Dedifferentiated Chondrosarcoma in the Dog and Cat: A Case Series and Review of the Literature
ABSTRACT
This retrospective case series describes seven dogs and one cat diagnosed with dedifferentiated chondrosarcoma, an uncommon, aggressive variant of chondrosarcoma. The purpose of the study is to describe clinical, imaging, and histopathological findings of this tumor. Medical records and the diagnostic laboratory database at Colorado State University from 2000 to 2015 were reviewed and complete medical records were available for the eight animals in this report. Similar to what has been reported in people, poor long-term survival and high metastatic rate, particularly to the lungs, was observed in our case series. A bimorphic pattern on imaging (radiographs, computed tomography, and MRI) consisting of mineralized and nonmineralized areas was seen mirroring the high-grade sarcomatous component adjacent to a low-grade chondroid component seen histopathologically. A review of the human literature including suspected etiology, imaging findings, histopathology, and survival times with various treatment options is presented. This article describes the first reported cases of dedifferentiated chondrosarcoma in the veterinary literature. Early accurate recognition could lead to treatment plans tailored to this variant.
Introduction
Chondrosarcoma is the second most common primary bone tumor in people and dogs and is characterized by tumor cells producing a cartilaginous matrix.1–5 In veterinary patients, this tumor has been reported in the axial and appendicular skeleton, nasal cavity, and extraskeletal sites.5–7 A variety of histological types including conventional, secondary, dedifferentiated, clear cell, periosteal, and mesenchymal chondrosarcomas have been reported in the human literature, with conventional chondrosarcoma being the most common.8 To the authors' knowledge, dedifferentiated chondrosarcoma, the most aggressive variant in people, accounting for 10% of all chondrosarcomas, has not been described in veterinary patients.8–12 A high-grade sarcomatous component adjacent to a low-grade cartilaginous component, referred to as a bimorphic pattern, confirms the diagnosis of a dedifferentiated chondrosarcoma on histopathology.
The purpose of this report is to describe the clinical, diagnostic, therapeutic, and histopathologic findings associated with a series of seven dogs and one cat diagnosed with dedifferentiated chondrosarcoma. Human literature is reviewed and the authors propose that this variant exists in veterinary medicine and is likely misdiagnosed as a high-grade conventional chondrosarcoma. Earlier diagnosis of this variant could lead to a tailored treatment plan and a more accurate prognosis in veterinary patients.
Materials and Methods
Dogs and cats with dedifferentiated chondrosarcoma were identified by searching the Colorado State University medical records database and submissions to the Colorado State University Veterinary Diagnostic Laboratory (VDL) from 2000 to 2015. For the 15 yr study period, two searches were performed. The first search comprised dogs and cats with histopathologically confirmed dedifferentiated chondrosarcoma, and the second search comprised all dogs and cats diagnosed with chondrosarcoma regardless of grade and subtype. The Colorado State University VDL anatomic pathologists and anatomic pathology residents trained to recognize this variant have been cataloging it as such since 2000, with confirmation of diagnosis in all cases by a veterinary pathologist (B.E.P.) at the diagnostic laboratory with the most experience in musculoskeletal oncologic pathology. Histopathology reports from the second search were reviewed in an attempt to help identify any cases not identified in the first search. Specifically, the reports were reviewed for mention of intermediate- to high-grade tumor designations, bimorphic pattern description, and/or sarcomatous component in the description. Slides from these cases concerning for dedifferentiation were then reviewed by the same pathologist (B.E.P.).
For cases sent to the VDL as external biopsy submissions either for primary or secondary review, the primary care veterinarian, referral hospital, and diagnostic laboratory were contacted for medical records and follow-up. Information obtained from medical records included date of diagnosis, signalment, location of the tumor, labwork, imaging when available, cytopathology reports, surgery reports, histopathology reports, treatment, time from detection of clinical signs to presentation, progression-free survival (PFS), and survival time (ST). For the purposes of this report, PFS was defined as the time from initiation of treatment (surgery, radiation therapy, or chemotherapy) until the first noticeable sign of disease progression. Disease progression included worsening of clinical signs, local recurrence, increase in size of the primary mass, development of additional masses, or pulmonary metastasis. Survival time was defined as the time from the date of diagnosis until death or euthanasia due to disease progression.
Results
During the 15 yr study period, one dog and one cat were treated at the Colorado State University . Twelve additional dogs, patients at other facilities, were identified from biopsy specimens analyzed by the Colorado State University VDL during the same time period. Review of histopathology reports for all animals with a diagnosis of chondrosarcoma regardless of subtype yielded 10 cases with a high-grade designation whose slide review did not confirm a diagnosis of dedifferentiated chondrosarcoma. Limited medical records were available for six dogs, including signalment, location of the tumor, sample submission history, and histopathology reports. All six dogs were large-breed dogs and with ages ranging from 3 to 12 yr. Tumor locations in this group included axial skeleton (n = 2; ribs), nasal cavity (n = 2), and extraskeletal sites (n = 2; flank and unknown subcutaneous location). Summary of signalment, tumor location, treatment, time from detection of clinical signs to presentation, PFS, and ST for the seven dogs and one cat with complete medical records is presented in Table 1. Tumor locations for this group of animals included axial/appendicular skeleton (n = 3; humerus, femur, mandible), nasal cavity (n = 3), and extraskeletal sites (n = 2; abdominal wall, paralumbar region).
Of the 14 known cases of dedifferentiated chondrosarcoma, tumors in the axial/appendicular skeleton (n = 5) and nasal cavity (n = 5) were most common, followed closely by extraskeletal sites (n = 4). Case reports of the eight animals with complete medical records presented in this manuscript have been grouped based on locations. Four of eight veterinary patients in this report had pretreatment biopsies (three incisional and one excisional). All four animals were initially misdiagnosed as having a conventional chondrosarcoma. The mean and median PFS times were 138 days (4.6 mo) and 147 days (4.9 mo). Regardless of location, rapid progression to metastasis and death occurred with mean and median STs of 238 days (7.9 mo) and 233 days (7.7 mo).
Case Report
Cases 1, 2, and 3 (Axial and Appendicular Skeleton)
Case 1, an 11 yr old male castrated domestic shorthair, was evaluated for a rapidly growing firm mass in the right proximal humeral region causing lameness. Radiographs of the right humerus showed osteolysis of the proximal humerus. An incisional biopsy performed was consistent with an intermediate- to high-grade chondrosarcoma. The patient was referred for further evaluation to the Colorado State University.
A complete blood count (CBC) and serum diagnostic chemistry profile (SDP) were unremarkable. A feline leukemia virus and feline immunodeficiency virus test was negative. Subsequent radiographs performed revealed a soft-tissue mass with areas of mineralization in the mid-diaphyseal region with periosteal reaction, lysis, and irregular margination of the cranial aspect of the diaphysis. Three-view thoracic radiographs performed were normal. A forequarter amputation was performed and a bimorphic histopathological pattern consisting of a well-differentiated low-grade chondrosarcoma of the bone and a dedifferentiated high-grade sarcoma of the mass in the muscles surrounding the humerus was noted, confirming a diagnosis of dedifferentiated chondrosarcoma. Surgical margins were tumor-free and no regional metastasis was noted in the axillary lymph node.
Thoracic radiographs and physical examinations performed 2 wk and 3 mo after surgery were unremarkable. The cat was evaluated again 8 mo after initial presentation for a rapidly growing large mass on the right rear limb. Radiographs of the thorax and right rear limb revealed multiple nodules ranging from 1 cm to 6 cm in size in the lungs consistent with metastatic neoplasia and a large soft-tissue mass with areas of mineralization as well as underlying periosteal reaction along the distal diaphysis of the femur consistent with probable neoplastic periostitis. Humane euthanasia was elected by the owner.
Case 2, a 10 yr old male castrated Australian shepherd, was evaluated for progressive weight-bearing lameness on the right rear limb. A large, firm mass in the subcutaneous tissue of the proximomedial aspect of the right femur was noted. Three-view thoracic radiographs performed were normal. Right femoral radiographs revealed a soft-tissue mass with associated bony lysis noted on the proximomedial aspect. Excisional biopsy with histopathology was performed and changes were reported as a low-grade chondrosarcoma with tumor extension to the margins of the sample submitted.
Two mo after mass removal, lameness recurred in the right rear limb. A large firm mass was noted in the musculature of the right caudal thigh in addition to recurrence at the proximomedial thigh. The dog was referred to a veterinary oncologist. Labwork was unremarkable. Thoracic radiographs were free of metastasis. Curative-intent surgery with a preoperative MRI to determine the margins needed with a hemipelvectomy, marginal excision with a coxofemoral disarticulation and adjuvant radiation therapy, coxofemoral disarticulation for palliation, and radiation therapy for palliation were discussed with the owner. Coxofemoral disarticulation for pain palliation was pursued. Histopathology evaluated at the Colorado State University revealed well-differentiated low-grade chondrosarcoma that was sharply demarcated from dedifferentiated high-grade areas (Figure 1). Effacement of the right inguinal lymph node with the high-grade sarcomatous component was noted. Surgical margins were narrow but complete.
Citation: Journal of the American Animal Hospital Association 54, 1; 10.5326/JAAHA-MS-6566
Six wk postamputation, the dog was evaluated for adjuvant chemotherapy. Thoracic radiographs performed showed a single 8 mm pulmonary nodule in the right cranial lung lobe consistent with early metastasis. Treatment with doxorubicina at 30 mg/m2 IV every 3 wk for four treatments and piroxicam at 0.3 mg/kg per os (PO) q 24 hr followed by cyclophosphamideb at 10 mg/m2 PO q 24 hr and piroxicam at 0.3 mg/kg PO q 24 hr was initiated. Eight mo following diagnosis, thoracic radiographs performed showed numerous pulmonary nodules consistent with progression of metastatic disease. The patient was humanely euthanized 10 mo following diagnosis.
Case 3, an 8 yr old male neutered golden retriever, was evaluated for an irregular mass causing displacement of teeth in the rostral mandible. No abnormalities were noted on thoracic radiographs. Lateral and oblique radiographs of the rostral mandible performed revealed a rostroventral mandibular soft-tissue mass with lysis of the adjacent bone most consistent with neoplasia. An intermediate- to high-grade chondrosarcoma was diagnosed based on an incisional biopsy. The patient was referred to a veterinary surgeon for a rostral mandibulectomy.
Preanesthetic labwork was unremarkable. A bilateral rostral mandibulectomy caudal to the canines was performed. Histopathology of the mandibular mass was consistent with a dedifferentiated chondrosarcoma; however, tumor cells were noted along the caudal margins of the decalcified mandible. A revision surgery was performed 1 mo after the first surgery to obtain an additional 1 cm of bone margins caudal to premolar 2. Inked surgical margins were free of neoplastic cells.
Six mo following the revision surgery, the dog was evaluated for a 5-day history of coughing and hemoptysis. Thoracic radiographs performed showed variably sized pulmonary nodules consistent with metastatic disease. Prednisonec at 1 mg/kg PO q 24 hr was prescribed for palliation. The dog passed away 3 wk later.
Cases 4, 5, and 6 (Nasal Cavity)
Case 4, a 7 yr old female spayed Labrador retriever, was evaluated for a 6-wk history of progressive upper respiratory obstruction. Several courses of antibioticsd,e,f were empirically tried with little response over that period. On exam, decreased airflow through the left nostril was noted. Labwork consisting of a CBC, SDP, and coagulation panel (PT, APTT) were unremarkable. Rhinoscopy revealed a focal polypoid mass in the left proximal naris, which was biopsied. A bimorphic pattern with well-differentiated tumor in a cartilaginous matrix adjacent to a poorly differentiated noncartilaginous tumor was noted on histopathology.
Six days following a diagnosis of dedifferentiated chondrosarcoma, an alternating chemotherapy protocol of carboplating at 300 mg/m2 IV and mitoxantroneh at 5.5 mg/m2 IV administered every 3 wk was initiated. Piroxicami at 0.2 mg/kg PO q 24 hr was initiated 2 wk after administration of the first carboplatin treatment. Due to an acute onset of epistaxis, the dog was anesthetized for rhinoscopy 8 wk after initial diagnosis. Progression of the tumor was noted with more than 75% occlusion of the nasopharynx at the level of the choanae. Carboplatin/mitoxantrone protocol was discontinued and Palladiaj at 1.5 mg/kg PO was initiated on a Monday, Wednesday, Friday schedule and piroxicam protocol was altered to 0.2 mg/kg PO Tuesday, Thursday, Saturday, and Sunday. Four wk after initiation of Palladia, the dog was clinically stable but continued to have decreased airflow and intermittent epistaxis through the left naris.
Four mo following diagnosis, the patient was evaluated for progressive difficulty breathing. Thoracic auscultation was unremarkable and no air flow was noted through either of the nares. The posterior nares were evaluated by retroflexion of an endoscope and showed a large polyp-like mass occluding the entire left side of the choanae (Figure 2A, B). This lesion was debulked with biopsy forceps for symptomatic relief. The posterior nares were evaluated again 6 mo after diagnosis and complete occlusion of the nasopharynx by a proliferative mass was noted. Seven mo after diagnosis, the dog developed a large swelling over the frontal sinus, which worsened over the following month. Eight mo after diagnosis, the dog passed away at home from respiratory difficulty.
Citation: Journal of the American Animal Hospital Association 54, 1; 10.5326/JAAHA-MS-6566
Case 5, a 9 yr old female spayed Labrador retriever, was evaluated for an 11-mo history of bilateral mucopurulent nasal discharge and a mass exiting the left naris. No improvement in clinical signs was noted with treatment with several different antibioticsk,l or with steroidsm.
Marked swelling over the bridge of the nose was noted. Neurologic exam was normal. A CBC and SDP performed showed an alkaline phosphatase increase (1082; reference range 10–150 U/L). Thoracic radiographs and abdominal ultrasound were declined by the owners. The dog was anesthetized and the mass was biopsied externally for histopathology and tissue culture. Unfortunately, the dog suffered cardiopulmonary arrest during anesthetic recovery. Resuscitation efforts were unsuccessful. An MRI was performed postmortem and showed a mixed intensity mass occupying the entire left nasal passage with extension into the right rostral nasal passage. There was marked lysis of the left nasal turbinates, mild lysis of the right rostral nasal turbinates, and mild lysis of the left rostral aspect of the cribiform plate. There was no distinct evidence of extension of the mass into the calvarium (Figure 3A, B). Histopathology of the mass was consistent with a dedifferentiated chondrosarcoma. Progression-free survival for this patient was unable to be determined because progression occurred over the entire 14-mo period from onset of clinical signs. Survival time was not calculated because a diagnosis was obtained postmortem.
Citation: Journal of the American Animal Hospital Association 54, 1; 10.5326/JAAHA-MS-6566
Case 6, a 6 yr old female spayed German shepherd mix was evaluated for a 1-wk history of mucopurulent right nasal discharge. On examination, right ocular and nasal discharge was noted. No response to empirical antibiotic treatmente,f was noted during a 4-wk period. Labwork performed was unremarkable.
Anesthetized radiographs of the skull revealed a generalized increase in soft-tissue opacity of the right nasal cavity with loss of turbinate detail consistent with a lytic infectious or neoplastic process (Figure 4). Three-view thoracic radiographs were normal. A dorsal rhinotomy was performed and a large reddish-grey mass was noted to be filling 80% of the right nasal cavity. The mass was debulked by the primary care veterinarian and evaluated histopathologically at the Colorado State University VDL. A poorly differentiated neoplasm with small islands of well-differentiated chondrocytes in chondroid matrix was consistent with a dedifferentiated chondrosarcoma.
Citation: Journal of the American Animal Hospital Association 54, 1; 10.5326/JAAHA-MS-6566
Two mo following the dorsal rhinotomy, the patient was doing relatively well, with occasional bouts of right-sided nasal discharge that have been responsive to antibiotics. Thoracic radiographs remain free of metastasis. The dog is alive at the time of submission of this report (100 days after initial presentation).
Cases 7 and 8 (Extraskeletal)
Case 7, an 8 yr old female spayed Welsh corgi, was evaluated for a rapidly growing, large, firm mass on the left caudal thoracic/cranial abdominal wall noted by the owner 4 wk earlier. A fine-needle aspirate of the mass revealed a mesenchymal cell proliferation with atypical cells in a thick pink background consistent with chondroid, osteoid, or collagen matrix suggestive of a neoplasm. Thoracic radiographs performed revealed a soft-tissue mass with mineralized internal component caudal to the last rib on the left abdominal wall, and no metastasis was noted in the lungs (Figure 5A). Small tissue fragments from an incisional biopsy were evaluated by a board-certified pathologist not affiliated with the Colorado State University VDL and findings were consistent with a chondrosarcoma (no grade assigned because of small tissue sample size). The dog was referred to the Colorado State University for further evaluation 2 mo after it was first noted. The owners reported the mass had doubled in size during that period.
Citation: Journal of the American Animal Hospital Association 54, 1; 10.5326/JAAHA-MS-6566
Labwork at the time of referral was unremarkable. A computed tomography (CT) scan of the abdomen pre- and postcontrast showed a minimally rim-enhancing, well-defined, mixed mineral and soft-tissue attenuating mass measuring approximately 16 mm in length × 54.2 mm in width × 62.5 mm in height in the left lateral abdominal wall. Invasion through the musculature into the peritoneal cavity or evidence of abdominal or sublumbar lymphadenopathy was not noted (Figure 5B). Because of rapid change in tumor size, the original biopsy specimen was further evaluated at the VDL at Colorado State University. A bimorphic histopathologic pattern of a well-differentiated chondrosarcoma with an abrupt transition to a poorly differentiated sarcoma was noted (Figure 5C). Curative-intent wide surgical excision with abdominal wall reconstruction, marginal excision followed by intensity-modulated radiation therapy, and stereotactic radiation therapy (SRT) for durable palliation were discussed. The owner elected to proceed with SRT delivered as 10 Gy per fraction over 3 fractions (total dose of 30 Gy).
No follow-up information regarding response to SRT was available for the 17 wk following completion of SRT. The dog presented to the primary care veterinarian for annual vaccinations and decreased energy levels over the previous week at the end of the 17-wk period. Enlargement of the mass with further extension cranially, and a fluid wave on ballottement of the abdomen was noted. Radiographs of the thorax and abdomen were declined by the owners. One wk following this appointment, the dog presented again for anorexia of 4 days' duration, extreme lethargy, and abdominal distention. Abdominal radiographs revealed loss of serosal detail consistent with marked abdominal effusion and enlargement of the mineralized lateral abdominal wall mass with displacement of the intestines. Thoracic radiographs performed revealed multiple variably sized pulmonary nodules consistent with metastasis. Humane euthanasia was elected. The PFS was 143 days and ST was 177 days.
Case 8, a 10 yr old male castrated Siberian husky, was evaluated for a 3-day history of a painful swelling over the right paralumbar region and weight-bearing lameness in the right rear limb. Radiographs of the pelvis including the lumbar spine were taken. An ill-defined ovoid soft-tissue density mass was noted in the right caudal paralumbar region at the level of the fifth to seventh lumbar vertebrae. An MRI performed showed the mass to incorporate the right lateral aspect of the vertebral bodies and the transverse processes of L4 to L7. An ultrasound-guided fine-needle aspirate of the mass post-MRI was performed and was consistent with a chondrosarcoma. Routine labwork was unremarkable. The dog was referred to a veterinary oncologist for further evaluation.
At the time of referral, the mass was measured to be 8 cm in diameter in the right caudal lumbar region with extension into the right flank. Three-view thoracic radiographs were free of metastasis. Cytoreductive surgical excision with histopathology was recommended, followed by adjuvant radiation therapy, because curative-intent surgery was not feasible in this location. Three wk following cytological diagnosis of a chondrosarcoma, marginal excision of all gross disease was performed. Lysis of the right sixth transverse process was noted during surgery. A diagnosis of a dedifferentiated chondrosarcoma was confirmed histopathologically when areas of well-differentiated cartilage characterized by spindloid to polygonal cells within lacunae in a cartilaginous matrix and areas of dedifferentiation consisting of polygonal cells within little to no matrix production were noted. Tumor cells were present at the tissue margins.
Two wk after surgery, the dog was markedly improved, with minimal residual lameness in the right rear limb. The owners elected not to pursue adjuvant radiation therapy. Monthly phone follow-ups were performed by the primary care veterinarian and the dog was clinically doing well with no recurrence of the mass for the first 4 mo after surgery. Five mo after surgery, the dog presented to the primary care veterinarian for recurrence of the mass in the right paralumbar region in addition to bilateral mucopurulent ocular discharge and conjunctivitis. No cause for the ocular discharge was evident on exam and fluorescein stain. Triple-antibiotic ointmentn for the eyes and Tramadol at 3 mg/kg PO q 12 hr for analgesia were initiated. The dog was humanely euthanized 2 wk after this appointment because of worsening pain from the paralumbar mass.
Discussion
Dedifferentiated chondrosarcoma is considered one of the most aggressive primary bone tumors in people.13–15 Although uncommon, the tumor is well documented and studied in the human literature. It was first described in 1971 as a cartilaginous neoplasm characterized by a low-grade chondrosarcoma adjacent to a nonchondroid high-grade sarcoma.16–18 Prognosis is determined by the high-grade component, which can further be classified as osteogenic sarcomas, undifferentiated or anaplastic sarcomas, rhabdomyosarcomas, angiosarcomas, leimyosarcomas, giant-cell tumors, and fibrosarcomas.13,19–22 There has been some controversy whether the anaplastic and cartilaginous components are derived from a common precursor cell or whether they represent separate genotypic lineages (collision tumor).23 Molecular, genetic, and epigenetic studies have shown that both tumor components share some genetic alterations and most likely derive from a single precursor.24,25 A substantial number of genetic alterations occur in the anaplastic components of the two components. This is more indicative that these two clones are separated in the early phases of the disease progress.
Metastasis is the primary reason for the poor STs in humans.9,10 Average time from diagnosis to metastasis in people is 9 wk.15,26 Metastatic lesions frequently occur to lungs (70–82%), viscera (20%), and bones (10%).13,14 Histologically, metastatic lesions consist only of the high-grade component, and metastasis noted at the time of diagnosis has been shown to be a negative prognostic indicator.12,20,24 Similar to human reports, the most common documented site of metastasis was to lungs in three of seven dogs and one cat. The only cat in this series had an additional metastatic lesion to the right femur. Regional lymph node metastasis was noted in one dog and consisted only of the high-grade sarcomatous component.
Imaging and accurate interpretation of the findings is imperative in establishing a preoperative diagnosis because prognosis in people has shown improvement with an aggressive treatment plan.15 Studies in people evaluating the use of radiography have shown similar findings in both central and peripheral dedifferentiated chondrosarcomas. Central dedifferentiated chondrosarcomas arise from within the bone and display an area of cortical breach and an adjacent soft-tissue mass that displays a bimorphic imaging pattern consisting of mineralized and nonmineralized areas.14 Pathologic fractures are common with central dedifferentiated chondrosarcomas. Peripheral dedifferentiated chondrosarcomas are uncommon and arise extracortically or from pre-existing exostoses. In recent publications evaluating radiographic, CT, and MRI findings in people with central and peripheral dedifferentiated chondrosarcomas, the majority of these tumors displayed mineralization that was best visualized on CT and often seen with a bimorphic pattern.27,28 The most consistent finding was the presence of a soft-tissue mass seen in 80% of patients on CT or MRI.27,28 A bimorphic pattern was only evident in one-third of plain radiographs, one-half of the CT scans, and one-third of the MRI images.28 Thus, combining an advanced imaging modality such as a CT or an MRI with conventional radiographs can increase the suspicion of a dedifferentiated chondrosarcoma. In both subtypes of dedifferentiated chondrosarcomas, there tended to be less of a soft-tissue component when the tumor composition had less of a noncartilaginous component appearing radiographically more like a well-differentiated chondrosarcoma. When a large dedifferentiated component was present, the tumor often demonstrated minimal characteristics of a chondrosarcoma.14,28
In the present veterinary report, radiology reports of the humeral and femoral lesions in the cat (Case 1) evaluated by a veterinary radiologist could be consistent with a bimorphic pattern because both a large soft-tissue mass with areas of mineralization and an underlying bone lesion were described (images unavailable for review). Computed tomography scan of the abdomen and abdominal radiographs in Case 7 also shows a mass consistent with a bimorphic pattern described in the human literature consisting of mineralized and nonmineralized areas (Figure 5).
An inaccurate pretreatment diagnosis is common and can result if only the noncartilaginous component is biopsied without careful evaluation of radiographs or cross-sectional CT and MRI images for the presence of a cartilaginous component.15,16 An inaccurate diagnosis can also occur if the lesion is biopsied from the cartilaginous component alone without a biopsy from the noncartilaginous component alone.15,16 Careful assessment of imaging in these tumors often reveals the indolent chondroid component from the aggressive anaplastic component and can help facilitate sampling of the tumor multifocally. Definitive diagnosis requires histopathologic evaluation of the tumor by a pathologist experienced in musculoskeletal oncology because the dedifferentiated component can be small and easily missed if the entire sample is not adequately evaluated.
Histopathologically, conventional chondrosarcomas are characterized by neoplastic cartilage cells in a hyaline cartilage matrix similar to the cartilaginous component of dedifferentiated chondrosarcomas.4 A three-tier grading system has been described and is statistically significant in predicting clinical behavior in nonnasal canine chondrosarcomas.7,29 Low-grade chondrosarcomas are poorly cellular with abundant hyaline cartilage matrix in contrast to high- grade chondrosarcomas that are highly cellular with frequent mitoses, and a mucomyxoid matrix.7,29 Common locations include flat bones; in particular, the nasal location of chondrosarcoma has been reported as being common, accounting for approximatey 30% occurrence in veterinary medicine.5 Distribution of dedifferentiated chondrosarcoma in this population of 14 animals was similar to that reported for conventional chondrosarcomas, with most tumors occurring in the axial and appendicular skeleton (femur, humerus, ribs, and mandible) and nasal cavity. A recent veterinary study evaluating dogs with appendicular chondrosarcomas that underwent amputation showed a pulmonary metastatic rate of 50% in high-, 31% in intermediate-, and 0% in low-grade tumors.29 Not surprisingly, the median STs were significantly associated with tumor grades, with 0.9 yr, 2.7 yr, and 6 yr reported for high-, intermediate-, and low-grade chondrosarcomas, respectively. It is likely that dedifferentiated chondrosarcomas with a median ST of 0.64 yr (7.7 mo) historically have not been distinguished from the high-grade chondrosarcomas in this and other veterinary studies.1–3,5,6,29–32
A diagnosis of a conventional chondrosarcoma was made in the four cases in this report with pretreatment biopsies (n = 2 for intermediate- to high-grade chondrosarcoma, n = 1 for low-grade chondrosarcoma, n = 1 grade not assigned because of small sample size). Re-evaluation of the existing tissue sample or additional samples by a pathologist experienced in musculoskeletal oncology resulted in a diagnosis of dedifferentiated chondrosarcoma. Possibilities as to why an inaccurate diagnosis was obtained with initial biopsies are that (1) only the chondroid component was biopsied, leading to a diagnosis of a conventional low- to intermediate-grade chondrosarcoma; (2) the sample was not thoroughly evaluated histopathologically and a dedifferentiated component was missed; and (3) no information is available in the veterinary literature regarding this tumor type, leading to these tumors being diagnosed as a high-grade conventional chondrosarcoma when an aggressive sarcoma component was seen adjacent to a chondroid component.
Prognosis with this tumor type could improve if an early diagnosis is made when the dedifferentiated component is relatively small and localized to where radical excision can be performed. Wide or radical surgical excision remains the treatment of choice in people with dedifferentiated chondrosarcoma, using guidelines established for sarcoma surgery. Local recurrence due to inadequate margins is seldom the reason for death; however, rate of local recurrence has been shown to depend on margins, with recurrence rates as high as 50–69% with dirty or marginal resections.13–15,20 Recurrence rates as low as 0–18.5% with radical and wide excisions have been reported, with an average time from diagnosis to recurrence being 32 wk.
Retrospective studies in people with dedifferentiated chondrosarcoma evaluating the use of adjuvant chemotherapy have shown little improvement in median STs, and efficacious chemotherapy agents have not been identified.9–11,13,20,33 One retrospective study with 78 patients reported some improvement in patients receiving surgery with adjuvant chemotherapy, with 2- and 5-yr survival rates of 33% and 22%, respectively, in comparison with 2- and 5-yr survival rates of 17% and 10% with surgical excision alone.13 The improvement in STs with the use of adjuvant chemotherapy was not statistically significant.13 A recent study investigated the use of ifosfamide, an alkylating chemotherapeutic drug, in a neoadjuvant and adjuvant setting in patients undergoing surgical excision of dedifferentiated chondrosarcoma.34 Although prognosis overall remained poor, the study demonstrated an improvement in the 2- and 5-yr disease-specific survivorship of 54% and 27%, respectively, compared with survivorship rates of 17% and 6% for patients who did not receive ifosfamide-based chemotherapy.
Because death is most often due to rapid progression of metastatic disease, it is not surprising that radiation therapy for better local control of disease in an adjuvant setting has shown minimal to no improvements in survival rates compared with surgery alone in humans.13 The 2- and 5-yr survival rates in humans receiving surgery and adjuvant radiation were 24% and 5%, respectively, similar to times reported with surgical excision alone.13 Although no set guidelines exist for the use of radiation therapy in humans with dedifferentiated chondrosarcoma, this modality is considered (1) if the tumor is incompletely resected with the goal of maximal tumor control (curative intent); (2) palliative intent if the tumor is nonresectable or morbidity with surgical excision is high. In the dog in Case 7, SRT, an external beam radiation modality that delivers high doses of radiation in a few fractions, was elected by the owners because of concerns of surgical morbidity associated with an abdominal wall resection. The impact of radiation therapy on local control and survival in veterinary patients with this variant is unknown.
The retrospective nature of the current study and rare diagnosis yielded only 14 cases, with some cases being more than a decade old. Therefore, the case series used for the study has a few limitations. Complete medical records (specialty and primary care veterinary) were only available for seven dogs and one cat. Similarly, not all of the imaging performed was available for review. Limited veterinary awareness regarding this tumor type resulted in (1) inconsistent restaging with thoracic radiographs, and thus an inability to determine time from diagnosis to metastasis; and (2) varied treatments leading to an inability to compare the efficacy of treatment modalities.
Conclusion
In summary, a bimorphic pattern consisting of mineralized and nonmineralized areas has been reported in one-third of radiographs, one-half of CT scans, and one-third of MRIs in human patients with dedifferentiated chondrosarcoma. Interpretation of imaging is crucial in helping guide multifocal biopsies to obtain an accurate preoperative diagnosis. Histopathological confirmation of a high-grade noncartilaginous sarcomatous component juxtaposed near a cartilaginous low-grade component is needed for definitive diagnosis. Surgery remains the treatment of choice with this variant in human medicine and with high local recurrence rates with intracapsular and marginal excision. Metastatic disease, primarily to the lungs, remains the cause of death in humans. In the past, chemotherapy has failed to improve the dismal STs. Recently, neoadjuvant and adjuvant treatment with ifosfamide, an alkylating agent, in people has shown promise. Animals in this case series with dedifferentiated chondrosarcoma appear to have a similar rapid clinical progression to metastasis. Accurate early diagnosis would allow for a tailored treatment plan and provide prognostic information.
Hematoxylin and eosin stain, × 20 magnification. Poorly differentiated sarcomatous component (A) is demarcated (black arrows) from the well-differentiated cartilaginous component (B).
Images of the posterior nares of the dog in Case 4 obtained with retroflexion of an endoscope 4 mo after diagnosis of a dedifferentiated chondrosarcoma. (A) A large polyp-like mass occluding the entire left side of the choanae is visible. (B) Image obtained after the mass was debulked for symptomatic relief.
T1 and T2 weighted sequences in an axial plane acquired through the skull postmortem in a dog with nasal dedifferentiated chondrosarcoma. (A) T2 weighted image at the level of the maxillary recesses. There is a mixed intensity, primarily T2 hyperintense and T1 isointense mass, within the left nasal cavity. (B) T1 weighted image of the caudal nasal cavity at the level of the rostral cribiform. There is a mixed intensity mass in the left caudal nasal cavity extending into the left frontal sinus with associated lysis of the left rostral aspect of the cribiform plate.
Open mouth ventrodorsal view of the maxilla. There is diffuse increase in soft-tissue opacity in the right nasal cavity with loss of nasal turbinates consistent with a lytic infectious or neoplastic process.
Abdominal radiograph, computed tomography, and histopathology of the dog in Case 7. A bimorphic pattern is seen in each of the images with demarcation of the dedifferentiated portion from the well-differentiated chondroid component. (A) Ventrodorsal abdominal radiograph. A mass with mineralized and nonmineralized areas is noted in the left lateral abdominal wall. (B) Computed tomography precontrast in bone algorithm. 2 mm axial slices were acquired through the abdomen. A bimorphic pattern consisting of an internal lobulated mineral attenuating component of the mass surrounded by a lobulated soft-tissue attenuating component is noted. The mass enhances minimally around its rim on additional postcontrast images (not shown). The mass is intimately associated with the musculature of the left body wall but does not appear to invade into the abdominal cavity. (C) Hematoxylin and eosin stain, ×20 magnification. Characteristic sharp demarcation (black arrows) between well-differentiated cartilage matrix formation (1) and poorly differentiated areas with no matrix (2). An increased mitotic rate is noted.
Contributor Notes
