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Case report: canine spinal cord nephroblastoma
Long-term prognosis is encouraging after cytoreductive surgery and radiation therapy in a young pug-beagle crossbreed.
Clinical history and owner complaint
A 1.5-year-old castrated pug-beagle crossbreed from Massachusetts presented to Red Bank Veterinary Hospital in Tinton Falls, New Jersey, for pelvic limb paresis (weakness) that progressed to paraplegia over a 2-week period.
- The dog was up to date on routine vaccinations and was receiving no medications other than heartworm and flea and tick prevention.
- According to the owner, the dog had no history of coughing, sneezing, vomiting, diarrhea, altered thirst or loss of appetite, and no change in body weight. The owner also reported no prior history of trauma or possibility of exposure to a toxin.
Physical and neurologic examinations
On presentation, the routine physical examination was normal, except the dog was overweight (BCS, 7/9). On neurologic examination, the dog displayed a normal mental state and normal cranial nerves but was paraplegic (lack of voluntary motor function of the pelvic limbs).
- Postural reactions were normal in the thoracic limbs, but postural reactions were absent in the pelvic limbs.
- Spinal reflex evaluation revealed normal withdrawal reflexes and muscular tone in the thoracic limbs; in the pelvic limbs, there were hyperreflexive patellar reflexes, normal withdrawal reflexes, and increased muscular tone bilaterally. Nociception was intact in all limbs.
- The dog had discomfort on palpation of the vertebral column at the thoracolumbar junction.
Anatomic and differential diagnoses
Based on the neurologic examination, the neuroanatomic diagnosis was a severe, focal or diffuse T3 to L3 myelopathy. Based on the signalment, history, and examination findings, the differential diagnoses consisted of:
- Infectious disease. Myelitis of infectious etiology must be a major consideration in a young dog with signs consistent with progressive spinal cord disease, including:
- Canine distemper virus and infections involving protozoal agents (Neospora caninum, Toxoplasma gondii), fungal agents (Cryptococcus neoformans), or rickettsial agents.
- Because the dog was up to date on vaccinations, canine distemper virus was considered unlikely.
- Other fungal etiologies with a predilection for the central nervous system, such as Blastomyces dermatitidis and Coccidioides immitis infection, were unlikely given the lack of travel history to regions of the country where these fungal organisms are more prevalent.
- Non-infectious inflammatory disease. Granulomatous meningoencephalomyelitis (GME) is an immune-mediated disease process of unknown etiology.
- Typically, GME results in multifocal neurological deficits involving the brain and spinal cord.
- A focal spinal cord lesion alone is less commonly observed in patients with GME.
- Neoplasia. Most neoplasms that affect the spinal cord occur in older, adult dogs.
- However, lymphoma is occasionally seen in young dogs.
- Of note, a unique spinal cord neoplasm, nephroblastoma, is seen in young dogs.1
- Vertebral malformation. Because of the typical congenital nature of conformational abnormalities and more common presentation earlier in life, malformation was considered less likely in this dog.
- Injury. Spinal cord injury secondary to trauma or intervertebral disc herniation typically does not present with progressive clinical signs as seen in this dog. Given the breed and young age of the dog, disc herniation was considered to be less likely.
- Degenerative disorders. Occasionally, young dogs have ligamentous or bony degenerative processes of the vertebral column that result in secondary spinal cord compression.
Complete blood count and serum chemistry findings were normal. Magnetic resonance imaging (MRI) of the vertebral column from C7 to L7 vertebrae was performed with a 1.5T Philips system.
- MRI sequences: Transverse and sagittal images using T1- and T2-weighted sequences were acquired. Additional transverse and sagittal T1-weighted sequences were obtained following administration of intravenous contrast medium (0.1 mmol/kg of gadopentetate dimeglumine).
- MRI Findings: A right-sided, well-demarcated intramedullary (within the spinal cord) mass was identified that extended from the level of the mid-body of the T13 vertebra to the level of the caudal endplate of the L1 vertebra. While the mass appeared intramedullary, an intraduralextramedullary location (within the subarachnoid space) also was considered.
- The mass was homogenously T2-hyperintense, as compared to the normal spinal cord, and displayed strong, uniform contrast enhancement.
- The mass caused severe compression of the spinal cord and attenuation of the subarachnoid space and epidural fat.
- At its largest extent, the mass occupied approximately 80% of the cross-sectional area of the spinal cord (Figure 1).
- Cranial and caudal to the mass was diffuse, non–contrast-enhancing, intramedullary T2-hyperintensity in the dorsal aspect of the spinal cord, consistent with vasogenic edema.
- The central canal was dilated immediately caudal to the mass and was prominent immediately cranial to the mass. The significance of this finding was uncertain.
- The MRI findings were consistent with a neoplasm or granuloma.
Analysis of cerebrospinal fluid obtained from the lumbar subarachnoid space yielded clear, strawcolored fluid with mononuclear pleocytosis (nucleated cells, 63 cells/µL [11% neutrophils, 70% small lymphocytes, 19% large mononuclear cells], normal 0-4 cells/µL; red blood cells, 1791 cells/L, normal less than 30 cells/µL) with an elevated total protein (protein, 477.9 mg/dL; normal less than 35 mg/ dL). Neoplastic cells or microbial agents were not identified.
Treatment options were discussed with the owners. Options included palliative care with corticosteroids and analgesic medications or surgical intervention in an attempt to achieve gross cytoreduction of the mass (surgical resection). Given the severity of the clinical signs, euthanasia was also considered. Based on the severity of the clinical signs and MRI findings, the owners elected cytoreductive surgery.
A right-sided hemilaminectomy was performed from the T13 to L2 vertebrae. The meninges at that site appeared grossly red-brown (Figure 2).
- Durectomy revealed a red gelatinous mass that was partially extramedullary but had also invaded the spinal cord (Figure 3).
- Gross cytoreduction of the extramedullary portion of the mass was achieved using Paton spatulas and gentle aspiration.
- To resect the portion of the mass that had invaded the spinal cord, the superficial white matter of the spinal cord was separated longitudinally with a right-angle nerve root retractor that allowed removal of the mass with gentle aspiration.
- Gross cytoreduction of the extramedullary portion of the mass was achieved using Paton spatulas and gentle aspiration.
Histopathology and definitive diagnosis
Histopathologically, the mass was composed of two (biphasic) populations of neoplastic cells (Figure 4):
- One population formed epithelial tubule- and rosette-like structures resembling primitive renal tubules and glomeruli, respectively.
- The tubules were lined by one to multiple layers of cuboidal to elongated cells with indistinct cell borders.
- The cells had scant-to-moderate amounts of eosinophilic cytoplasm and round-to-oval nuclei with single or multiple, indistinct nucleoli.
- The second population of neoplastic cells was comprised of spindle-shaped cells with scant basophilic cytoplasm and oval nuclei (blastemal cells). Mitotic figures were rare.
- The mass displayed immunopositive staining for the Wilms tumor antigen 1.
- The biphasic population of neoplastic cells combined with immunopositivity to the Wilms tumor antigen provided a definitive diagnosis of a spinal cord nephroblastoma.
Postsurgical day 2 and discharge at day 4
- By the second postoperative day, the dog regained the ability to walk with moderately severe paraparesis that was worse on the right side.
- At the time of discharge four days after surgery, the dog had shown continued improvement and was walking with a mild general proprioceptive ataxia and upper motor neuron paraparesis.
- 14 days after surgery: The dog began definitive intent radiation therapy. The dog was treated to a total of 45 gray (Gy) in 2.5-Gy fractions for a total of 18 fractions delivered daily Monday through Friday for 3.5 weeks.
- The dog did not experience any complications. Over the course of treatment, he showed continued neurologic improvements.
- At the time of his final radiation treatment, the dog exhibited only subtle deficits in the right pelvic limb.
- Eight weeks after completing radiation therapy (98 days after surgery): The dog had a normal gait, normal postural reactions, and no evidence of discomfort at the previous surgical site.
- Over the subsequent four years following completion of radiation therapy, the owner periodically reported by email and accompanying videos that the patient remained normal.
- 1414 days after surgery: Follow-up neurologic examination was normal.
- 2175 days after surgery: The owner corresponded (via email) that the dog, now 7 years of age, continued to have normal strength and gait in the pelvic limbs.
Magnetic resonance imaging
MRI is ideal for identification of neoplasms involving the vertebral column and/or the spinal cord. While radiographs can be useful in identifying neoplasms that involve bony structures, which cause bone proliferation or lysis, many neoplasms will not cause such changes or may only involve soft tissues.
In comparison to plain radiography, myelography can provide more diagnostic information. Myelography is a specialized radiographic procedure in which iodinated contrast medium is injected into the subarachnoid space. Radiographically, the contrast medium opacifies the subarachnoid space. Myelography enables indirect visualization of the spinal cord through identification of attenuation of iodinated contrast in the subarachnoid space. Three distinctive myelographic patterns are recognized based on the location of a lesion in relationship to the meninges and spinal cord: extradural, intraduralextramedullary, and intramedullary (Figure 5A).
Injection of iodinated contrast medium into the subarachnoid space is invasive and is accompanied by risks including worsening of clinical signs, iatrogenic spinal cord damage, and seizures. Moreover, with severe spinal cord compression or extensive spinal cord swelling, there may be a lack of contrast medium in the subarachnoid space which hampers interpretation. Likewise, improper injection technique in which contrast medium enters the epidural space may create non-diagnostic images. Crosssectional imaging such as computed tomography (CT) and MRI are preferred imaging techniques for the evaluation of the vertebral column and spinal cord. CT combined with myelography (iodinated contrast in the subarachnoid space) improves the diagnostic utility over CT alone. However, MRI is considered the gold standard for imaging of the vertebral column and spinal cord as it provides for excellent contrast resolution which enables differentiation of the various tissues.2,3 With MRI, lesions are characterized based on signal intensity (the shades of the gray scale from white [hyperintense] to black [hypointense or signal void]), size, shape, and delineation of a lesion, location of the lesion in relationship to the meninges, extent of spinal cord compression, and degree of contrast enhancement. Such MRI characteristics allow for a presumptive diagnosis of various neoplastic and non-neoplastic lesions. As in the case herein, signalment, history, and MRI characteristics combined with the location and extent of the neoplasm may suggest a specific histologic type of neoplasm. Although MRI can suggest a relatively accurate presumptive diagnosis, definitive diagnosis necessitates microscopic evaluation of a lesion.
With MRI, classification of a lesion in relationship to the meninges and spinal cord is divided into extradural, intradural-extramedullary, or intramedullary (Figure 5B).2 Extradural neoplasms arise from either bony (vertebrae) or soft tissue structures outside of the dura mater, causing a varying degree of spinal cord compression as evidenced by deviation of the spinal cord and attenuation of the signal provided by the cerebrospinal fluid (CSF) within the subarachnoid space. Intraduralextramedullary lesions arise within the subarachnoid space (between the dura mater and the spinal cord). A lesion within the subarachnoid space causes spinal cord compression and deviation of the dura mater away from the spinal cord. As a result, there is often an expansion of the subarachnoid space cranial and/or caudal to the lesion. The signal from the CSF filling the expanded subarachnoid space may take on a shape referred to as a “golf tee” sign.4 Intramedullary lesions expand the spinal cord and/or cause spinal cord swelling which results in circumferential attenuation of the signal from CSF.2
- Despite the improved visualization of lesions with cross-sectional imaging, differentiation between intradural-extramedullary and intramedullary lesions can be challenging.
- In the dog described here, the mass was intradural with a portion that extended into the spinal cord. Therefore, the neoplasm was characterized as having an intramedullary component. The MRI was not able to discriminate between intraduralextramedullary and intramedullary.
Accuracy of presumed differential diagnosis
Classification of the location of the neoplasm in relationship to the meninges and spinal cord helps prioritize an accurate differential diagnosis, which enables clinicians to provide owners with therapeutic options and prognosis.
- Extradural neoplasms are most common and account for approximately 50% of neoplasms that affect the spinal cord.5
- Extradural neoplasms largely comprise primary (ie, osteosarcoma, fibrosarcoma, hematopoietic neoplasia [plasma cell neoplasia and lymphoma]) and secondary (metastatic) vertebral neoplasia.
- Intramedullary neoplasms are least common and account for approximately 15% of spinal cord neoplasms.5
- Intramedullary neoplasia most commonly consists of gliomas and metastatic neoplasms.5
- Intradural-extramedullary neoplasia accounts for approximately 30% of neoplasms that affect the spinal cord.5
- Intradural-extramedullary neoplasms include meningiomas, nerve sheath neoplasms, and nephroblastomas.
- In general, intradural-extramedullary neoplasms tend to be slow-growing and cause gradual compression of the spinal cord, with progression of clinical signs often seen over a period of weeks to months.5
Pathophysiology of nephroblastoma
Spinal cord nephroblastoma is an embryonic neoplasm that is theorized to arise from portions of the nephrogenic primordium (intermediate mesoderm), which develops into the adult kidney (Figures 6 and 7). Nephrogenic primordium is thought to become entrapped within the developing meninges and undergoes postnatal malignant transformation (Figure 8).1,6
- Typically, there is early onset of clinical signs, with the mean age at presentation being 1.6 years of age.7 Breed predilection has been described in the German shepherd and retriever families.1 No sex predisposition has been identified.1
Given the location of the developing kidneys, spinal cord nephroblastoma typically occurs between the T9 and L3 vertebrae6-8 and causes a T3-L3 myelopathy. Owners can recognize this as a progressive pelvic limb gait abnormality, often with asymmetric signs as described in this dog.1,7 Progression typically occurs over days to weeks. Affected dogs display varying degrees of pain. In some cases, affected dogs may not appear in pain at all.
Nephroblastoma is the canine analog of the human Wilms tumor, and an immunohistochemical test is available to detect Wilms tumor antigen (WT-1) in cases of suspected canine nephroblastoma.9 With immunohistochemistry, nephroblastoma typically shows positive WT-1 immunoreactivity, although one study of 11 histologically confirmed spinal nephroblastomas revealed that two tumors did not stain positive with WT-1 antibody, indicating that a combination of immunohistologic features is ideal for diagnosis.7 Other identifying features include positive staining for epithelial markers (cytokeratin) and blastemal markers (vimentin),10 with lack of labeling for markers of cells of neuroectodermal origin (GFAP).11 Although it is not known why some nephroblastomas do not show positive WT-1 immunoreactivity, this test may still help confirm the diagnosis in cases that may not display typical histomorphology.
On MRI, a spinal cord nephroblastoma typically presents as a focal, well demarcated mass that causes variable degrees of compression. A spinal cord nephroblastoma may appear as an intraduralextramedullary or intramedullary lesion. The mass is typically T2-hyperintense and T1-iso to T1-hypointense in comparison to the spinal cord. The mass strongly and uniformly enhances. Varying degrees of T2-hyperintensity may be seen in the spinal cord as a result of vasogenic edema or gliosis. Metastasis is rare but may be identified elsewhere along the spinal cord. In one report of a 2-yearold Basset hound, two lesions were identified: one intradural-extramedullary mass at the T11-12 spinal cord segments and a second intradural-extramedullary mass affecting the spinal cord between the L4 through L6 segments. Histologically, both masses were diagnosed as spinal nephroblastoma based on morphologic and immunohistochemical staining characteristics.12 The mass in the lumbar segments had more features of malignancy, displayed less differentiation, and infiltrated the nerve roots and perivascular regions of the spinal cord white and grey matter. Therefore, the mass at T11-T12 was considered the primary neoplasm whereas the mass located in the lumbar vertebral column was considered metastatic. While less likely, separate de novo neoplasms were also considered. Given that the spinal cord nephroblastoma was located within the subarachnoid space, a potential route of metastatic spread could have occurred via migration in CSF. Spread along the subarachnoid space has been proposed as a means of explaining multifocal lesions in which the histologic appearance of the lesions did suggest that one focus was the primary tumor while the other sites represented metastases.13 Spread along the route of flow of CSF (ie, within the ventricular system of the brain, central canal of the spinal cord, or subarachnoid space) is known to occur with other neoplasms that are adjacent to CSF such as choroid plexus neoplasms.14 Alternatively, metastasis may have been hematogenous.
In the end, despite their rarity, the finding of multifocal intradural-extramedullary or intramedullary lesions in a young dog should not exclude consideration of spinal cord nephroblastoma. It is important to recognize that spinal cord nephroblastoma does not imply abnormalities in the kidneys. Primary renal nephroblastoma has also been reported in dogs and appears to have a different profile of malignancy and tendency to metastasize. Therefore, dogs with known or suspected spinal cord nephroblastoma do not need imaging of their kidneys unless there is another indication (ie, the presence of polyuria/polydipsia, azotemia, or proteinuria). In such a case, an alternative disease process is likely to underlie these urinary abnormalities.
Conservative therapy vs definitive therapies
Conservative therapy often consists of corticosteroids and analgesics.6 Regardless of the mechanism of effect, conservative therapy typically loses efficacy as the neoplasm continues to grow and compresses the spinal cord.6 Definitive therapies include cytoreductive surgery alone or combined with radiation therapy. The disparity between the following two studies is not understood but may reflect the small case numbers in each study. Differences in owner decisions to euthanize an affected patient, surgical techniques and experience, or location of the neoplasm (ie, whether there is spinal cord invasion) also may be factors affecting the reported survival time in these reports:
- In one study, cytoreductive surgery or radiation therapy (median survival time, 374 days) resulted in longer survival times as compared with conservative treatment (median survival time, 55 days).6
- In another study, median survival time was only 70.5 days in dogs treated with cytoreductive surgery as compared with a survival time of 2 days in the one dog treated conservatively.7
- When considering all histological types of neoplasia affecting the spinal cord, an intramedullary location of a neoplasm results in a shorter survival time (median 140 days) as compared with an intradural-extramedullary neoplasm (median 380 days).6
Benefits of cytoreductive surgery and radiation treatment
Although the benefit of cytoreductive surgery has been studied, few reports have detailed the efficacy of radiation therapy as adjunctive or sole treatment in dogs with nephroblastoma of the spinal cord.
- One dog treated with radiation therapy alone (total dose of 51 Gy given in 3-Gy fractions for 17 fractions) survived 269 days, at which time it died from progressive local disease.6
- • Another dog treated with cytoreductive surgery and perioperative 30% polyethylene glycol therapy, followed by corticosteroids and radiation therapy (total dose of 45 Gy given in 3-Gy fractions for 15 fractions) survived more than 2.5 years following treatment without recurrence.7
- Another dog treated with cytoreductive surgery and postoperative radiation therapy (total dose of 44 Gy given in 4-Gy fractions for 11 fractions) survived 5.5 years, at which time the dog was euthanized because a vertebral osteosarcoma had developed at the site of radiation treatment.15 It was thought to represent radiation-induced osteosarcoma. No evidence of the original nephroblastoma was observed at necropsy.
As demonstrated, present-day recommendations for radiation therapy vary in an effort to minimize late radiation-induced side effects. The benefits of highly conformational techniques, such as intensity-modulated radiation therapy and volumetric modulated arc therapy, remain unknown.
As significant advancements in radiation therapy have been made, postoperative radiation therapy is becoming increasingly utilized for veterinary patients with a wide array of neoplasms. Intensity modulated radiation therapy and volumetric modulated arc therapy are methods by which highly accurate dosing of radiation can be directed at the target tissue (ie, neoplasm).16 Importantly, modern radiation units with on-board cone beam CT (a method by which the radiation unit can acquire CT images with submillimeter resolution as a means of ensuring the accuracy of delivery of radiation) enable precise dosing of the target tissue with each treatment while sparing the surrounding normal spinal cord. Precise and accurate planning and delivery of radiation is of utmost importance when treating neoplasms that are in close proximity to the spinal cord. While relatively insensitive to the acute effects of radiation, the spinal cord can suffer late radiation adverse effects.17 Late effects are typically observed after a latent period of more than 6 months to sometimes years following radiation therapy. Late effects include radiation induced fibrosis, atrophy, and vascular and neural tissue damage.17 These late effects become important to consider when contemplating radiation therapy in patients that may experience long term control of their cancer. In cases of spinal cord nephroblastoma, cytoreductive surgery followed by radiation therapy may provide survival times long enough that the patient may realize late radiation therapy. The main benefit to using highly conformational radiation therapy methods is to help minimize the risk of late effect to the spinal cord. Consultation with a radiation oncologist is always recommended to obtain the latest information and treatment recommendations.
While the current literature suggested a guarded prognosis, this case reported here, along with isolated case reports, exemplifies the potential for marked, long-term survival following cytoreductive surgery and radiation therapy in dogs with nephroblastoma affecting the spinal cord. Further studies are needed to document the therapeutic benefits of cytoreductive surgery or radiation therapy alone or in combination.
Moreover, until improved prognostic indicators can be identified and survival times defined, clinicians should not only provide owners with survival times as reported in dogs with spinal cord nephroblastoma but also cautiously describe anecdotal case examples that highlight the potential for long-term survival with cytoreductive surgery and radiation therapy. Ultimately, practitioners should consult an ACVIM board-certified neurologist or oncologist or an ACVR board-certified radiation oncologist for current recommendations in dogs with spinal cord nephroblastoma.
Drs Meiman and Glass, a board-certified neurologist and neurosurgeon, are affiliated with Red Bank Veterinary Hospital in Tinton Falls, New Jersey; Dr Kent is professor of neurology, small animal medicine and surgery at University of Georgia College of Veterinary Medicine; Dr Silver is a board-certified neurologist and neurosurgeon affiliated with Massachusetts Veterinary Referral Hospital, Woburn; and Dr Song is a board certified neurologist and neurosurgeon with Animal Emergency & Specialty Center in Parker, Colorado.
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