Suspected recurrent sarcoma resembling feline injection-site sarcoma with spinal cord invasion in a cat

Abstract

Case summary

A 6-year-old, neutered male domestic shorthair cat was referred for evaluation of a recurrent subcutaneous mass on the right caudodorsolateral hip, 4 months after excision of a presumed feline injection site sarcoma (FISS). Advanced imaging revealed a bilobed soft tissue mass closely associated with the sciatic nerve and rectum. Surgical excision was limited by adjacent structures, and histopathology confirmed a sarcoma with incomplete margins. Definitive-intent radiation therapy was administered postoperatively. Follow-up imaging initially demonstrated no evidence of local recurrence. Approximately 9 months after completion of radiation therapy, the cat developed progressive pelvic limb paraparesis, fecal incontinence and urinary retention. MRI identified a large contrast-enhancing extradural spinal lesion extending from L5 to the sacrum, with suspected intramedullary invasion and marked thickening of the lumbosacral nerve roots. Surgical exploration with hemilaminectomy and spinal cord biopsy revealed a poorly differentiated sarcoma histologically similar to the original tumor. Progressive disease was confirmed on follow-up imaging, and palliative radiation therapy was administered. Despite treatment, the cat developed severe neurologic deterioration and was humanely euthanized.

Relevance and novel information

This report describes the first documented case of spinal cord invasion secondary to a FISS-like fibrosarcoma without local recurrence at the primary site. Perineural invasion along the sciatic nerve is proposed as a biologically plausible mechanism of tumor extension. This case highlights an uncommon but severe pattern of disease progression and underscores the importance of considering perineural spread in incompletely excised FISS-like tumors associated with major peripheral nerves.

Plain language summary

Recurrent tumor affecting the spinal cord in a cat

Injection site sarcomas are aggressive cancers in cats that can develop at sites of previous injections or inflammation. These tumors often grow quickly and can be difficult to fully remove with surgery, especially when they are located near important structures such as nerves or organs. In this case, a 6-year-old cat developed a cancerous mass on his right hip that recurred shortly after initial surgery. Because the tumor was close to the sciatic nerve and rectum, complete removal with wide margins was not possible. Radiation therapy was used to help control the disease, and imaging initially suggested the cancer was stable. Several months later, the cat began showing signs of nerve damage, including weakness in the back legs, difficulty jumping, and loss of bowel and bladder control. Advanced imaging of the spine revealed a new mass compressing and invading the spinal cord. Surgery and biopsy confirmed that this lesion was also cancerous and likely related to the original tumor. Despite additional radiation treatment, the cancer progressed, leading to severe neurologic decline. The cat was ultimately euthanized for quality-of-life reasons. This case is important because it documents a previously unreported complication of injection site sarcoma: spread of the tumor into the spinal cord. The findings suggest that cancer cells may travel along nerves, even when no mass is visible at the original surgery site. Greater awareness of this potential behavior may help veterinarians better monitor and manage cats with aggressive sarcomas, particularly when tumors are located near major nerves.

Introduction

Feline injection site sarcomas (FISS) are malignant mesenchymal tumors characterized by rapid growth, local invasiveness and frequent recurrence. ¹ Approximately one in 10,000 cats receiving injections develops FISS (0.010%), and distant metastasis to the lungs or draining lymph nodes occurs in 10–25% of cases.^1–4 Wide surgical excision is the cornerstone of treatment; however, even with margins of 5 cm laterally and two fascial planes deep, recurrence occurs in approximately 14% of cases. ⁵ Recurrence rates are influenced by adjuvant therapy, most commonly radiation therapy, electrochemotherapy or doxorubicin-based chemotherapy, as well as the ability to obtain wide margins based on tumor location and size, and surgeon skill level, among other factors. ⁵

The pathogenesis of FISS is incompletely understood but is hypothesized to involve malignant transformation of fibroblasts and myofibroblasts induced by chronic local inflammation.^6–9 Histopathologic features often include lymphocytic infiltration, necrosis and multinucleated giant cells.^2,3,8,10,11 Although most FISS are classified as fibrosarcoma, other sarcoma subtypes have been reported, including rhabdomyosarcoma, liposarcoma, myxosarcoma, poorly differentiated or undifferentiated sarcoma, nerve sheath tumor, chondrosarcoma and extraskeletal osteosarcoma.^8,12–15

Although most commonly associated with vaccination-related inflammation, similar tumors have been described along surgical scars and associated with foreign material, such as non-absorbable suture, microchips, and injectable chemotherapeutics.^6,13,16–20 Here, we report a case of a recurrent FISS-like sarcoma involving the right caudodorsolateral hip with subsequent spinal cord invasion, representing either aggressive local recurrence, perineural extension or, less likely, regional metastasis.

Case description

A 6-year-old, neutered male domestic shorthair cat was presented for assessment of a firm, fixed, approximately 2 cm subcutaneous mass on the right caudodorsolateral hip. Four months prior, a mass was incompletely excised from a similar location by the referring veterinarian and diagnosed as fibrosarcoma, presumed FISS, with a mitotic index of 22 mitotic figures per 10 high-power fields at 400× magnification and moderate peritumoral lymphocytic infiltration. The cat had a history of receiving rabies vaccinations in the same anatomical region with the primary veterinarian. The new mass developed approximately 2 months after excision and was distinct from the original surgical scar. Physical examination revealed no abnormalities other than the subcutaneous mass.

Pre-referral laboratory testing identified a moderate thrombocytopenia with platelet clumping (108  × 10³ platelets/μl, reference interval [RI] 300–700), mild hyperproteinemia (total protein 8.3 g/dl, RI 5.8–8.0) and mildly increased creatine kinase (444 U/l, RI 10–250). Owner consent for all diagnostics and treatments was obtained. Thoracic and pelvic CT revealed a lobulated subcutaneous soft tissue mass along the right caudodorsolateral thigh with peripheral contrast enhancement (Figure 1). Two 2 mm contrast-enhancing nodules in the cutaneous tissues cranial to the mass and mild right sacral lymphadenopathy were noted.

Figure 1.

Pelvic CT revealed a lobular, subcutaneous soft tissue structure along the right caudodorsolateral thigh. (a) Transverse plane after contrast showing a lobular, rounded, soft tissue mass (outlined by red arrowheads). The lateral lobule of the mass measured 2.6 × 1.9 × 2.0 cm; the medial lobule measured approximately 2.3 × 1.0 × 1.0 cm. (b) Sagittal plane showing the caudodorsolateral thigh mass (outlined by red arrowheads). (c) The mass (red circle) was closely associated with the sciatic nerve (yellow arrowheads). (d) The medial lobule of the mass (outlined by red arrowheads) terminated adjacent to the rectum (blue circle)

Surgical excision was performed with approximately 1 cm lateral margins and one fascial plane deep, limited by the proximity of the rectum and sciatic nerve. Histopathology revealed an infiltrative neoplasm composed of interwoven bundles of spindle cells with moderate anisocytosis and anisokaryosis, occasional karyomegaly and binucleation, and a mitotic index of 40 with bizarre mitotic figures (Figure 2). Low to moderate numbers of macrophages and multifocal lymphocytic aggregates were observed. The mass was diagnosed as a sarcoma, suspected to be recurrence of the original fibrosarcoma, and neoplastic cells extended to within <1 mm of the margins. Immunohistochemistry was not performed.

Figure 2.

Histopathology of the primary tumor revealed an infiltrative neoplasm composed of interwoven and streaming bundles of neoplastic spindle cells (hematoxylin and eosin staining, 200× magnification, scale bar 50 µm)

Definitive-intent radiation therapy (RT; 2.7 Gray [Gy] × 20 daily fractions using a volumetric-modulated arc therapy technique) was administered to the surgical site and right sacral lymph node 21 days postoperatively (Table 1). Treatment was delivered with 6 megavolt photons using a CT-guided isocentric plan. A restaging CT performed 155 days after RT demonstrated no gross evidence of tumor recurrence (Figure 3). Mild splenomegaly was noted.

Table 1.

Dose statistics (reported in Gray [Gy]) for the definitive radiation therapy course, delivered using a Varian TrueBeam linear accelerator (Varian Medical Systems)

September 2021 2.7 Gy × 20 (VMAT, consecutive days)
Structure	D2.0% (near max)	D50% (mean)	D98% (near min)
PTV (CI 0.97)	56.45	55.29	51.64
Colon	54.04	7.89	0.27
Spinal cord	55.21	0.91	0.21
Urethra	51.98	33.34	18.53

Treatment consisted of 6 megavolt photons at a 6 Gy/min dose rate. The plan was a CT-guided, isocentric (single isocenter) computer-planned volumetric modulated arc therapy (VMAT) technique with a 5 mm bolus over the treated area. Hemoclips and the surgical scar were contoured as the gross tumor volume to guide the treatment field. A 3 cm expansion was applied to generate the clinical target volume (CTV) around the primary target (no CTV expansion around the lymph node, respecting normal tissue planes, resulting in an asymmetric CTV), followed by a 3 mm isometric expansion for planning target volume (PTV) (CTV and PTV cropped to skin). Total dose delivered was 2.7 Gy × 20 daily fractions

CI = conformity index

Figure 3.

Abdominal CT performed 155 days after radiation therapy (RT) showed no recurrence at the previous surgical site. (a,b) Transverse planes showing the previous surgical site after contrast administration. There was no contrast enhancement at the surgical site. Hemoclips placed intraoperatively at the surgical margins for RT planning are shown by the blue arrowheads. There was diffuse mild to moderate atrophy of the right-sided gluteal musculature. (c) Sagittal plane of the previous surgical site after contrast administration. There was no contrast enhancement at the surgical site. Hemoclips placed intraoperatively at the surgical margins for RT planning are shown by the blue arrowheads

At 281 days after RT, the cat presented for fecal incontinence and progressive bilateral plantigrade posture. Physical examination revealed urinary bladder distention and severe caudal thigh musculature atrophy. No mass was palpated. Neurologic examination revealed severe ambulatory paraparesis, proprioceptive ataxia, plantigrade posture, withdrawal hyporeflexia, delayed extensor postural thrust reaction, decreased anal tone, and tail plegia. The patellar reflexes were normal, tail nociception was intact and no pain was elicited on paraspinal palpation. The thoracic limbs were normal, consistent with an L4–S3 myelopathy. MRI identified a large, space-occupying lesion extending from the caudal endplate of L5 to the end of the sacrum, occupying the majority of the diameter of the spinal canal. The lesion appeared to be extradural because of elevation of the epidural/subarachnoid ventral space at L5/6 and dorsal displacement of the spinal cord. Intramedullary infiltration was suspected owing to a loss of delineation of the spinal cord and cauda equina distal to the L6–L7 intervertebral disc space. In comparison to the spinal cord, the lesion was mildly T2 hyperintense and heterogeneous, isointense and homogeneous on T1-weighted images, and severely, diffusely, mildly heterogeneously enhancing after contrast administration. The central canal cranial to the lesion was mildly widened. The L7–S1 nerve roots were severely thickened, right worse than left and enhanced similarly to the space-occupying lesion. Representative images from the MRI examination are presented in Figure 4. Because lymphoma was a differential diagnosis, an abdominal ultrasound and splenic aspirates were performed 301 days after RT. There was no evidence of neoplasia.

Figure 4.

MRI showed a large, space-occupying lesion suspected to be extradural and intramedullary, extending from caudal L5 to the end of the sacrum. (a) T1-weighted (T1W) sagittal planes before (a.1) and after (a.2) contrast. The post-contrast image shows an isointense and homogeneous lesion (red arrowheads) beginning at the caudal endplate of the L5 vertebra. (b) T1W transverse planes after contrast. (b.1) T1W transverse plane at midbody of the L5 vertebra showed a normal spinal cord with no enhancement. (b.2) T1W transverse plane at the caudal aspect of the L5 vertebra showed a diffusely enhancing lesion (outlined by red dashed line). (b.3) T1W transverse plane at midbody of the L6 vertebra showed a diffusely enhancing lesion (outlined by red dashed line) occupying nearly the entire diameter of the spinal canal. (c) A dorsal plane short tau inversion recovery sequence identified focal widening of the central canal (blue arrows) at midbody of the L5 vertebra, just cranial to where the space-occupying lesion was visualized. (d) A T1W transverse plane post-contrast image showing severe thickening of the L7–S1 nerve roots, with more significant thickening of the right (red arrowheads) compared with the left (blue arrowheads)

At 322 days after RT, the cat presented to our surgical oncology service for evaluation of the spinal cord lesion. The owner reported the cat was fecally incontinent and required bladder expression every 8 h. Physical examination noted severe atrophy of the pelvic limb musculature bilaterally. Neurologic examination revealed bilateral plantigrade posture, proprioceptive ataxia in the pelvic limbs, decreased withdrawal reflexes, decreased anal tone, severely delayed pelvic limb hopping and tail plegia. The risks of proceeding with a hemilaminectomy, including inability to excise the suspected mass and worsening clinical signs, were discussed with the owner preoperatively.

An L4–L7 hemilaminectomy and durotomy were performed. The spinal cord cranial to L6 appeared grossly normal. Caudal to L6, there was a red-to-brown discoloration of the spinal cord without a distinct mass (Figure 5). Surgical biopsies were collected and submitted for histopathology. The cat recovered uneventfully, remained neurologically stable and was discharged 3 days later.

Figure 5.

An L4–L7 left hemilaminectomy revealed gross abnormality and red-to-brown discoloration of the spinal cord extending from L6 caudally (white dashed line). No extradural mass was appreciated. The spinal cord cranial to L6 appeared grossly normal (white arrow). Surgical biopsies were taken from the discolored portion of the spinal cord

Histopathology identified a proliferative neoplasm of poorly differentiated cells forming haphazard streams and whorls, with large hyperchromatic nuclei, frequent bizarre multinucleated cells, marked anisocytosis and anisokaryosis, and a mitotic index of 12 (Figure 6). There were occasional foci of pale basophilic granular material. The cells were negative for CD45 and pan-cytokeratin and strongly positive for vimentin, consistent with sarcoma of unknown origin. Given the cat’s history of incompletely excised FISS-like fibrosarcoma with close proximity to the sciatic nerve and the spinal cord lesion beginning at L6, extension of the previously incompletely excised fibrosarcoma is considered the most likely diagnosis.

Figure 6.

Histopathology and immunohistochemistry of the spinal cord surgical biopsies. (a) Hematoxylin and eosin photomicrograph of the neoplastic cells. (b) Photomicrograph of the negative staining pan-cytokeratin immunohistochemistry. (c) Photomicrograph of the CD45 immunohistochemical staining demonstrating scattered positive intracytoplasmic staining interpreted as infiltrating non-neoplastic macrophages and negative staining of the neoplastic cells. (d) Photomicrograph of vimentin immunohistochemical staining demonstrating strong positive intracytoplasmic staining of the neoplastic cells. The scale bar in all panels represents 20 µm, 400× magnification

A follow-up MRI performed 29 days later (352 days after RT), owing to worsening ambulation and for RT planning, revealed progression of the intramedullary lesion with extension into the paralumbar musculature through the hemilaminectomy site (Figure 7). Palliative RT (4 Gy × 5 daily fractions using a three-dimensional conformal radiation therapy technique) (Table 2) was administered using a CT-guided isocentric plan, with the field focused on the primary mass without inclusion of regional lymph nodes. The cat’s neurologic signs gradually progressed to tetraplegia with tachypnea, and he was humanely euthanized 474 days after RT. Necropsy was declined. A summary timeline of this case can be found in Table 3.

Figure 7.

A limited series MRI for palliative radiation therapy (RT) planning revealed progression of the intramedullary sarcoma when compared with the previous MRI. (a) At 290 days after RT, a T1-weighted (T1W) post-contrast administration transverse plane showing a contrast-enhancing space-occupying lesion (outlined by red dashed line). This slice was located at the caudal aspect of the L6 vertebra. (b) At 352 days after RT, a limited series MRI was performed because of worsening neurologic deficits. A T1W post-contrast administration transverse plane at L6 showed that the lesion (outlined by blue dashed line) was occupying nearly the entirety of the vertebral canal with extension into the paralumbar musculature. There was marked diffuse muscle atrophy relative to the MRI performed 290 days after RT

Table 2.

Dose statistics (reported in Gray [Gy]) for the palliative radiation therapy course, delivered using a Varian TrueBeam linear accelerator (Varian Medical Systems)

September 2022 4 Gy × 5 (3D-CRT, consecutive days)
Structure	D2.0% (near max)	D50% (mean)	D98% (near min)
PTV	20.95	20.52	19.64
Colon	20.34	9.14	0.41
Spinal cord	20.44	1.88	0.18
Urethra	14.54	0.86	0.24

Treatment consisted of 6 megavolt photons at a 6 Gy/min dose rate. The plan was a CT-guided, isocentric, computer-planned three-dimensional conformal radiation therapy (3D-CRT) technique using five beams, with field-in-field segments as needed to improve dose homogeneity, and a 5 mm bolus over the treated area. A 5–10 mm expansion around the gross tumor volume was used to generate the clinical target volume (CTV) depending on proximity to organs at risk, followed by a 3 mm isometric expansion for the planning target volume (PTV) (CTV cropped out of colon; CTV and PTV cropped to just inside the skin). Total dose delivered was 4 Gy × 5 daily fractions

Table 3.

Timeline of significant events during case management

Day	Event
–47	Initial presentation to surgical oncology for evaluation of a recurrent fibrosarcoma
–46	Surgical excision of recurrent mass; incomplete excision due to close association with sciatic nerve
–45	Patient discharged
–25	Start of definitive-intent radiation therapy with radiation oncologist (2.7 Gray × 20 fractions)
0	Definitive-intent radiation therapy completed
155	No obvious tumor recurrence appreciated on abdominal and pelvic CT scan
281	Patient presented to radiation oncologist for progressive plantigrade stance and fecal incontinence
290	MRI identified intraspinal space-occupying lesion extending from L5 to the sacrum
322	Patient presented to our surgical oncology service for evaluation and removal of spinal mass
323	L4–L5, L5–L6 and L6–L7 hemilaminectomy with abnormal spinal cord surgical biopsies performed
325	Patient discharged
352	Repeat MRI performed because of worsening ambulation and for radiation planning; progressive disease identified
356	Start of palliative radiation therapy
360	Palliative radiation therapy completed
495	Patient humanely euthanized

Discussion

One prior report described a FISS-like rhabdomyosarcoma that was found within the spinal canal at recurrence, 3 months after initial excision; that cat received no adjuvant therapy and the recurrence was untreated. ²¹ As in our case, the cat developed progressive paraparesis leading to paraplegia and was euthanized. Unlike our case, necropsy of the previously reported cat identified two epidural masses causing epidural compression and regional myelomalacia, with no evidence of intramedullary invasion on histopathology. ²¹

Our case is the first report of spinal cord invasion secondary to a FISS-like tumor and the first to describe attempted definitive treatment. The approximately 1-year survival exceeds that reported for the cat with rhabdomyosarcoma in the spinal canal and for incompletely excised FISS-like tumors at other sites.^2–5,12,21 Progression to tetraplegia was most likely due to cranial tumor extension, as progressive disease was noted on follow-up MRI. Because necropsy was declined, a late adverse effect from radiation, ascending myelomalacia or multifocal metastatic disease cannot be definitively excluded; however, these are considered less likely. In particular, progressive myelomalacia is rare in cats and has been attributed to trauma, vascular events, fibrocartilaginous embolisms, or infiltrative round cell neoplasia compressing the spinal cord.^22–27

Spinal cord infiltration in this case was suspected to be an extension of the incompletely excised primary tumor. Local recurrence is reported in 14% of FISS with 5 cm lateral margins. ⁵ In this case, wide margins were not possible and incomplete excision was confirmed. The risk of local recurrence with incomplete excision is up to 10 times the risk with complete excision. ²⁸ However, metastasis or a novel intramedullary sarcoma cannot be definitively excluded. Despite the primary tumor’s close association with the sciatic nerve, a peripheral nerve sheath tumor is considered unlikely because of the lack of Verocay bodies and Antoni A patterns on histopathology. ²⁹ The histopathology of the biopsies was similar to the initial tumor, supporting that the intramedullary sarcoma was due to local extension or metastasis. Although the metastatic biopsies demonstrated a lower mitotic count than the primary tumor, similar decreases in proliferative markers between primary and metastatic sites have been documented in other tumor types, and may reflect microenvironment‑dependent shifts in tumor cell behavior rather than true biological regression.^30–32 The lungs and regional lymph nodes are the most common sites for metastatic FISS; other previously reported sites include skin, spleen, eye and disseminated disease through multiple organs.^12,21,33,34 Infiltrative metastasis to the central nervous system has not been previously described.

This case supports further investigation of perineural invasion as a possible mechanism of FISS extension without local recurrence at the primary site. Perineural invasion is well described in human oral squamous cell carcinomas, pancreatic, prostatic, gastric, biliary and colorectal carcinomas, and is a negative prognostic indicator in colorectal tumors.^35–37 Although not previously documented in fibrosarcoma, specifically, perineural invasion has been reported in osteosarcoma, pleomorphic dermal sarcoma, and Ewing sarcoma.^38,39 In this case, proximal perineural invasion along the sciatic nerve is a plausible mechanism by which the tumor infiltrated the spinal cord. The absence of primary tumor recurrence at the surgical site on follow-up CT is notable, although microscopic perineural extension may not be detectable with current imaging modalities. This case illustrates the need for greater understanding of FISS extension and metastatic mechanisms to improve monitoring strategies and guide therapeutic recommendations.

Conclusions

This case is the first reported instance of spinal cord invasion secondary to a FISS-like fibrosarcoma without local recurrence at the primary site. Perineural invasion along the sciatic nerve is proposed as a plausible mechanism of tumor extension to the spinal cord. There is a need to further investigate FISS-like tumor extension along peripheral nerves, particularly when the primary tumor is closely associated with major nerves and incompletely excised. Further investigations into central nervous system involvement in FISS-like tumors is warranted to improve prognostication and guide treatment planning.