Dedifferentiated Chondrosarcoma of the Larynx: A Case Report and Review of the Literature

Chondrosarcoma (CS) is a slow-growing malignant mesenchymal tumor with cartilaginous differentiation. CS, as a whole, is relatively common [1-4]. These tumors are most commonly located in the pelvis, femur, ribs, humerus, scapula, fibula, sacrum, or sternum; accounting for about 10-20% of malignant primary bone tumors [1-3,5-8]. Paranasal sinuses, nasal cavity, temporal bone, mandible and larynx were the most common sites of head and neck chondrosarcomas origin [9]. Laryngeal chondrosarcomas are a raretumor, and account for only <0.2% of all head and neck malignancies [1,2,4,6,10-12]. Among the subtypes of CS, dedifferentiated CS (DC) is a rare, sinister variant associated with a poor prognosis of an average life-expectancy of 6 months, and a 5-year survival rate of 10.5%.


Introduction
International Journal of Cell Science & Molecular Biology appeared endoscopically to be subglottic stenosis. He underwent a head, neck and chest CT scan to rule out any sinister lesions along the course of the recurrent laryngeal nerve. Imaging revealed a 4 x 4cm left cricoid chondrosarcoma ( Figure 1). The CT scan revealed a chondrosarcoma, a poorly defined mixed soft tissue and calcified mass measuring 3.0 x 2.0cm in the axial dimension, and 3.5cm in the superior-inferior dimension, centered on theposterior left lateral aspect of the cricoid cartilage. The mass extended superiorly to the false vocal cords, and inferiorly, just below the true vocal cords. Just below the true vocal cords, there was significant narrowing of the airway. The lumen measured 2.5cm in the anterior-posterior dimension, and only 4mm in the transverse dimension. Destruction of most of the cricoid cartilage was identified. There was no evidence of cervical lymphadenopathy. The lungs were clear and there was no mediastinal lymphadenopathy. Diffuse fatty filtration of the liver was present with a poorly defined 1.2cm hypodense mass in the right lobe.
Shortly after the CT scan was done, the patient was admitted to hospital with severe respiratory distress and complete aphasia, he subsequently underwent a microlaryngoscopy, biopsy and tracheostomy. The patient's dyspnea resolved following the procedure. Due to the histological findings concluding laryngeal chondrosarcoma with a non-functional larynx, he underwent a narrow field total laryngectomy, cricopharyngeal myotomy, and tracheoesophageal puncture with placement of voice prosthesis. Postoperatively, he recovered well and his speech was 100% intelligible.
Within the total laryngectomy specimen, a firm tumor located in the left larynx was identified ( Figure 2).The tumor extended proximally from the false vocal cords, and distally, into the subglottis. The tumor invaded both, the thyroid and cricoid cartilages. The resection superior and inferior margins were negative. The anterior margins were 4mm, and the posterolateral and posterior margins appeared to potentially involve the tumor. The histological findings, shown in Figure 3, revealed areas of well-differentiated cartilaginous regionsjuxtaposed with poorlydifferentiated spindle cell sarcoma, arising from the cricoid cartilage. This finding was consistent with dedifferentiated chondrosarcoma.

International Journal of Cell Science & Molecular Biology
A PET scan was completed to rule out persistent or recurrent disease in the pharyngeal region. There was no evidence of hypermetabolic adenopathy, pulmonary nodules, or hypermetabolic activity in the neckintraabdominal or pelvic organs. However, focal hypermetabolism was present in the superior aspect of thesternal body, either associated with a fracture or alternatively, a metastatic lesion. Further, imaging with theMRI revealed a healing non-displaced sternal fracture. There was no evidence of metastatic bone disease.
Radiation treatment to the laryngeal bed is recommended for intermediate and poorly dedifferentiated chondrosarcoma due to an ominous prognosis, high risk of local recurrence and distant metastases. Furthermore, in the patient's case, radiation is recommended due to the close margins revealed in the total laryngectomy specimen. In this case, a total dose of 66Gy in 33 fractions of external beam radiation therapy was completed. The patient will continue to receive ongoing assessment, including 3-monthly appointments for the first two years, 4-monthly appointments in the third year, and following with 6-monthly appointments. Moreover, a chest x-ray twice annually, and further CT scans as indicated.
Dedifferentiated chondrosarcomas of the larynx are extremely rare. Currently there are 14 cases reported in the literature, including this report (Table 1 & Figure 4). The term dedifferentiated chondrosarcoma was first termed by Dahlin and Beabout in 1971 [9,18,22,23]. DC, a rare entity of chondrosarcoma, has an estimated incidence of 8-14% of all laryngeal chondrosarcomas [9]. DC are aggressive and present with a poor prognosis [13,20]. DC commonly arise among the older adult population, with a male predilection [10]. Compared to the cases of DC reported in the literature, the clinical presentation, investigations and treatments were all similar.
Diagnosis of DC includes a combination of pertinent information on history, physical examination, imaging, and histological and immunocytochemical analyses. Definite diagnosis can be established by incisional biopsy and histopathological examination. The utility of FNA has only been described in 1 DC case. FNA can be performed in an outpatient setting with minimal complications; it is also efficient and costeffective. Despite the advantages, the senior author does not recommend FNA in the case of chondrosarcoma; there is a risk of collecting non-representative tissue, it is difficult distinguishing benign and malignant tumors, and grading and classifying lesions [9].

Figure 4:
Comparing the patients diagnosed with laryngeal dedifferentiated chondrosarcoma described in the literature who were treated with a total laryngectomy compared to those treated with less than a total laryngectomy. Between the two groups, who received adjuvant radiation and which patients did not receive adjuvant radiation. Of those patients, who died regardless of treatment.

International Journal of Cell Science & Molecular Biology Symptomology
Presenting symptoms vary depending on the anatomic location of the tumor. In the literature, common symptoms reported include hoarseness due to narrowing of the glottis and compression of the inferior laryngeal nerves, dyspnea and airway obstruction as a result of endolaryngeal and subglottic growth, dysphagia due to extralaryngeal growth of the tumor originating in the posterior cricoid, and a painless neck mass from tumor the involving the thyroid cartilage [7,10,11,12,13,18]. Rapid progression of symptoms over days or weeks should raise the suspicion of the lesion may be more aggressive than the standard laryngeal well-differentiated chondrosarcoma.

Histopathology
Histopathologic grading of chondrosarcomas is based on the criteria first described by Lichtenstein and Jaffe in 1943. The grading system stratifies the tumor into three different grades, from low to high grade according to cellularity, nuclear size and pleomorphism, necrosis and mitotic activity. This classification system assists with delineating the tumor's aggressiveness and prognosis, and subsequent treatment. Higher-grade neoplasms are associated with higher aggressiveness and a poorer prognosis [6,7,15,16,20,23]. Histological analysis remains the goldstandard for diagnostic purposes [3,6,10]. The histopathologic hallmark of DC concluded in case studies is the presence of an abrupt transition between low grade cartilaginous component juxtaposed on a high-grade, noncartilaginous, spindle cell sarcoma with pleomorphism, vesicular nuclei, giant cells, and numerous mitoses [4,5,9,10,13,18,23]. The cartilaginous portion of the tumor can contain some cells of DC, and thus the entire tumor must be examined.

Immunohistochemistry
Immunochemical findings were not described in this case, however other studies concluded that the malignant spindle cell component of DC is strongly positive for vimentin, focally positive for alpha-1-anti-chymotrypsin, and negative for cytokeratins, S-100 protein, desmin and muscle-specific act in [9,13,18,22].

Imaging
According to the literature, CT scan is the imaging modality of choice. Stippled to coarse calcifications within the tumor is a patho gnomonic finding for laryngeal chondrosarcoma. This feature can be seen in tumors of any grade. Thus, imaging alone is not sufficient to make the diagnosis of dedifferentiated chondrosarcoma [2,4,6,7,10,12,15,16,18]. This finding cannot be appreciated on MRI. MRI is a useful complementary image modality for determining the extent of the tumor, as well as treatment planning and prognosis.
Destructive invasion of the cartilage, bone or soft tissue may suggest a high-grade tumor [10]. One study outlined the feasibility of multimodality imaging with PET and MRI, including DW-MRI. PET and MRI provide additional information regarding the hyper metabolic, aggressive dedifferentiated component, and the hyper metabolic, low-grade component [4].

Treatment
The standard treatment for laryngeal cartilaginous tumors is surgical excision, with preservation of the function of the larynx, if feasible [2][3][4]8,11,14,16,17,20]. However, due to the aggressiveness of the DC, the definitive treatment remains total laryngectomy [4,21]. Nonetheless, partial laryngectomy has been reported in a few cases. It is also recommended that patients with laryngeal DC receive adjuvant radiotherapy [2]. Although in this case, the patient received adjuvant radiation therapy, there have been previously reported cases in the literature in which the patient did not receive adjuvant therapy following surgical excision [5,17]. The role of radiation therapy remains undetermined [4]. Follow-up reveals a variable clinical course among the reported cases. Some patients remain disease free, whilst others develop metastatic disease [10,20].

Prognosis
Compared to low-grade chondrosarcomas, DC has been shown to have a poorer prognosis with a high rate of recurrence and a predisposition of distant metastases [3,4,8,13,18,23]. The average life-expectancy reported is 6 months, and a 5-year survival rate of 10.5%. Approximately 70% of patients develop pulmonarymetastatic disease some time during their disease course [18,23].

Conclusion
DC is a rare entity in the larynx. DC typically arises in the cricoid cartilage, presenting with rapidly Progressive dyspnea, hoarseness, dysphagia, and a painless neck mass. Due to the aggressiveness of thetumor, it is essential to include DC as a differential diagnosis among the other laryngeal tumors [24,25].