JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

September 2022

I-N13

 

SLIDE A

SIGNALMENT (JPC #3007635): Tissue from a dog (breed unspecified)

 

HISTORY: Unknown

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin and subcutis: Expanding the subcutis and elevating the overlying dermis and epidermis is a 1x2 cm, unencapsulated, well-circumscribed, densely cellular neoplasm composed of spindle cells arranged in short interlacing streams and bundles that often whorl around capillaries and collagen fibers. Neoplastic cells are often arranged in an Antoni A-like pattern with cells closely packed and separated by a small amount of collagenous matrix, and occasional nuclear clusters, or, less frequently, an Antoni B-like pattern with cells more widely separated and surrounded by a pale, loose, amphophilic matrix, with occasional variably sized areas of cystic degeneration partially separating cells. Neoplastic cells occasionally have stacked parallel rows of palisading nuclei (Verocay bodies). Neoplastic cells have variably distinct cell borders, a scant to moderate amount of eosinophilic fibrillar cytoplasm, and oval to elongate nuclei with finely stippled chromatin and 1 to 2 variably distinct nucleoli.  Anisocytosis and anisokaryosis are mild, with less than 1 mitotic figure per 2.37mm². There are occasional multinucleated neoplastic cells. Multifocally, admixed are few macrophages with intracytoplasmic, brown globular pigment (hemosiderin), lymphocytes, plasma cells, and multifocal hemorrhage, fibrin and edema. 

 

MORPHOLOGIC DIAGNOSIS: Haired skin and subcutis: Soft tissue sarcoma, grade 1, favor peripheral nerve sheath tumor, breed unspecified, canine.

 

SLIDE B

SIGNALMENT (JPC #2923392): Ten-year-old Belgian Malinois (Military Working Dog)

 

HISTORY: This dog presented with a pedunculated mass on the left thigh. At necropsy, there were multiple lung nodules (histologically confirmed metastases).

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin, left thigh: Extending to all margins is a multilobulated, unencapsulated, infiltrative, densely cellular neoplasm composed of spindle cells arranged in with short streams and interlacing bundles that occasionally whorl around vessels and form storiform patterns. Neoplastic cells are separated by a scant to moderate fibromyxomatous matrix. There is Antoni A-like pattern with cells closely packed and separated by a small amount of collagenous matrix as well as Antoni B pattern, with cells separated and surrounded by a pale, loose, amphophilic matrix. Neoplastic cells have variably distinct borders, scant eosinophilic fibrillar cytoplasm, and oval to elongate nuclei with finely stippled chromatin and 1 to 3 distinct nucleoli. Anisocytosis and anisokaryosis are moderate, with 25 mitotic figures per 2.37mm², and there are occasional multinucleate cells. Multifocally affecting greater than 50% of the tissue section are large areas of coagulative necrosis. There is a focally extensive ulcer overlain by a serocellular crust composed of eosinophilic cellular and karyorrhectic debris (necrosis), fibrin, hemorrhage, abundant degenerate neutrophils, and numerous superficial basophilic cocci. Blood vessels subjacent to the ulcer often contain fibrin thrombi.

 

MORPHOLOGIC DIAGNOSIS: Haired skin, left thigh: Soft tissue sarcoma, grade III, favor peripheral nerve sheath tumor, Belgian Malinois, canine

 

GENERAL DISCUSSION:

• Soft tissue sarcomas (STSs) encompass a heterogenous group of canine cutaneous and subcutaneous spindle cell neoplasms considered together due to similar microscopic appearance, clinical features, and prognosis; STSs utilize a single grading scheme (see below)
  1. Included in STS group: Peripheral nerve sheath tumor (PNST) (nonbrachial plexus), fibrosarcoma, myxosarcoma, liposarcoma, perivascular wall tumors, pleomorphic sarcoma, malignant mesenchymoma, and undifferentiated sarcoma
  2. Excluded from STS group: Histiocytic sarcoma, lymphangiosarcoma, hemangiosarcoma, synovial cell sarcoma, leiomyosarcoma, rhabdomyosarcoma, fibrosarcomas of the oral cavity, and brachial plexus PNSTs
  3. Visceral sarcomas are also excluded from the STS group
• Peripheral nerve sheath tumors (PNSTs) are tumors of peripheral nerves (cranial or spinal nerves). PNSTs can originate from Schwann cells, fibroblasts, or perineural cells. They are relatively common in the skin and subcutis of dogs
• Benign PNSTs:
  1. Schwannomas: Benign tumors originate from Schwann cells. Reported in dogs, cattle, and horses and less often in cats, goats, and pigs
  2. Neurofibroma: Composed of a mixed population of Schwann cells, perineural cells, and fibroblasts but arise from Schwann cells; rare in domestic animal, most common in dogs and horses
     • Neurofibromatosis generally seen in cattle (see Comp Path)
  3. Perineurioma (also called perineuroma): A tumor of perineurial cells; described only in dogs; very rare
• Malignant Peripheral Nerve Sheath Tumors (MPNSTs): Far rarer than benign PNSTs; rare variants reported
• PNSTs in canines are graded using the STS grading scheme (Dennis et al, Vet Pathol. 2011):
  1. Differentiation
     • 1:  Sarcomas closely resembling normal adult mesenchymal tissue
     • 2:  Sarcomas in which histologic type can be determined, but differentiation is poor
     • 3:  Undifferentiated sarcomas, sarcomas of unknown type 
  2. Mitotic score (mitoses per 10 HPF 400x)
     • 1:  0-9 mitoses 
     • 2:  10-19 mitoses
     • 3:  >19 mitoses
  3. Tumor necrosis rate
     • 0:  No necrosis
     • 1:  ≤ 50%
     • 2:  > 50%
  4. Histologic grade: total score
     • Grade I:  ≤3
     • Grade II:  4-5
     • Grade III:  ≥6
  5. Note: Recent studies have shown that prognosis refers more to overall survival, rather than tumor recurrence. 

 

TYPICAL CLINICAL FINDINGS:  

• They are usually solitary, well-circumscribed, slow-growing, soft to firm nodules in middle-aged to older animals
  1. Schwannomas are usually subcutaneous in dogs; dermal in cats
  2. Delicate finger-like projections of tumor cells commonly extend into adjacent tissues and between fascial planes, accounting for frequent recurrence
• PNSTs may also occur in cranial or spinal nerves; if associated with cranial nerves, signs may include unilateral muscle atrophy or Horner’s syndrome 
• PNSTs all exhibit endoneurial spread (distinct from perineurial growth pattern of nonneural tumors which are only invading an ensnared nerve)
• MPNSTs: Commonly reported sites include spinal nerves of dogs and eyelids of dogs and particularly cats
  1. Occasionally metastasizes to the lung and other organs

 

TYPICAL GROSS FINDINGS:

• Firm or soft (gelatinous), white or gray, nodular masses; nodular (sometimes diffuse) growth inside a nerve, which may or may not be visible, +/- encapsulation
• Schwannoma: Generally solitary infiltrating lesions at any site on a nerve trunk; gross appearance differs by distance from CNS:
  1. Distant from CNS: Unencapsulated and poorly-defined; difficult to dissect, with an ordinary fibrous appearance and texture
  2. Close to CNS (arising from nerve root): Well-defined and fusiform; may branch to involve other nerves (+/- spread through vertebral foraminae); may arise and remain with the dura mater and can occasionally have expansive intradural growth, compressing CNS structures; brachial plexus commonly involved
• Neurofibroma: Most often reported in the dermis and subcutis 
• MPNSTs may be locally invasive within soft tissue +/- necrosis

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• Schwannoma
  1. Spindle-shaped Schwann cells in predominately an Antoni type A pattern (densely cellular monomorphic sheets, fascicles, and whorls), and less so in an Antoni type B pattern (cell-poor regions with cells that have inconspicuous cytoplasm and nuclei that appear suspended in a copious myxoid, often microcystic, matrix) with nuclei commonly arranged in rows, between which are parallel arrays (stacks) of Verocay bodies
  2. Unconventional changes (less common)
     • “Ancient change”: Pronounced karyomegaly with remarkable nuclear atypia and folding; bears no impact on prognosis
     • Melanocytic Schwannoma: Tumor cells are making melanin
• Neurofibroma: Heterogeneous in appearance; low cellularity, unencapsulated mixture of Schwann cells, perineural cells, and fibroblasts within variable amounts of collagen fibers and mucoid matrix; nuclei often appear “bent” or comma-shaped and hyperchromatic
  1. Three histologic subtypes: Localized (nodular or polyp-like, from skin-derived precursors), diffuse (exist in large, thick, cellular lesions), and plexiform (generally associated with large-caliber nerves, but also seen in smaller nerves)
• Perineurioma: “Pseudo-onion bulb” of neoplastic spindle cells arranged in concentric patterns around a central, variably myelinated axon
• MPNST: Invasive and hypercellular with elevated mitotic index (>4 per 10 HPF used in human MPNSTs); spontaneous necrosis and hemorrhage noted; anisokaryosis with karyomegaly common

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Immunohistochemistry: PNSTs express vimentin, S-100 protein, SOX10, myelin basic protein, neuronspecific enolase, and glial fibrillary acidic protein (GFAP) (other more common cutaneous tumors do not)
  1. Schwannoma:  Laminin and collagen IV should reveal delicate tendrils of the basement membrane surrounding individual cells
  2. Perineurioma:  Laminin

 

DIFFERENTIAL DIAGNOSIS:  

• Other spindle cell tumors, other STSs
• Fibroma (I-N15A): Less cellular, lack palisading and whirling
• Fibrosarcoma (I-N15B): Increased mitotic activity and atypical mitoses; lack palisading and whirling

 

COMPARATIVE PATHOLOGY: 

• Canine
  1. Schwannoma: Tend to have unilateral schwannomas affecting intradural spinal nerve roots; reported in canine eyes (arising within the iris and extend into the ciliary body); may commonly arise from nerve branches feeding the brachial plexus (posterior cervical to anterior thoracic) 
     • Note: Canine brachial plexus PNSTs excluded from the STS group
     • Cranial Nerve V (Trigeminal nerve) schwannomas described
  2. Multiple neurofibromas reported in 7-week-old puppy with spindle cell rhabdomyosarcoma
  3. Neurofibramatosis-like condition reported in a dog with multiple cutaneous and concurrent cardiac PNSTs (see Bovine neurofibromatosis below) 
  4. MPNST reported in the bladder of a dog
• Feline: “Triton tumour”, a rare, bi-phasic form of MPNST with progression towards a rhabdomyosarcoma phenotype, reported in a domestic cat
• Bovine
  1. Schwannoma far more common within the heart; rarely involve the skin
  2. Neurofibramatosis: Seen in older cattle (rarely very young calves); multiple neural tumors that usually involve deep nerves and viscera (autonomic ganglia, plexuses, and nerves), rarely skin; nerves thickened, firm, gray +/- yellow-gray nodules; ganglia can be markedly enlarged and lobulated 
• Porcine
  1. Cutaneous pigmented neurofibroma reported 
  2. MPNST reported in a mixed-breed sow
• Lab animal
  1. Rats: Endocardial schwannoma reported
• NHP: 
  1. Intestinal schwannoma reported in a rhesus macaque (following administration of the carcinogen methylnitrosourea)
  2. Collared brown lemur: Schwannoma reported in a case
• ZEW
  1. Tasmanian devil: Devil facial tumor disease (DFTD) transmissible neoplasm (one of two naturally transmissible neoplasms of vertebrates); highly significant in species conservation; often fatal within 6 months of visible lesions; two recognized types:
     • DFT1:
       • Tumor of Schwann cell origin
       • Lesions occur around mouth and face, transmission of tumor allografts by fighting/facial biting
       • Large, firm, soft tissue masses that often with central ulceration/necrosis; often from facial or oral dermis/submucosa
       • Cells possess the same extensive set of chromosomal rearrangements, suggesting that the tumor arose from a single female Tasmanian devil; tumor allografts down-regulate MHCs to evade rejection; disease most common in 3-year-olds
       • Metastases occur in 2/3 of cases
       • Schwann cell origin; IHC positive for periaxin
     • DFT2: Rare (reported in five Tasmanian devils), grossly similar, cytogenically distinct from DFT1; cells contain a Y chromosome, indicating origin is a male Tasmanian devil; IHC negative for periaxin
  2. Dromedary camel Multicentric schwannoma reported
  3. Fish: Dermal nerve sheath tumors are comparatively common in fish; benign and malignant PNSTs reported in lake trout (neurofibroma, neurolemmoma, neurofibrosarcoma, schwannoma, and hemangiopericytoma); dermal PNSTs reported in goldfish and gray snappers 
  4. Bats: MPNST reported in a Seba's short-tailed bat: originated in lumbar region dorsal spinal nerve root sheath with splenic metastasis
  5. Reptiles: Multicentric benign PNST reported in bearded dragons (IHC immunoreactive to S-100)
  6. Dolphins: PNST with schwannomatous differentiation reported in a Rough-toothed Dolphin
  7. Hedgehog: MPNST reported

 

REFERENCES:  

1. Alves-Motta MR, Luz-Carvalho V, et al. Facial Squamous Cell Carcinoma and Abdominal Peripheral Nerve Sheath Tumour with Rhabdomyoblastic Differentiation in a Rough-toothed Dolphin (Steno bredanensis). J Comp Pathol. 2020;176:122-127. 
2. Avallone G, Rasotto R, et al. Review of Histological Grading Systems in Veterinary Medicine. Vet Pathol. 2021 Sep;58(5):809-828.
3. 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; 2016:404-405.
4. Castiglioni V, Caielli C, et al. Cutaneous spindle cell tumors with features of peripheral nerve sheath tumors and concurrent cardiac involvement: neurofibromatosis type 1-like presentation in a Labrador Retriever dog. J Vet Diagn Invest. 2022;34(3):535-538. 
5. Dennis MM, McSporran KD, Bacon NJ, Schulman FY, Foster RA, Powers BE. Prognostic factors for cutaneous and subcutaneous soft tissue sarcomas in dogs. Vet Pathol. 2011;48:73-84.
6. Franzen J, Soto S, et al. Malignant Peripheral Nerve Sheath Tumour in a Seba's Short-Tailed Bat (Carollia perspicillata). J Comp Pathol. 2021;184:72-76. 
7. Higgins D, Rose K, Spratt D.  Monotremes and Marsupials. In: Terio K, McAloose, St. Leger J eds. Pathology of Wildlife and Zoo Animals. 1st ed. London, United Kingdom. Elsevier. 2018: 462-3. 
8. Hoon-Hanks LL, Frank CB, Edmondson EF. Primary Meningeal Rhabdomyosarcoma of the Spinal Cord of a Young Dog with Neuromelanocytosis and Multiple Cutaneous Neurofibromas. J Comp Pathol. 2018;165:57-61. 
9. Lanigan LG, Russel DS, et al. Comparative Pathology of the Peripheral Nervous System. Vet Pathol; 2021;58(1):10-33. 
10. Lee S-W, Baek S-M, et al. Malignant Peripheral Nerve Sheath Tumour in the Urinary Bladder of a Dog. J Comp Pathol. 2020;175:64-68. 
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12. Miller AD. Neoplasia and Proliferative Disorders of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, Morris T, ed. Nonhuman Primates in Biomedical Research. Volume 2: Diseases. 2nd ed. Oxford, UK: Elsevier Inc; 2012: 345. 
13. Miller AD, Porter BF. Nervous System. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier Mosby; 2022:631, 988-989.
14. Stilwell JM, Rissi DR. Pathology and immunohistochemistry of a malignant nerve sheath tumor in a pig: case report and brief review of the literature. J Vet Diagn Invest. 2019;31(1)122-127.
15. Stoll AL, Suarez-Bonnet, Summers BA, Priestnall SL. Malignant cutaneous peripheral nerve sheath tumour with rhabdomyosarcomatous differentiations (triton tumour) in a domestic cat. J Comp Path. 2018;165:1-5.
16. Terio K, McAloose, St. Leger J. Various Chapters in: Pathology of Wildlife and Zoo Animals. 1st ed. London, United Kingdom. Elsevier. 2018: 193, 339, 513, 959. 961-2, 965, 889. 
17. Warran AL, Miller AD, et al. Four Cases of the Melanotic Variant of Malignant Nerve Sheath Tumour: a Rare, Aggressive Neoplasm in Young Dogs with a Predilection for the Spinal Cord. J Comp Pathol. 2020;178:1-8. 
18. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1209-1219.
19. Zacharopoulou M, Guillaume E, et al. Causes of Mortality and Pathological Findings in European Hedgehogs (Erinaceus europaeus) Admitted to a Wildlife Care Centre in Southwestern France from 2019 to 2020. J Comp Pathol. 2022;190:19-29. 

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