lesions of unknown etiology in a 7-week-old Labrador retriever puppy (Hoon-Hanks et al., J Comp Pathol 2018)
• Cat:
  • PNSTs most frequently occur in the dermis on the head, neck, and distal limbs; can involve skin, subcutis, skeletal muscle, and/or mucous membranes; malignant PNST is rare in cats; ocular Schwannomas has been reported in cats
  • MPNSTs with rhabdomyosarcomatous differentiation (triton tumour) has been reported in a domestic cat; dermal/subcutaneous mass composed of spindle and polygonal cell components with progression towards a rhabdomyosarcomatous phenotype (Stoll et al., J Comp Pathol 2019)
    • IHC: both cell populations strongly immunoreactive for vimentin, multifocal immunoreactivity to S100 and desmin, weak immunoreactivity to myoglobin in the cells expressing desmin, strong immunoreactivity for alpha-sarcomeric actin and weak muscle actin; strong labeling for myogenin
• Laboratory animals:
  • Mice - Histiocytic sarcomas (elongated cell type) have been misdiagnosed as malignant Schwannomas
  • SCID mice are used as an animal model for human neurofibromatosis
  • Rat
    • Endocardial spindle cell proliferation (fibroproliferative lesions termed endocardial fibromatosis, fibroelastosis, endocardiosis, and endocardial fibromatous proliferation) may be a precursor to schwannomas
    • 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 has been reported with cell populations that included both benign and malignant PNSTs; the benign PNST cells were of myofibroblastic origin

 Equine:

Donkey - Case report of an endocardial PNST with features of a benign schwannoma, strongly immunoreactive for S100 and GFAP; first cardiac tumor reported in a donkey (Paraschou et al., J Comp Pathol 2017)

Horses - Reported in horses 3+ years of age; PNSTs are most common on the eyelids

• Case report: granular cell variant neurofibroma (Civello et al., J Comp Pathol 2017)
• Report of a primary PNST localized to the parotid gland exhibiting characteristics of a benign Schwannoma
• A study suggests PNSTs or sarcoids that resemble PNSTs should be classified as soft tissue sarcomas with nerve sheath tumor histomorphology (Epperson et al., Vet Pathol. 2017)
• Swine: PNSTs are rare in pigs
  • Case report of a cutaneous pigmented neurofibroma in a juvenile female hybrid pig, composed of clusters of melanin-laden, epithelioid cells and spindle cells forming bundles and nodules surrounded by perineurial-like cells; single Wagner-Meissner-like corpuscles were present; epithelioid cells immunoreactive for S100, melan A, and p75 neurotrophin receptor; spindle cells immunoreactive for S100, sex determining region Y-box 2, p75 neurotrophin receptor, Krox20, growth associated protein 43, and GFAP; perineural-like cells immunoreactive for p75 neurotrophin receptor, alpha-smooth muscle actin and cytokeratin (Becker et al., J Comp Pathol 2019)
  • Case report of a MPNST in a pig with bony invasion; immunoreactive for cladin-1, laminin and vimentin, weak to moderately immunoreactive for S100 and Sox-10, weakly immunoreactivity for NSE (Stilwell et al., J Vet Diagn Invest 2019)
  • Piglets – Develop traumatic neuromas following tail docking: non-neoplastic proliferations of epineurial, perineurial, and endoneurial connective tissue, Schwann cells, and regenerating cells representing attempts at regeneration
• Goat: Single case report
• Camelids: Peripheral nerve sheath tumors are reported
• Chicken: Single case report of perineurioma (Cusack et al., J Vet Diagn Invest 2017)
• Humans: Three common PNSTs from Schwann cells (schwannomas, neurofibroma and MPNST); neurofibromatosis type 1 (NF1) and type 2 (NF2)
  • Neurofibromatosis type 1 (NF1, von Recklinghausen's disease) is a common (more common than NF2), multisystemic genetic (autosomal dominant) growth disorder; an analogous disease with multiple subtypes of neurofibromas has been described in dogs, horses and a chicken
    • Systemic disease mostly associated with noneoplastic disease and neoplastic lesions [i.e., neurofibromas of all types (cutaneous, diffuse, plexiform), MPNSTs, gliomas of the optic nerve, other glial tumors and hamartomatous lesions, and pheochromocytomas]
      • MPNSTs can occur sporadically in the absence of NF1 association
  • NF2, also autosomal dominant disorder, associated with neoplastic lesions (most commonly bilateral eighth nerve schwannomas, multiple meningiomas, and ependymomas of the spinal cord)
    • Associated benign lesions include schwannosis, meningioangiomatosis and glial hamartia
• NHP: Schwannoma is one of the rare tumors of the nervous system that has been reported in captive nonhuman primates; has been reported in a collared brown lemur
• Exotic and Wildlife:
  • Multicentric benign peripheral nerve sheath tumor reported in bearded dragons
  • Neurofibromas are reported in Chondrichthyes (cartilaginous fish)
  • Single case report in an African pygmy hedgehog, and a grizzly bear
  • Tasmanian devil - Devil facial tumor disease (DFTD) is a transmissible neoplasm that is a peripheral nerve sheath neoplasm of Schwann cell origin; periaxin is the most sensitive and specific marker
  • Fallow deer – Case report of two pigmented schwannomas in a captive herd in southern Oregon; immunoreactive for laminin and negative for melan A (Hughes et al., J Vet Diagn Invest 2017)
  • Raccoons - MPNSTs reported in the olfactory bulb in wild raccoons; a raccoon polyomavirus may have a role in neuro-oncogenesis (Giannitti et al., Vet Pathol 2014)
  • Birds - Neurofibrosarcomas are reported in captive water birds
  • Pet birds - Schwannomas are reported as sporadic tumors; immunoreactive to basic myelin protein
  • Bat: A MPNST was reported in a Sheba’s short-tailed bat from a zoo; IHC for typical PNST markers was negative, few neoplastic cells were immunoreactive for smooth muscle actin and desmin; primary lesion in a lumbar dorsal spinal nerve root sheath with metastatic lesion in the spleen (Franzen et al., J Comp Pathol 2022)
• Fish
• Dermal nerve sheath tumors are reported as common in fish
  • Nerve sheath tumors are reported in gray snappers
  • Damselfish neurofibromatosis: Bicolored damselfish develop multiple cutaneous neurofibromas; a viral etiology is likely; used as an animal model for human neurofibromatosis 1 (NF1)
  • Lake trout (Salvelinus namaycush): Nerve sheath tumors (neurofibroma, neurolemmoma, neurofibrosarcoma, schwannoma, and hemangiopericytoma) are reported; etiology unknown
  • Zebrafish: Several lines of zebrafish with cancer-associated genetic mutations develop MPNSTs; cells express S100 and CD57 (White, Vet Pathol. 2017); used as a model for malignant peripheral nerve sheath tumors
• Dolphin – Case report of abdominal PNST with rhabdomyoblastic differentiation in an aged free-ranging rough-toothed dolphin; rhabdomyoblastic components suggested with phosphotungstic acid haematoxylin (PTAH) stain (Alves-Motta et al., J Comp Pathol 2020)
• A recent review article discusses comparative pathology of peripheral nervous system lesions (neuronopathy, axonopathy, and myelinopathy, and major categories of PNS disease including toxic, metabolic, and paraneoplastic neuropathies; infectious and inflammatory diseases; and neoplasms to include PNSTs) (Lanigan et al., Vet Pathol 2021)

 

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