Conference 1 - 2016 Case: 1 20160824

Signalment:

4-year-old male castrated sable ferret (Mustela putorius furo).The ferret presented with a oneweek history of ataxia. The owner noted a mass on the left neck. The ferret was eating but otherwise lethargic. Owners elected euthanasia due to worsening of clinical signs and the inoperable nature of the mass.

Gross Description:

Within the subcutis and skeletal muscle of the neck just caudal to the skull, there is a large, firm, multinodular, smooth, white to tan, 5 x 3.5 x 1.5 cm mass extending to the left lateral and ventral aspect of the neck. The mass is adhered to the first cervical vertebra, extending caudally to the mid-cervical region and ventrally to the level of the trachea, but is not adhered to the trachea or esophagus. The central region of the mass is attenuated. After removal of the skull, evaluation of C1 reveals that the mass infiltrates into and effaces the left cranial articular fovea (articular facet of the atlas). After decalcification, further sectioning of the mass reveals that it extends into the vertebral canal and compresses the cervical spinal cord. In the caudal aspect of the left cranial lung lobe, a 0.5 cm diameter firm, smooth, white nodule is observed. The spleen is diffusely congested and enlarged, and contained a 2 x 2 x 1.2 cm soft, smooth, red nodule. Two renal cortical cysts are observed in the right kidney, measuring approximately 0.4 cm each.

Histopathologic Description:

A decalcified transverse section through the cervical vertebra, cervical spinal cord and surrounding skeletal muscle is examined. Infiltrating into the epaxial musculature, cervical vertebral pedicle, articular processes and extending into the vertebral canal with compression of the adjacent cervical spinal cord is a multilobular, infiltrative, poorly demarcated neoplasm. Neoplastic lobules are separated by eosinophilic fibrovascular connective tissue. Lobules are comprised of large polygonal cells with distinct cell borders and abundant, amphophilic to clear, vacuolated cytoplasm (physaliferous cells) surrounded by variable amounts of amphophilic, mucinous stroma. Nuclei are round to oval and often peripheralized, with finely stippled chromatin and multiple nucleoli. There are zero mitotic figures in 10 high power (400x) fields. Multifocally in the center and at the periphery of lobules, scattered aggregates of cartilage and woven bone are interspersed within the physaliferous cells. Bony trabeculae contain osteocytes and are lined by osteoblasts. Chondrocytes lie within a lightly eosinophilic to amphophilic matrix or are occasionally entrapped within bone. Rare binucleate cells are found. Small aggregates of lymphocytes, plasma cells and macrophages are present at the periphery of the mass.

Vertebral bone has scalloped borders, with osteoclasts in Howships lacunae. Fragmented woven bone (reactive bone) is interspersed with numerous plump osteoblasts and fibroblasts. Neoplastic compression of the cervical spinal cord results in shifting of the ventral medial fissure away from the mass. The white matter of the spinal cord exhibits mild, multifocal vacuolation in the dorsal, lateral and ventral funiculi, within which are few Gitter cells containing myelin degradation products. Scattered, multifocal swollen axons (spherocytes) are present in the ventral and lateral funiculi. Variation in neuronal cytoplasmic staining is present with no loss of Nissl substance (decalcification artifact, presumptive). Surrounding epaxial skeletal muscles, and more prominently, muscle adjacent to the dorsal spinous process undergoes degeneration and regeneration, manifesting as myocyte size variation, sarcoplasmic hypereosinophila and vacuolation, loss of striation, satellitosis, central nuclei, and nuclear rowing.

Morphologic Diagnosis:

1. Cervical spine: Chordoma, with local infiltration of skeletal muscle, vertebral bone and vertebral canal.

2. Cervical spinal cord: Focal compression with midline shift, mild, moderate Wallerian degeneration and spheroid formation.

3. Cervical skeletal muscles: Multifocal myodegeneration and regeneration.

4. Lung (caudal aspect left cranial lung lobe, not submitted): Multifocal chordoma metastasis.

Lab Results:

N/A

Condition:

Chordoma

Contributor Comment:

Chordomas are the 5th most common tumor in domestic ferrets, and the most common musculoskeletal tumor.^1,11 Chordomas are slow growing, locally aggressive neoplasms derived from remnant fetal notochord ^1,4,6-12,14 believed to originate from the primitive mesoderm.^1,2 The notochord persists between the vertebrae and expands to form the nucleus pulposus of intervertebral disks in some animals (visible in the section).^1,5,8,9 Cell rests of residual notochord remain outside of the intervertebral disks in an estimated 2% of humans, and chordomas are thought to arise from these cell rests.^1,4,8,9 Histologically, ferret chordomas are characterized by lobules of physaliferous cells surrounding cartilage with a central core of bone and cartilage. ^1,4,6-12,14 Notochordinduced differentiation of bone and cartilage within the neoplasm is one hypothesis for the bone and cartilage formation within these neoplasms.⁴

Chordomas can occur anywhere along the axial skeleton. In the ferret, common sites include the tail tip (most common site), cervical vertebral column (second most common site), thoracic vertebral column, and the coccygeal region.^1,4,6-12,14 The sacrococcygeal and spheno-occipital regions are the most common sites of chordoma occurrence in humans, with the remainder found in the vertebral axis.^4,14 Up to 30% of human chordomas are reported to metastasize, typically during the phase of recurrent disease, with common sites of metastasis reported to be bone, lung, lymph node, skin and liver.^1,4,14 Rare cases of local and distant skin metastases have been reported in the ferret.^1,4,14 Vascular invasion was equivocal in the submitted section, however, was observed rarely in other sections of the mass and pulmonary metastases were present. One study evaluated cell proliferation indices in 5 ferret chordomas, and found that they were not predictive of metastatic potential.⁸

In humans, there are 3 recognized subtypes of chordoma: classic chordoma, chondroid chordoma, and chordoma with malignant spindle cell component (dedifferentiated). It has been suggested that ferret chordomas may act as an animal model for the chondroid subtype of human chordoma.^4,14 Differentiation between classic and chondroid subtypes in humans is significant, as chondroid chordomas are associated with a survival rate 3 times greater than that of classic chordomas.^1,8 Although the chondroid component was not prominent in the submitted section, it was more frequently observed in other sections of the mass.

Immunohistochemical analysis of chordomas in the ferret typically show dual expression of cytokeratin and vimentin, with variable expression of S-100 protein and neuron specific enolase (NSE).^1,4,6-12,14 In one study of chordomas in 20 ferrets, 75% were positive for S-100 and 85% were positive for NSE.⁴ The S-100 positivity is thought to be due to glycosaminoglycan content within the stroma, and NSE is expressed in cells with high metabolic activity.^1,4

JPC Diagnosis:

Cervical vertebra (axis): Chordoma.

Conference Comment:

This case nicely characterizes an example of a common neoplasm in the axial skeleton of a ferret. The contributor provides an excellent histologic description, including the ancillary findings of degeneration of the spinal cord, peripheral nerves, and adjacent skeletal muscle as a result of compression from this infiltrative neoplasm.

Aside from humans and ferrets, chordomas have been rarely reported in the axial skeleton of Fischer 344 rats¹¹, mice¹³, dogs^6,9, and cats². In addition, 24 cases of spontaneous primary intestinal chordomas as well as nine spontaneous vertebral chordomas, were recently reported in the aged laboratory zebrafish³. In dogs, chordomas have been reported in the brain, spinal cord, and skin⁶. Of the three reported cases of feline chordoma, one was initially diagnosed as chronic granulomatous inflammation due to the interpretation of the characteristic physaliferous cells as atypical, foamy macrophages; it was subsequently dis-covered to be an example of a classic chordoma-like subtype, which then metastasized to multiple lymph nodes².

In all species, chordomas tend to be slow growing and locally invasive.^1-14 Typically, distant metastasis is associated with the classic chordoma and dedifferentiated spindle cell subtypes in humans, rather than the chondroid type which forms islands of cartilage and bone most commonly in the ferret and mink.^1,4,8,10,14 In a large study of Fischer 344 rats there was an exceptionally high 75% incidence of pulmonary metastasis in animals diagnosed with chordomas.¹¹ The histomorphology of chordomas in the Fischer rat is similar to the classic type in humans, which may explain the more aggressive biologic behavior in these rodents as compared to other animals.¹¹ Prior to this case, visceral metastasis had not yet been reported in the ferret. However, the contributor recently published this case report, to include pulmonary metastasis via hematogenous spread; this is the first known case of visceral metastasis in the ferret⁵. The authors hypothesized that the metastatic potential in ferrets may increase over time, highlighting the importance of prompt surgical excision. Most cases of ferret chordomas occur at the tail tip making complete surgical excision relatively simple.^1,4,5,14 Chordomas in other locations, such as this case, are substantially more difficult to excise.⁵

Chordomas in ferrets may histologically resemble chondrosarcomas due to the cartilaginous component. Conference participants briefly discussed immunohistochemistry as a method by which to differentiate chordoma from chondrosarcoma. As mentioned by the contributor, chordomas consistently demonstrate dual immunopositivity for vimentin and cytokeratin, while chon-drosarcomas are immunonegative for cytokeratin. Chordomas are also typically positive for S-100 and neuron-specific enolase (NSE); the S-100 and NSE positivity does not suggest neural crest origin, however.^10,12 Other neoplasms of interest that typically express both vimentin and cytokeratin include: mesothelioma, synovial sarcoma, meningioma, renal cell carcinoma, adrenal carcinoma, and endometrial sarcoma.¹²

References:

1. Camus MS Rech RR, Choy FS, Fiorello CV, Howerth EW. Pathology in practice, chordoma on the tip of the tail of a ferret. J Am Vet Med Assoc. 2003;235(8):949-51.

2. Carpenter JL, Stein BS, King NW Jr, Dayal YD, Moore FM. Chordoma in a cat. J Am Vet Med Assoc. 1990;197:240-242.

3. Cooper T, Murray K, et al. Primary intestinal and vertebral chordomas in laboratory zebrafish (Danio rerio). Vet Pathol. 2015;52(2):388-392.

4. Dunn DG, Harris RK, Meis JM, Sweet DE. A histomorphologic and immuneohistochemical study of chordoma in twenty ferrets (Mustela putorius furo). Vet Pathol. 1991;28:467-473.

5. Frohlich J, Donovan T. Cervical chordomas in a domestic ferret (Mustela putorius furo) with pulmonary metastasis. J Vet Diagn Invest. 2015;27(5)656-659. 6. Gruber A, Kneissi S, Vidoni B, Url A. Cervical spinal chordoma with chondromatous component in an dog. Vet Pathol. 2008;45(5):650653.

7. Koestner A, Bilzer T, Fatzer R, Schulman FY, Summers BA, Van Winkle TJ. Chordoma. In: Histological Classification of Tumors of the Nervous System of Domestic Animals, 2nd series, vol. V, pp. 36. Armed Forces Institute of Pathology, Washington, D.C., 1999.

8. Munday JS Brown CA, Richey LJ. Suspected metastatic coccygeal chordoma in a ferret (Mustela putorius furo). J Vet Diagn Invest. 2004;16(5):454-458.

9. Munday JS, Brown CA, Weiss R. Coccygeal chordoma in a dog. J Vet Diagn Invest. 2003;15(3):285-288.

10. Pye GW, Bennett RA, Roberts GD, Terrell SP. Thoracic vertebral chordoma in a domestic ferret (Mustela putorius furo). J Zoo Wildl Med 2000;31(1):107-111.

11. Stefanski SA, Elwell MR, Mitsumori K, Yoshitomi K, Dittrich K, Giles HD. Chordomas in Fischer 344 rats. Vet Pathol. 1988;25(1):42-47.

12. Takeshi Y, Tetsuo O, et al. Histochemical and immunohistochemical characterization of chordoma in ferrets. J Vet Med Sci. 2015;77(4):467-473.

13. Taylor, K, Garner M, et al. Chordomas at high prevalence in the captive population of the endangered Perdido Key Beach mouse (Peromyscus polinotus trissyllepsis). Vet Pathol. 2016;53(1):163-169.

14. Williams BH, Eighmy JJ, Berbert MH, Dunn DG. Cervical chordoma in two ferrets (Mustela putorius furo). Vet Pathol. 1993;30:204-206.