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Chondroid tumors of the larynx: A clinicopathologic study of 19 cases, including two dedifferentiated chondrosarcomas
Annals of
DIAGNOSTIC PATHOLOGY VOL 8, NO 4
AUGUST 2004
ORIGINAL ARTICLES
Chondroid Tumors of the Larynx: A Clinicopathologic Study of 19 Cases, Including Two Dedifferentiated Chondrosarcomas Odile Casiraghi, MD, Fernando Martinez-Madrigal, MD, Keyla Pineda-Daboin, MD, Gerad Mamelle, MD, Leonard Resta, MD, and Mario A. Luna, MD We studied 19 cases of chondroid tumors of the larynx: two chondrometaplastic nodules, two chondromas and 15 chondrosarcomas (including two dedifferentiated chondrosarcomas). One of chondromas recurred 18 months after resection because of inadequate surgical treatment. Chondrosarcomas were separated as low-grade (nine cases), intermediate (three cases), high-grade (one case), and dedifferentiated (two cases) according to histologic appearance. Chondrosarcomas are nearly always histologically low grade, make up the largest numbers of the neoplasms, and arise from the cricoid cartilage. Conservative surgical management, when possible, is advocated to preserve the larynx. Chondrometaplastic nodules are to be distinguished from chondrosarcoma and the rarely occurring chondroma. The nodules are not neoplastic and have a low to nil recurrent potential. Ann Diagn Pathol 8: 189-197, 2004. © 2004 Elsevier Inc. All rights reserved. Index Words: Chondrosarcomas, larynx sarcomas, chondrometaplasia
C
HONDROID tumors of the larynx are an uncommon neoplasm comprising up to 1% of all laryngeal neoplasms.1,2 They may be classified into
From the Departments of Histopathology A and Surgery of the Institut Gustave-Roussy, Villejuif, France; Centro de Investigacio´n Biome´dica de Michoaca´n and Department of Histopathology of the Hospital Regional de Zona No. 1, Instituto Mexicano del Seguro Social, Morelia, Michoaca´n, Me´xico; Department of Pathology Hospital Militar “Carlos Arvelo” and Instituto Anatomopatologico, Universidad Central de Venezuela, Caracas, Venezuela; Instituto di Anatomia Patologica, Universidad degli Studi di Bari, Italy; and the Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX. Address reprint requests to Mario A. Luna, MD, Department of Pathology, M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 85, Houston TX 77030. © 2004 Elsevier Inc. All rights reserved. 1092-9134/04/0804-0001$30.00/0 doi:10.1053/j.anndiagpath.2004.04.001
four groups: (1) metaplastic cartilagenous nodules (chondrometaplasia); (2) chondromas; (3) chondrosarcomas; and (4) cartilage within otherwise classified neoplasms such as pleomorphic adenoma and chondroblastic osteosarcoma.2-12 This article presents 19 additional patients with chondroid tumors of the larynx: two condrometaplasias, two chondromas, and 15 chondrosarcomas (including two dedifferentiated chondrosarcomas), with surgical results as well as long-term follow-up. Materials and Methods Nineteen patients with chondroid tumors of the larynx were studied. Five cases were identified at the Institut Gustave-Roussy (Villejuif, France) from 1978 to 1997. One case was from the consultation service, one case is from the Academic Hospital of Bari (Italy), and 12 cases
Annals of Diagnostic Pathology, Vol 8, No 4 (August), 2004: pp 189-197
189
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Casiraghi et al Table 1. Chondroid Tumors of the Larynx: Patient and Tumor Data
Case No.
Age/Sex
Symptoms
Cartilage
1
42/M
Hoarseness
Thyroid
2 3
55/F 69/M
Cricoid Cricoid
4
83/M
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
61/M 65/M 60/M 70/M 69/M 43/M 57/M 53/M 53/M 66/M 58/M 58/M 68/M 51/F 54/M
Hoarseness Hoarseness Dyspnea Dyspnea CLL Dyspnea Hoarseness Hoarseness Hoarseness Hoarseness Mass Lt neck Mass Rt neck Hoarseness Dyspnea Dyspnea Hoarseness Hoarseness Hoarseness Hoarseness None
Treatment
Diagnosis
Chondroma Low grade
Cricoid
1) Endoscopic excison 2) Surgical excision Cricoid ring excision TL, ND XRT Chemotherapy for CLL
Cricoid Cricoid Cricoid Arytenoid Thyroid Thyroid Thyroid Thyroid Cricoid Cricoid Cricoid Cricoid Cricoid Vocal cord Ventricle
TL, ND TL TL, ND TL T.L PL TL. PL. TL TL TL PL PL Ex EX
DDCS Low grade High grade SSCC Low grade Low grade Low grade Grade 2 Low-grade Grade 2 Grade 2 DDCS Low grade Low grade CMN CMN
Follow-Up
Chondroma NED (13 y) NED (9 y) NED (7 y) Low grade DOC (4 mo) NED (5 y) NED (7 y) LFU (7 mo) NED (12 y) NED (13 y) NED (22 y) NED (10 y) NED (12 y) NED (9 y) NED (5 y) DOD (2 y) NED (7 y) NED (9 y) NED (8 y) NED (10 y)
Abbreviations: CML, chronic myelogenous leukemia; TL, total laryngectomy; PL, partial laryngectomy; ND, neck dissection; XRT, radiotherapy; Ex, excision; NED, alive with no evidence of tumor; DOC, died of other cause; LFU, lost to follow-up; DDCS, dedifferentiated chondrosarcoma; SCCC, synchronous squamous cell carcinoma; CMN, chondrometaplastic nodule.
were from the files of the Department of Pathology of M. D. Anderson Cancer Center (Houston, TX). At least 5 years of follow-up information was available in each case. For all 19 cases, the clinical and radiologic records were reviewed. All laryngectomy specimens from the Institut Gustave-Roussy were processed by the method described by Michaels and Gregor.13 The laryngectomy specimen from the other institutions were processed by the conventional method. Histologic sections embedded in paraffin 5 m thick were stained with hematoxylin and eosin. Grading of chondrosarcomas was based on their light microscopic features. The tumors were classified as lowgrade (grade 1), intermediate-grade (grade 2), highgrade (grade 3), and dedifferentiated according the classification system described by Devaney et al11 and Evans et al.14
Results The histologic diagnoses, tumor data, and clinical evolutions of all 19 patients are summarized in Table 1.
Chondromas Chondromas were observed in two patients (cases 1 and 2). One located in the cricoid cartilage, the other in the thyroid cartilage. The first tumor of patient 1 was treated with endoscopic excision. Recurrence appeared 18 months later and it was treated by surgical resection. The patient is alive and free of disease 13 years after treatment. The second patient (case 2) underwent cricoid-ring excision (Fig 1) and dissection of the left subdigastric lymph nodes; she is alive and free of disease 9 years later. Grossly, these chondromas appeared as solid, white hard masses that measured 1.2 cm (case 1) and 3.3 cm (case 2) in largest diameter (Fig 1A). Histologically, they consisted of lobulated proliferations of cartilaginous tissue showing a homogeneous, monotonous pattern (Fig 1B). The chondrocytes were monomorphous, with small and normochromic nuclei surrounded by a dense and homogeneous chondroid substance with sporadic calcification. No mitosis was present.
Chondroid Tumors of the Larynx
191
Figure 1. Histologic section of a chondroma of the cricoid cartilage. (A) The tumor is small and well delimited. (B) There is low cellularity with abundant hyaline cartilage matrix resembling normal cartilage.
Chondrosarcomas (Cases 3 Through 17) All patients with a chondrosarcoma were men, with ages ranging from 43 to 83 years. Ten tumors were located in the cricoid, four in the thyroid, and one in the arytenoid cartilage. One patient (case 4) complained of dyspnea during chemotherapy for chronic granulocytic leukemia. Another patient (case 7) underwent total laryngectomy for squamous cell carcinoma of the right ventricular band. The other 13 patients had hoarseness and different degrees of dyspnea for 2 months to 4 years. One of these patients (case 5) had received radiotherapy
40 years before presentation for treatment of cervical lymphadenopathy of unknown origin. Laryngeal computed tomography was performed on 13 patients and showed a widening of the partially calcified tumor and soft tissue involvement (Fig 2). The patient with leukemia was not treated for his chondrosarcoma; he died of leukemia 4 months later. Nine patients underwent total laryngectomy with or without partial neck dissection, and five patients had partial laryngectomy (Table 1). Grossly, chondrosarcomas appeared as nodular
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Casiraghi et al
Figure 2. Axial computed tomography scan at the level of the larynx. A large tumor involving cricoid cartilage is seen.
white masses that measured from 2.2 to 5.5 cm (Fig 3). Low-grade chondrosarcomas consisted of a proliferation of mesenchymal cells with cartilagenous differentiation. In contrast to chondromas, these tumors show more cellularity with nuclear atypias (Fig 4); all cases showed binucleated cells in almost all fields. The neoplastic cells were polymorphous and medium in size. The nuclei showed irregular clumping of chromatin, and nucleoli were occasionally seen. The chondroid substance was less abundant than in chondromas. Four patients underwent total laryngectomy, and four had partial laryngectomy. Eight patients were alive without evidence of disease from 7 to 22 years after treatment. One died of leukemia 4 months after diagnosis. Intermediate chondrosarcoma (cases 11, 13, and 14) manifest a significant increase in cellularity, particularly at the periphery of the invading lobules, and enlarged binucleated cells are relatively easy to find, mitosis are infrequent. All three patients underwent total laryngectomy and were alive without evidence of disease 5, 9, and 10 years after treatment. High-grade chondrosarcomas (case 7) consisted
of neoplastic proliferations with a high degree of cellularity and neoplastic nodules with a central area of mature cartilaginous matrix. These nodules were surrounded by immature sarcomatous spindle cells (Fig 5). There were also areas of necrosis with granulocytic cell infiltration. In one case (case 7), the patient also had a synchronous squamous cell carcinoma of the right ventricular band. He was treated with total laryngectomy and was lost to follow-up 7 months after treatment. Dedifferentiated chondrosarcoma was observed in two cases (cases 5 and 15), in addition to small undifferentiated cells. Areas of low-grade chondrosarcoma were also seen (Fig 6) One patients died of tumor 2 years after treatment and the other is alive after 5 years. Chondrometaplasia Two patients (case 18 and 19) had condrometaplastic nodules in the soft tissues of the false vocal cord and of the ventricle, they measured 5 and 3 mm, respectively. The nodules were nonlobulated (Fig 7), and were composed of benign cartilage with mucochondroid changes (Fig 8). The borders were indistinct and appear to be merging with the surrounding
Chondroid Tumors of the Larynx
193
Figure 3. (A) Laryngectomy specimen opened posteriorly shows a large lobulated tumor arising from the cricoid ring. (B) Horizontal section of a laryngectomy specimen shows chondrosarcoma arising from the cricoid cartilage.
soft tissues. Both patients were alive without recurrence 8 and 10 years after treatment, respectively. Discussion Laryngeal cartilagenous tumors, although rare, are the most frequent mesenchymal tumors of the larynx. They represent up to 1% of all laryngeal
Figure 4. Low-grade laryngeal chondrosarcoma, scant cellularity, and nuclear atypia are evident as compared with chondromas.
tumors and 0.12% of all tumors of the head and neck region.1-5 Traditionally, studies of cartilagenous tumors of the larynx report on more malignant than benign tumors.2-12 No definitive etiology for laryngeal chondrosarcomas is known, although the speculation most commonly accepted is an initial disordered ossification of the laryngeal car-
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Casiraghi et al
Figure 5. High-grade laryngeal chondrosarcoma. Prominent cellularity and pleomorphism are evident.
tilages.3,15 It has been suspected that ischemia in a chondroma may also contribute to the development of chondrosarcoma.2 Finally, laryngeal chondrosarcomas have been described after Teflon injection4 and radiation therapy16 Previous radiation was identified in one patient (case 5) in this study. The patient received radiation therapy 40 years previous to the diagnosis of chondrosarcoma for cervical adenopathy of unknown type. The probability of malignancy of chondroid tumors of the larynx increases with age. The majority
Figure 6. Dedifferentiated laryngeal chondrosarcoma showing small cell sarcomatous component. A lowgrade chondrosarcoma is evident along the left side of the picture.
of cases in the literature occurred in older groups, most between 50 to 80 years of age.2-5,15 This compares favorably with our patients, who ranged in age from 69 to 83 years. The age at onset of chondrosarcoma is reported in the literature to range from 33 to 91 years, with an average age of approximately 61 years, depending on the study.2-12 The male:female ratio is about 4:1.2-5 The most frequent site affected is the cricoid ring (75%), followed by the thyroid ala (17%), and more rarely the epiglottis and arytenoid cartilages
Chondroid Tumors of the Larynx
195
Figure 7. Metaplastic chondroid nodule in soft tissue of the supraglottic larynx. Notice the non-lobulated shape of the nodule.
(5%).2-12 It is of interest to note in reported series of patients with laryngeal chondroma that they develop 10 years earlier than patients with chondrosarcomas.3-5,11,12 Whereas the anatomic loca-
tion and sex predominance is identical to that of chondrosarcoma.11 The symptoms of chondroid tumors are hoarseness and/or dyspnea, Less frequently, cricoid chon-
Figure 8. High-power view of a chondrometaplastic nodule.
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Casiraghi et al
droid tumors may compress the esophagus, causing dysphagia, or they may grow outside the larynx as a cervical mass; because of the slow growth of the tumor, it can take up to 9 years before a diagnosis is made. The most common physical finding is a hard mass covered by an altered mucosa, starting from the cricoid or thyroid cartilages, and obstructing the aerodigestive tract. Cases with an obvious laterocervical mass may be mistaken, even on radiologic examinations, for some of the most common pathologic conditions of the thyroid gland.10 Histologically, chondroid tumors of the larynx are easily diagnosed because of the characteristic appearance of the cartilagenous substance. Errors in diagnosis may occur when tumors are mistaken for either the rare pleomorphic adenoma of the larynx, which develops from the minor salivary glands, or more often for chondroid metaplasia, a non-neoplastic lesion characterized by a small nodule or nodules of elastic cartilage present in the soft tissues of the false vocal cord or of ventricles.14,15 Batsakis and Raymond12 listed the following criteria to recognize a chondrometaplastic nodule: (1) an absence of lobular growth pattern that characterized neoplastic cartilage; (2) a mucochondroid change in the soft tissue matrix forming the metaplastic nodules; (3) an often indistinct zone of merger of the nodule with surrounding soft tissue; and (4) elastophilia in mature metaplastic nodules. The size and number of the lesion also helps to separate metaplastic nodules from cartilageous neoplasms. The nodules usually measure less than 1 cm and are often multiple; whereas true chondroid neoplasms are larger and single.3,12 The differentiation between chondroma and well differentiated chondrosarcoma can be very difficult, often coming down to a matter of personal interpretation. Chondromas will lack nuclear atypia, mitotic figures, necrosis, and invasive character.3,11,12 The diagnosis of chondroma should never lull the pathologist or surgeon into a false sense of security for the patient. Not only can misleading chondroma-like areas be present in the biopsy of a chondrosarcoma,2,12 but the clinical behavior of a bona fide chondroma is most often indistinguishable from a low-grade chondrosarcoma.2-5,12 We agree with Thompson and Gannon2 who state “It is probably wise to consider the treatment of chondroma as indistinguishable from chondrosarcoma to assure the most conservative but still meaningful, surgical management.”
Osseous and laryngeal chondrosarcomas may be further divided into low-grade (grade 1), intermediate-grade (grade 2), and high-grade (grade 3) chondrosarcomas based on the criteria proposed by Evans et al.14 This histologic grading is based on cellularity, mitotic index, and cellular and nuclear atypia. Low-grade chondrosarcomas may show only a minimally increased cellularity and nuclear atypia in many areas. Binucleation may suggest a malignancy when it is frequent. However, these criteria for malignancy may be insufficient for a diagnosis in many tumors. Therefore, as stated by Devaney et al,11 the diagnosis of a benign cartilaginous tumor is affirmed when the entire lesion is examined and the tumor does not recur over a period of several years. For some investigators, the recurrence of a cartilagenous laryngeal tumor is a significant criteria for the diagnosis of malignancy.1,9 It is worth remembering, however, that chondromas can also recur when they have not been completely removed. This was observed in case 2, which showed local recurrence after laryngoscopic extirpation; however, after complete radical resection there was no further recurrence. In our opinion, the diagnosis of malignancy should be based on cytologic criteria. Nearly all the reported cases of laryngeal chondrosarcomas have been of low or intermediate grade.2-12 Survival of patients with chondrosarcomas is usually long, and their life expectancy is not far from that of the general population.3 Although local recurrence is possible, metastases have been reported in up to 10% of cases in the literature.2-12 Most of the cases are associated with dedifferentiated tumors.17 These laryngeal dedifferentiated chondrosarcomas are rare and more aggressive than conventional ones, but they have a better prognosis than their axial counterparts (Table 2).17 In our series, the only metastasis were found in patients with dedifferentiated chondrosarcomas. Two of our cases had other synchronous neoplasms in addition to chondroid tumors: a chronic granulocytic leukemia and squamous cell carcinoma of the false vocal cord. There was no apparent relationship with the primary chondroid tumor in both cases. In fact, the carcinoma and chondrosarcoma were separate, which eliminates the possibility of sarcomatoid carcinoma. Treatment of laryngeal chondrosarcoma is controversial and has been the subject of many treaties.1,3-5,9,15 The treatment modalities fall into five
Chondroid Tumors of the Larynx Table 2. Summary of Patients With Dedifferentiated Laryngeal Chondrosarcoma No. of patients 12 Age range in years 41-74 (mean, 62.9 years) Male:Female ratio 6:1 Location Cricoid cartilage 10 Thyroid cartilage 2 Treatment Total laryngectomy 10 Partial laryngectomy 2 Recurrences 5 Metastasis 4 Alive with no evidence of disease 7 (5-10 yrs) Dead of tumor 4 (1-5 yrs) Lost to follow-up 1 Modified from Garcia et al.17 Two additional cases from present series have been added.
main categories: (1) endoscopic removal of small tumors of epiglottis or arytenoids; (2) laryngofissure for moderate-sized tumors that can be removed without destroying laryngeal function; (3) extralaryngeal approach for tumors of the thyroid cartilage; (4) partial laryngectomy when technically feasible; and (5) total laryngectomy for large, bulky neoplasms or for cricoidal chondrosarcomas necessitating resection of the cricoid ring, which would thereby leave an unstable larynx.2-12 It is evident that size and location are the principal determinants, with histologic grade of the sarcoma being secondary. Where possible, conservative local excision with a sufficient margin of normal uninvolved cartilage is the treatment of choice.2-5 When recurrence develops,wide excision can again be used, depending on the extent of the tumor, until functional compromise and the inability to reconstruct an adequate airway dictate the necessity for total laryngectomy.2-12 According to the literature, he recurrence rate after conservative excision varies form 18% to 65%,2-5,18 and from 3% to 10% for laringectomy.1-12,18 Recurrences appear to be slightly more probable in patients with grade 2 chondrosarcomas and thyroid cartilage sarcomas.1-5 Because chondrosarcomas of the larynx are usually slow-growing neoplasms, recurrences become apparent over a wide range of time. In one series, the mean time was 6 years after the initial
197
surgical procedure (range, 21 months to 16 years).1,5 Approximately 10% of patients with laryngeal chondrosarcomas die as result of the neoplasm, perhaps a testimony to the low-grade biologic behavior of this type of sarcoma.1-12,15,18 References 1. Gorenstein A, Neel B III, Weiland L, Devine K: Sarcoma of the larynx. Arch Otolaryngol 1980;106:8-12 2. Thompson LD, Gannon FH: Chondrosarcoma of the larynx: a clinicopathologic study of 111 cases with a review of the literature. Am J Surg Pathol 2002;26:836-851 3. Thome R, Thome DC, de la Cortina RA: Long-term follow up of cartilagenous tumors of the larynx. Otolaryngol Head Neck Surg 2001;124:634-640 4. Rinaldo A, Howard DJ, Ferlito A: Laryngeal chondrosarcoma: a 24 year experience at the Royal National Throat, Nose and Ear Hospital. Acta Otolaryngol 2000;120:680-688 5. Lewis JE, Olson KD, Inwards CY: Cartilagenous tumors of the larynx: clinicopathologic review of 47 cases. Ann Otol Rhinol Laryngol 1997;106:94-100 6. Aznar E, Nogues J, Moya J, et al: Crico-tracheal chondrosarcoma. Acta Otorrinolaringol Esp 2000;52:603-606 7. Moran CA, Suster S, Carter D: Laryngeal chondrosarcoma. Arch Pathol Lab Med 1993;117:914-917 8. Valdazo A: Condromas and low-grade chondrosarcomas of the larynx: a case report. Ann Otolaryngol Chir Cervicofac 2002; 119:252-256. 9. Tiwari RM, Snow GB, Balm AJM, Gerristsen GJ, Vos W, Bosma A: Cartilagenous tumors of the larynx. J Laryngol Otol 1987;101:266-275 10. Windfuhr JP: Pitfalls in the diagnosis and management of laryngeal chondrosarcoma. J Laryngol Otol 2003;117:651-655 11. Devaney KO, Ferlito A, Silver CE: Cartilagenous tumors of the larynx. Ann Otol Rhinol Laryngol 1995;101:251-255 12. Batsakis JG, Raymond AK: Cartilage tumors of the larynx. South Med J 1988;81:481-484 13. Michaels L, Gregor RT: Examination of the larynx in the histopathology laboratory. J Clin Pathol 1980;33:705-710 14. Evans H, Ayala AG, Romsdhal M: Prognostic factors in chondrosarcomas of bone: A clinicopathologic analysis with emphasis on histologic grading. Cancer 1977;40:818-831 15. Bradwein M, Moore S, Som P, et al: Laryngeal chondrosarcomas: a clinicopathologic study of 11 cases, including two “dedifferentiated” chondrosarcomas. Laryngoscope 1992;102: 858-867 16. Glaubiger DL, Casler DC, Garrett WL, et al: Chondrosarcoma of the larynx after radiation treatment for vocal cord cancer. Cancer 1991;68:1828-1831 17. Garcia RE, Gannon FH, Thompson LD: Dedifferentiated chondrosarcoma of the larynx: a report of two cases and review of the literature. Laryngoscope 2002;112:1015-1018 18. Escher A, Escher F, Zimmermann A. Zur Klink und Pathologie chondromatoser Tumoren des Larynx. HNO 1984; 32:269-285.
DIAGNOSTIC PATHOLOGY VOL 8, NO 4
AUGUST 2004
ORIGINAL ARTICLES
Chondroid Tumors of the Larynx: A Clinicopathologic Study of 19 Cases, Including Two Dedifferentiated Chondrosarcomas Odile Casiraghi, MD, Fernando Martinez-Madrigal, MD, Keyla Pineda-Daboin, MD, Gerad Mamelle, MD, Leonard Resta, MD, and Mario A. Luna, MD We studied 19 cases of chondroid tumors of the larynx: two chondrometaplastic nodules, two chondromas and 15 chondrosarcomas (including two dedifferentiated chondrosarcomas). One of chondromas recurred 18 months after resection because of inadequate surgical treatment. Chondrosarcomas were separated as low-grade (nine cases), intermediate (three cases), high-grade (one case), and dedifferentiated (two cases) according to histologic appearance. Chondrosarcomas are nearly always histologically low grade, make up the largest numbers of the neoplasms, and arise from the cricoid cartilage. Conservative surgical management, when possible, is advocated to preserve the larynx. Chondrometaplastic nodules are to be distinguished from chondrosarcoma and the rarely occurring chondroma. The nodules are not neoplastic and have a low to nil recurrent potential. Ann Diagn Pathol 8: 189-197, 2004. © 2004 Elsevier Inc. All rights reserved. Index Words: Chondrosarcomas, larynx sarcomas, chondrometaplasia
C
HONDROID tumors of the larynx are an uncommon neoplasm comprising up to 1% of all laryngeal neoplasms.1,2 They may be classified into
From the Departments of Histopathology A and Surgery of the Institut Gustave-Roussy, Villejuif, France; Centro de Investigacio´n Biome´dica de Michoaca´n and Department of Histopathology of the Hospital Regional de Zona No. 1, Instituto Mexicano del Seguro Social, Morelia, Michoaca´n, Me´xico; Department of Pathology Hospital Militar “Carlos Arvelo” and Instituto Anatomopatologico, Universidad Central de Venezuela, Caracas, Venezuela; Instituto di Anatomia Patologica, Universidad degli Studi di Bari, Italy; and the Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX. Address reprint requests to Mario A. Luna, MD, Department of Pathology, M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 85, Houston TX 77030. © 2004 Elsevier Inc. All rights reserved. 1092-9134/04/0804-0001$30.00/0 doi:10.1053/j.anndiagpath.2004.04.001
four groups: (1) metaplastic cartilagenous nodules (chondrometaplasia); (2) chondromas; (3) chondrosarcomas; and (4) cartilage within otherwise classified neoplasms such as pleomorphic adenoma and chondroblastic osteosarcoma.2-12 This article presents 19 additional patients with chondroid tumors of the larynx: two condrometaplasias, two chondromas, and 15 chondrosarcomas (including two dedifferentiated chondrosarcomas), with surgical results as well as long-term follow-up. Materials and Methods Nineteen patients with chondroid tumors of the larynx were studied. Five cases were identified at the Institut Gustave-Roussy (Villejuif, France) from 1978 to 1997. One case was from the consultation service, one case is from the Academic Hospital of Bari (Italy), and 12 cases
Annals of Diagnostic Pathology, Vol 8, No 4 (August), 2004: pp 189-197
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Casiraghi et al Table 1. Chondroid Tumors of the Larynx: Patient and Tumor Data
Case No.
Age/Sex
Symptoms
Cartilage
1
42/M
Hoarseness
Thyroid
2 3
55/F 69/M
Cricoid Cricoid
4
83/M
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
61/M 65/M 60/M 70/M 69/M 43/M 57/M 53/M 53/M 66/M 58/M 58/M 68/M 51/F 54/M
Hoarseness Hoarseness Dyspnea Dyspnea CLL Dyspnea Hoarseness Hoarseness Hoarseness Hoarseness Mass Lt neck Mass Rt neck Hoarseness Dyspnea Dyspnea Hoarseness Hoarseness Hoarseness Hoarseness None
Treatment
Diagnosis
Chondroma Low grade
Cricoid
1) Endoscopic excison 2) Surgical excision Cricoid ring excision TL, ND XRT Chemotherapy for CLL
Cricoid Cricoid Cricoid Arytenoid Thyroid Thyroid Thyroid Thyroid Cricoid Cricoid Cricoid Cricoid Cricoid Vocal cord Ventricle
TL, ND TL TL, ND TL T.L PL TL. PL. TL TL TL PL PL Ex EX
DDCS Low grade High grade SSCC Low grade Low grade Low grade Grade 2 Low-grade Grade 2 Grade 2 DDCS Low grade Low grade CMN CMN
Follow-Up
Chondroma NED (13 y) NED (9 y) NED (7 y) Low grade DOC (4 mo) NED (5 y) NED (7 y) LFU (7 mo) NED (12 y) NED (13 y) NED (22 y) NED (10 y) NED (12 y) NED (9 y) NED (5 y) DOD (2 y) NED (7 y) NED (9 y) NED (8 y) NED (10 y)
Abbreviations: CML, chronic myelogenous leukemia; TL, total laryngectomy; PL, partial laryngectomy; ND, neck dissection; XRT, radiotherapy; Ex, excision; NED, alive with no evidence of tumor; DOC, died of other cause; LFU, lost to follow-up; DDCS, dedifferentiated chondrosarcoma; SCCC, synchronous squamous cell carcinoma; CMN, chondrometaplastic nodule.
were from the files of the Department of Pathology of M. D. Anderson Cancer Center (Houston, TX). At least 5 years of follow-up information was available in each case. For all 19 cases, the clinical and radiologic records were reviewed. All laryngectomy specimens from the Institut Gustave-Roussy were processed by the method described by Michaels and Gregor.13 The laryngectomy specimen from the other institutions were processed by the conventional method. Histologic sections embedded in paraffin 5 m thick were stained with hematoxylin and eosin. Grading of chondrosarcomas was based on their light microscopic features. The tumors were classified as lowgrade (grade 1), intermediate-grade (grade 2), highgrade (grade 3), and dedifferentiated according the classification system described by Devaney et al11 and Evans et al.14
Results The histologic diagnoses, tumor data, and clinical evolutions of all 19 patients are summarized in Table 1.
Chondromas Chondromas were observed in two patients (cases 1 and 2). One located in the cricoid cartilage, the other in the thyroid cartilage. The first tumor of patient 1 was treated with endoscopic excision. Recurrence appeared 18 months later and it was treated by surgical resection. The patient is alive and free of disease 13 years after treatment. The second patient (case 2) underwent cricoid-ring excision (Fig 1) and dissection of the left subdigastric lymph nodes; she is alive and free of disease 9 years later. Grossly, these chondromas appeared as solid, white hard masses that measured 1.2 cm (case 1) and 3.3 cm (case 2) in largest diameter (Fig 1A). Histologically, they consisted of lobulated proliferations of cartilaginous tissue showing a homogeneous, monotonous pattern (Fig 1B). The chondrocytes were monomorphous, with small and normochromic nuclei surrounded by a dense and homogeneous chondroid substance with sporadic calcification. No mitosis was present.
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191
Figure 1. Histologic section of a chondroma of the cricoid cartilage. (A) The tumor is small and well delimited. (B) There is low cellularity with abundant hyaline cartilage matrix resembling normal cartilage.
Chondrosarcomas (Cases 3 Through 17) All patients with a chondrosarcoma were men, with ages ranging from 43 to 83 years. Ten tumors were located in the cricoid, four in the thyroid, and one in the arytenoid cartilage. One patient (case 4) complained of dyspnea during chemotherapy for chronic granulocytic leukemia. Another patient (case 7) underwent total laryngectomy for squamous cell carcinoma of the right ventricular band. The other 13 patients had hoarseness and different degrees of dyspnea for 2 months to 4 years. One of these patients (case 5) had received radiotherapy
40 years before presentation for treatment of cervical lymphadenopathy of unknown origin. Laryngeal computed tomography was performed on 13 patients and showed a widening of the partially calcified tumor and soft tissue involvement (Fig 2). The patient with leukemia was not treated for his chondrosarcoma; he died of leukemia 4 months later. Nine patients underwent total laryngectomy with or without partial neck dissection, and five patients had partial laryngectomy (Table 1). Grossly, chondrosarcomas appeared as nodular
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Figure 2. Axial computed tomography scan at the level of the larynx. A large tumor involving cricoid cartilage is seen.
white masses that measured from 2.2 to 5.5 cm (Fig 3). Low-grade chondrosarcomas consisted of a proliferation of mesenchymal cells with cartilagenous differentiation. In contrast to chondromas, these tumors show more cellularity with nuclear atypias (Fig 4); all cases showed binucleated cells in almost all fields. The neoplastic cells were polymorphous and medium in size. The nuclei showed irregular clumping of chromatin, and nucleoli were occasionally seen. The chondroid substance was less abundant than in chondromas. Four patients underwent total laryngectomy, and four had partial laryngectomy. Eight patients were alive without evidence of disease from 7 to 22 years after treatment. One died of leukemia 4 months after diagnosis. Intermediate chondrosarcoma (cases 11, 13, and 14) manifest a significant increase in cellularity, particularly at the periphery of the invading lobules, and enlarged binucleated cells are relatively easy to find, mitosis are infrequent. All three patients underwent total laryngectomy and were alive without evidence of disease 5, 9, and 10 years after treatment. High-grade chondrosarcomas (case 7) consisted
of neoplastic proliferations with a high degree of cellularity and neoplastic nodules with a central area of mature cartilaginous matrix. These nodules were surrounded by immature sarcomatous spindle cells (Fig 5). There were also areas of necrosis with granulocytic cell infiltration. In one case (case 7), the patient also had a synchronous squamous cell carcinoma of the right ventricular band. He was treated with total laryngectomy and was lost to follow-up 7 months after treatment. Dedifferentiated chondrosarcoma was observed in two cases (cases 5 and 15), in addition to small undifferentiated cells. Areas of low-grade chondrosarcoma were also seen (Fig 6) One patients died of tumor 2 years after treatment and the other is alive after 5 years. Chondrometaplasia Two patients (case 18 and 19) had condrometaplastic nodules in the soft tissues of the false vocal cord and of the ventricle, they measured 5 and 3 mm, respectively. The nodules were nonlobulated (Fig 7), and were composed of benign cartilage with mucochondroid changes (Fig 8). The borders were indistinct and appear to be merging with the surrounding
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Figure 3. (A) Laryngectomy specimen opened posteriorly shows a large lobulated tumor arising from the cricoid ring. (B) Horizontal section of a laryngectomy specimen shows chondrosarcoma arising from the cricoid cartilage.
soft tissues. Both patients were alive without recurrence 8 and 10 years after treatment, respectively. Discussion Laryngeal cartilagenous tumors, although rare, are the most frequent mesenchymal tumors of the larynx. They represent up to 1% of all laryngeal
Figure 4. Low-grade laryngeal chondrosarcoma, scant cellularity, and nuclear atypia are evident as compared with chondromas.
tumors and 0.12% of all tumors of the head and neck region.1-5 Traditionally, studies of cartilagenous tumors of the larynx report on more malignant than benign tumors.2-12 No definitive etiology for laryngeal chondrosarcomas is known, although the speculation most commonly accepted is an initial disordered ossification of the laryngeal car-
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Figure 5. High-grade laryngeal chondrosarcoma. Prominent cellularity and pleomorphism are evident.
tilages.3,15 It has been suspected that ischemia in a chondroma may also contribute to the development of chondrosarcoma.2 Finally, laryngeal chondrosarcomas have been described after Teflon injection4 and radiation therapy16 Previous radiation was identified in one patient (case 5) in this study. The patient received radiation therapy 40 years previous to the diagnosis of chondrosarcoma for cervical adenopathy of unknown type. The probability of malignancy of chondroid tumors of the larynx increases with age. The majority
Figure 6. Dedifferentiated laryngeal chondrosarcoma showing small cell sarcomatous component. A lowgrade chondrosarcoma is evident along the left side of the picture.
of cases in the literature occurred in older groups, most between 50 to 80 years of age.2-5,15 This compares favorably with our patients, who ranged in age from 69 to 83 years. The age at onset of chondrosarcoma is reported in the literature to range from 33 to 91 years, with an average age of approximately 61 years, depending on the study.2-12 The male:female ratio is about 4:1.2-5 The most frequent site affected is the cricoid ring (75%), followed by the thyroid ala (17%), and more rarely the epiglottis and arytenoid cartilages
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Figure 7. Metaplastic chondroid nodule in soft tissue of the supraglottic larynx. Notice the non-lobulated shape of the nodule.
(5%).2-12 It is of interest to note in reported series of patients with laryngeal chondroma that they develop 10 years earlier than patients with chondrosarcomas.3-5,11,12 Whereas the anatomic loca-
tion and sex predominance is identical to that of chondrosarcoma.11 The symptoms of chondroid tumors are hoarseness and/or dyspnea, Less frequently, cricoid chon-
Figure 8. High-power view of a chondrometaplastic nodule.
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droid tumors may compress the esophagus, causing dysphagia, or they may grow outside the larynx as a cervical mass; because of the slow growth of the tumor, it can take up to 9 years before a diagnosis is made. The most common physical finding is a hard mass covered by an altered mucosa, starting from the cricoid or thyroid cartilages, and obstructing the aerodigestive tract. Cases with an obvious laterocervical mass may be mistaken, even on radiologic examinations, for some of the most common pathologic conditions of the thyroid gland.10 Histologically, chondroid tumors of the larynx are easily diagnosed because of the characteristic appearance of the cartilagenous substance. Errors in diagnosis may occur when tumors are mistaken for either the rare pleomorphic adenoma of the larynx, which develops from the minor salivary glands, or more often for chondroid metaplasia, a non-neoplastic lesion characterized by a small nodule or nodules of elastic cartilage present in the soft tissues of the false vocal cord or of ventricles.14,15 Batsakis and Raymond12 listed the following criteria to recognize a chondrometaplastic nodule: (1) an absence of lobular growth pattern that characterized neoplastic cartilage; (2) a mucochondroid change in the soft tissue matrix forming the metaplastic nodules; (3) an often indistinct zone of merger of the nodule with surrounding soft tissue; and (4) elastophilia in mature metaplastic nodules. The size and number of the lesion also helps to separate metaplastic nodules from cartilageous neoplasms. The nodules usually measure less than 1 cm and are often multiple; whereas true chondroid neoplasms are larger and single.3,12 The differentiation between chondroma and well differentiated chondrosarcoma can be very difficult, often coming down to a matter of personal interpretation. Chondromas will lack nuclear atypia, mitotic figures, necrosis, and invasive character.3,11,12 The diagnosis of chondroma should never lull the pathologist or surgeon into a false sense of security for the patient. Not only can misleading chondroma-like areas be present in the biopsy of a chondrosarcoma,2,12 but the clinical behavior of a bona fide chondroma is most often indistinguishable from a low-grade chondrosarcoma.2-5,12 We agree with Thompson and Gannon2 who state “It is probably wise to consider the treatment of chondroma as indistinguishable from chondrosarcoma to assure the most conservative but still meaningful, surgical management.”
Osseous and laryngeal chondrosarcomas may be further divided into low-grade (grade 1), intermediate-grade (grade 2), and high-grade (grade 3) chondrosarcomas based on the criteria proposed by Evans et al.14 This histologic grading is based on cellularity, mitotic index, and cellular and nuclear atypia. Low-grade chondrosarcomas may show only a minimally increased cellularity and nuclear atypia in many areas. Binucleation may suggest a malignancy when it is frequent. However, these criteria for malignancy may be insufficient for a diagnosis in many tumors. Therefore, as stated by Devaney et al,11 the diagnosis of a benign cartilaginous tumor is affirmed when the entire lesion is examined and the tumor does not recur over a period of several years. For some investigators, the recurrence of a cartilagenous laryngeal tumor is a significant criteria for the diagnosis of malignancy.1,9 It is worth remembering, however, that chondromas can also recur when they have not been completely removed. This was observed in case 2, which showed local recurrence after laryngoscopic extirpation; however, after complete radical resection there was no further recurrence. In our opinion, the diagnosis of malignancy should be based on cytologic criteria. Nearly all the reported cases of laryngeal chondrosarcomas have been of low or intermediate grade.2-12 Survival of patients with chondrosarcomas is usually long, and their life expectancy is not far from that of the general population.3 Although local recurrence is possible, metastases have been reported in up to 10% of cases in the literature.2-12 Most of the cases are associated with dedifferentiated tumors.17 These laryngeal dedifferentiated chondrosarcomas are rare and more aggressive than conventional ones, but they have a better prognosis than their axial counterparts (Table 2).17 In our series, the only metastasis were found in patients with dedifferentiated chondrosarcomas. Two of our cases had other synchronous neoplasms in addition to chondroid tumors: a chronic granulocytic leukemia and squamous cell carcinoma of the false vocal cord. There was no apparent relationship with the primary chondroid tumor in both cases. In fact, the carcinoma and chondrosarcoma were separate, which eliminates the possibility of sarcomatoid carcinoma. Treatment of laryngeal chondrosarcoma is controversial and has been the subject of many treaties.1,3-5,9,15 The treatment modalities fall into five
Chondroid Tumors of the Larynx Table 2. Summary of Patients With Dedifferentiated Laryngeal Chondrosarcoma No. of patients 12 Age range in years 41-74 (mean, 62.9 years) Male:Female ratio 6:1 Location Cricoid cartilage 10 Thyroid cartilage 2 Treatment Total laryngectomy 10 Partial laryngectomy 2 Recurrences 5 Metastasis 4 Alive with no evidence of disease 7 (5-10 yrs) Dead of tumor 4 (1-5 yrs) Lost to follow-up 1 Modified from Garcia et al.17 Two additional cases from present series have been added.
main categories: (1) endoscopic removal of small tumors of epiglottis or arytenoids; (2) laryngofissure for moderate-sized tumors that can be removed without destroying laryngeal function; (3) extralaryngeal approach for tumors of the thyroid cartilage; (4) partial laryngectomy when technically feasible; and (5) total laryngectomy for large, bulky neoplasms or for cricoidal chondrosarcomas necessitating resection of the cricoid ring, which would thereby leave an unstable larynx.2-12 It is evident that size and location are the principal determinants, with histologic grade of the sarcoma being secondary. Where possible, conservative local excision with a sufficient margin of normal uninvolved cartilage is the treatment of choice.2-5 When recurrence develops,wide excision can again be used, depending on the extent of the tumor, until functional compromise and the inability to reconstruct an adequate airway dictate the necessity for total laryngectomy.2-12 According to the literature, he recurrence rate after conservative excision varies form 18% to 65%,2-5,18 and from 3% to 10% for laringectomy.1-12,18 Recurrences appear to be slightly more probable in patients with grade 2 chondrosarcomas and thyroid cartilage sarcomas.1-5 Because chondrosarcomas of the larynx are usually slow-growing neoplasms, recurrences become apparent over a wide range of time. In one series, the mean time was 6 years after the initial
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surgical procedure (range, 21 months to 16 years).1,5 Approximately 10% of patients with laryngeal chondrosarcomas die as result of the neoplasm, perhaps a testimony to the low-grade biologic behavior of this type of sarcoma.1-12,15,18 References 1. Gorenstein A, Neel B III, Weiland L, Devine K: Sarcoma of the larynx. Arch Otolaryngol 1980;106:8-12 2. Thompson LD, Gannon FH: Chondrosarcoma of the larynx: a clinicopathologic study of 111 cases with a review of the literature. Am J Surg Pathol 2002;26:836-851 3. Thome R, Thome DC, de la Cortina RA: Long-term follow up of cartilagenous tumors of the larynx. Otolaryngol Head Neck Surg 2001;124:634-640 4. Rinaldo A, Howard DJ, Ferlito A: Laryngeal chondrosarcoma: a 24 year experience at the Royal National Throat, Nose and Ear Hospital. Acta Otolaryngol 2000;120:680-688 5. Lewis JE, Olson KD, Inwards CY: Cartilagenous tumors of the larynx: clinicopathologic review of 47 cases. Ann Otol Rhinol Laryngol 1997;106:94-100 6. Aznar E, Nogues J, Moya J, et al: Crico-tracheal chondrosarcoma. Acta Otorrinolaringol Esp 2000;52:603-606 7. Moran CA, Suster S, Carter D: Laryngeal chondrosarcoma. Arch Pathol Lab Med 1993;117:914-917 8. Valdazo A: Condromas and low-grade chondrosarcomas of the larynx: a case report. Ann Otolaryngol Chir Cervicofac 2002; 119:252-256. 9. Tiwari RM, Snow GB, Balm AJM, Gerristsen GJ, Vos W, Bosma A: Cartilagenous tumors of the larynx. J Laryngol Otol 1987;101:266-275 10. Windfuhr JP: Pitfalls in the diagnosis and management of laryngeal chondrosarcoma. J Laryngol Otol 2003;117:651-655 11. Devaney KO, Ferlito A, Silver CE: Cartilagenous tumors of the larynx. Ann Otol Rhinol Laryngol 1995;101:251-255 12. Batsakis JG, Raymond AK: Cartilage tumors of the larynx. South Med J 1988;81:481-484 13. Michaels L, Gregor RT: Examination of the larynx in the histopathology laboratory. J Clin Pathol 1980;33:705-710 14. Evans H, Ayala AG, Romsdhal M: Prognostic factors in chondrosarcomas of bone: A clinicopathologic analysis with emphasis on histologic grading. Cancer 1977;40:818-831 15. Bradwein M, Moore S, Som P, et al: Laryngeal chondrosarcomas: a clinicopathologic study of 11 cases, including two “dedifferentiated” chondrosarcomas. Laryngoscope 1992;102: 858-867 16. Glaubiger DL, Casler DC, Garrett WL, et al: Chondrosarcoma of the larynx after radiation treatment for vocal cord cancer. Cancer 1991;68:1828-1831 17. Garcia RE, Gannon FH, Thompson LD: Dedifferentiated chondrosarcoma of the larynx: a report of two cases and review of the literature. Laryngoscope 2002;112:1015-1018 18. Escher A, Escher F, Zimmermann A. Zur Klink und Pathologie chondromatoser Tumoren des Larynx. HNO 1984; 32:269-285.