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The American Journal of Surgical Pathology 26(3): 386–392, 2002

© 2002 Lippincott Williams & Wilkins, Inc., Philadelphia

Case Report

Clear Cell Chondrosarcoma of the Larynx
A Case Report of a Rare Histologic Variant in an
Uncommon Localization

B. Kleist, Ph.D., M. Poetsch, Ph.D., C. Lang, Ph.D., A. Bankau, Ph.D.,
G. Lorenz, Ph.D, K. Süess-Fridrich, Ph.D., G. Jundt, Ph.D., and
E. Wolf, Ph.D.

The authors describe a clear cell chondrosarcoma of the larynx.
The clear cell type is a rare variant of chondrosarcoma that only
twice has been reported in this localization. The lightmicroscopic diagnosis of the actual case was confirmed by
immunohistochemical results, in particular by positive staining
for S-100 protein and collagen type II, and ultrastructural findings. Loss of heterozygosity analysis demonstrated allelic loss
at 9p22 and 18q21, but neither in the region of the Rb gene on
chromosome 13q nor at the p53 locus on chromosome 17p
where allelic loss has already been reported in chondrosarcomas. Furthermore, our molecular genetic investigations revealed a methylation of the cell cycle control gene p16, which
is localized on chromosome 9p. This characteristic has been
recorded previously only in high-grade chondrosarcomas. Mutations in the exons of p16, alterations of the putative tumor
suppressor gene MMAC1/PTEN on chromosome 10q, or an
amplification of the cyclin D1 gene (CCND1) on 11q13, which
were found to be changed in other studies of chondrosarcomas,
could not be demonstrated here.
Key Words: Clear cell chondrosarcoma—Larynx—
Immunohistochemistry—Ultrastructure—Molecular genetics.

is an uncommon variant that accounts for about 2% of
these tumors.10 It was first described as a pathologic
entity in 1976.33 The epiphyses of long bones, in particular of the proximal and distal femur, of the proximal
humerus and proximal tibia, are characteristically involved. Cases have also been reported in the ulna, rib,
small bones of the hand and foot, pelvis, sternum, vertebrae, temporal bone, and maxilla.8,10,31 To the best of
our knowledge, clear cell feature in a laryngeal chondrosarcoma has only twice been recorded previously.21,28
In this article we present a histologic, immunohistochemical, ultrastructural, and molecular genetic characterization of a further clear cell chondrosarcoma with
uncommon localization in the larynx.

CASE REPORT
In November 1997, a 57-year-old man presented with
dyspnea. He was admitted to the hospital, where direct
laryngoscopy revealed a subglottic neoplasm originating
from the left side of cricoid cartilage, extending to the
trachea and having caused two thirds occlusion of the
upper tracheal lumen. Magnetic resonance imaging
documented a mainly exophytic tumor mass that measured 3.0 × 2.5 cm (Fig. 1). The tumor was resected
through a laryngeal fissure. Fifteen and 20 months after
the first diagnosis recurrences occurred and were again
locally removed. Thirteen months after the last surgical
procedure a third relapse was diagnosed. Magnetic resonance imaging showed a 3.0 × 3.0 cm tumor mass originating from the left side of cricoid cartilage and extending to paratracheal tissue. Because of tumor extension
with airway obstruction and the tendency to recur, a laryngectomy was performed in August 2000. A neck dissection and a left side hemithyroidectomy were included

Am J Surg Pathol 26(3): 386–392, 2002.

Chondrosarcoma of the larynx is a rare tumor comprising 3% of all chondrosarcomas and <1% of malignant laryngeal tumors.5 In a recent review of the literature 250 published laryngeal chondrosarcomas were
compiled.11 Within chondrosarcomas the clear cell type
From the Institute of Pathology (B.K., G.L.), Institute of Forensic
Medicine (M.P.), and the Department of Oto-Rhino-Laryngology
(C.L., A.B.), Ernst-Moritz-Arndt-University, Greifswald, Germany; the
Center of Bone Tumors of Swiss Society of Pathology (K.S.-F., G.J.),
Institute of Pathology, University of Basel, Basel, Switzerland; and the
Institute of Pathology (E.W.), Regional Hospital, Stralsund, Germany.
Address correspondence and reprint requests to Britta Kleist, PhD,
Institute of Pathology, Ernst-Moritz-Arndt-University, F.-LoefflerStrasse 23e, D-17489 Greifswald, Germany; e-mail:
kleist@uni-greifswald.de

386

1:10. 15 mmol/L Tris/HCl. 26. UK). Germany).CLEAR CELL CHONDROSARCOMA OF THE LARYNX 387 because of the presence of clinically suspicious lymph nodes and the close proximity of the tumor to the left thyroid lobe. 3. which caused airway compression. FIG. epithelial membrane antigen (1:25. chromosome 17 (D17S513. 2002 . sectioned.gdb.). were obtained from Genome Data Base (http://gdbwww. D13S263). Novocastra Laboratories Ltd. Dako. Dako). 200 ␮mol/L of each dNTP. G. and infiltration embedding was performed with araldite resin 1 ␮m-sections were stained with thionin and examined by light microscopy. paraffin-embedded tissue was stained by the streptavidin-biotin-peroxidase method (Dako LSAB [2] system) with 3-amino-9-ethyl-carbazol as chromogen. Representative areas were chosen. cytokeratin (clone MNF116. 1:50.genetics.-F.5 ␮L containing 50–80 ng DNA. and cytogenetic location was obtained from the genetic location database (ftp://cedar. HEX. 1. It was postfixed with osmium tetroxide and stained en bloc with uranyl acetate. D9S171. Germany).uk/publichtml). routinely processed. S-100 protein (polyclonal.J. chromosome 13q12–14 (D13S217. Am J Surg Pathol. The polymerase chain reaction was performed in three multiplex analyses each comprising three different labeled primers in a final volume of 12. Electron Microscopy Microsatellite Analysis The material for ultrastructural examination was initially formalin fixed. 1. 55°C for 90 seconds. Ki67 antigen (clone MIB-1. Dako). Newcastle upon Tyne. Dako). The patient has been free of disease until now. stained with lead citrate. Dehydration was performed with graded solutions of acetone. No. Weiterstadt.ac.. Oberkochem. The specimens underwent additional independent histopathologic review in the Center of Bone Tumors of Swiss Society of Pathology (K.S. which presented clinically a nodular goiter. A panel of nine fluorochrome (6-FAM. Vol. and collagen type II (1:15. proliferating cell nuclear antigen (PCNA) (1:50. and 1 unit AmpliTaq Gold (Applied Biosystems. Denmark). 72°C for 120 seconds. The tissue was subsequently fixed in glutaraldehyde and buffered in sodium cacodylate. chromosome 11q25 (D11S910). Glostrup. and an additional Isolation of DNA From Paraffin-Embedded Material DNA isolation from paraffin-embedded tumor and non-neoplastic tissue was performed as previously described 23 with the High Pure PCR Template Preparation Kit (Roche Molecular Biochemicals. Magnetic resonance image demonstrating a tumor mass of the larynx (arrow).5% phosphate-buffered formalin (pH 7). 1:150.3 ␮mol/L of each primer.org). and embedded in paraffin wax using standard methods. 0. Four-micrometer sections were stained with hematoxylin and eosin. or TAMRA) labeled polymerase chain reaction primer pairs that amplified informative dinucleotide repeat microsatellite loci. Germany) by denaturing at 95°C for 10 minutes. 50 mmol/L KCl. periodic acid–Schiff (PAS) with and without diastase predigestion. Mannheim.soton. The antibodies used included vimentin (1:15. D9S197). followed by 35 cycles of 95°C for 30 seconds. D17S786). Dako). the tissue was fixed in 4. located on chromosome 9p22–21 (D9S162. and toluidine blue. Immunohistochemistry Formalin-fixed. Dako). and examined in an EM 910 LEO electron microscope (LEO. and chromosome 18 (D18S58).5 ␮mol/L MgCl2. MATERIALS AND METHODS Histology and Histochemistry For light microscopy examination.

Cytokeratin (MNF116) and epithelial membrane antigen were negative. (B) Proliferation of clear cells with numerous small.5 × 2. which were consistent with lowgrade conventional chondrosarcoma. and determination of methylation status of p16 were carried out as described before. RESULTS Macroscopic Findings The recurrent tumors excised in 1997 and 1999 consisted of several gray–white and brown firm specimens measuring up to 2. and electrophoresed with the ABI 310 DNA sequencer (Applied Biosystems). PCNA staining showed a positive rate of 48%. Scattered throughout the tumor. The cytoplasm of a few tumor cells and tiny foci of interposed chondroid matrix were weakly stained by collagen type II (Fig. Binucleated cells as well as mitotic figures were extremely rare. 1. 2.13 Am J Surg Pathol. Germany). denatured at 90°C for 120 seconds. Loss of heterozygosity was determined as described by Canzian et al. Inset: Higher magnification showing tumor cells with abundant powdery-to-clear cytoplasm and distinct boundaries (PAS. 2002 The tumor cells were positive for S-100 protein and vimentin. irregularly shaped trabeculae of bone. Histology and Histochemistry FIG. PAS/diastase-PAS staining demonstrated small amounts of intracellular glycogen. KLEIST ET AL. Multinucleated osteoclast-like giant cells were frequently seen. 2). mutation analysis of both exons of p16.5 ␮L ROX-labeled internal lane standard.5). 3). The cut surface had a red–brown and gray–white glassy appearance. The completely resected larynx showed a subglottic firm lobulated tumor mass of 5.5 ␮L polymerase chain reaction product was mixed with 12 ␮L deionized formamide and 0. The left thyroid lobe was composed of collapsed and cystic distended colloid-containing follicles in a nodular configuration without evidence of malignancy. original magnification ×350). No. Chondroid matrix formation was rare within the clear cell component but abundant in little tumor foci containing medium-sized or widely spaced chondrocytes with small dense or moderately enlarged nuclei. Invasion of blood or lymphatic vessels and lymph node metastases were absent.5 cm originating from the left cricoid and protruding the overlying intact mucosa.0 × 4. Staining with Ki67 antigen (MIB-1) demonstrated a low proliferative index of <5% of tumor cells.24 Analysis of cyclin D1 (CCND1) amplification was performed as described by Hibberts et al. numerous small newly formed irregularly shaped trabeculae of osteoid and woven bone were present. The centrally located nuclei were enlarged with moderate polymorphism and surrounded by abundant clear cytoplasm. original magnification ×175). A few spindle-shaped cells and a fibrous tissue with ectatic blood vessels were interposed between the clear cell areas. The tumor was separated from thyroid gland tissue and striated muscles by a small fibrotic rim of <1 mm. The tumor consisted of densely packed large tumor cells with distinct boundaries (Fig. Göttingen. 10 minutes at 72°C with the Trio Thermocycler (Biometra. original magnification ×87. Multinucleated osteoclast-like giant cells are scattered in the tumor (hematoxylin and eosin. (A) Clear cell chondrosarcoma (right part) merged into an area of conventional chondrosarcoma (left part) at the outer margin of the tumor (hematoxylin and eosin. snap-cooled on ice. Vol. 3. The neoplasm had led to obstruction of the laryngeal and tracheal lumina and was situated close to the removed left thyroid lobe.388 B. but neoplastic osteoid formation was lacking.6 The findings were similar in resection specimens and tissue of the laryngectomy. . 26.5 cm. Immunohistochemistry Molecular Genetic Analysis Mutation analysis of the nine exons of the PTEN/MMAC1 gene.

D17S786. but we could not detect any mutations in the exons or the sequenced part of the introns. we were able to demonstrate a methylation of the promoter of p16 (data not shown). 5). The nuclei were frequently indented and had a finely dispersed chromatin. 4B).4 The first laryngeal chondrosarcoma was described by New in 1935. Neither an amplification nor a loss of heterozygosity could be found for the CCND1 gene (cyclin D1).11 Thereafter. In a few cells a prominent nucleolus occurred.000). Vol.000). D17S513. Collagen type II positive staining was present in the cytoplasm of a few tumor cells (original magnification ×100). 3. (A) Electron micrograph showing a cell with irregularly outlined cytoplasm. 3. Loss of heterozygosity was found at D9S162 (9p22-p21) and D18S58 (18q21) (Fig. Electron Microscopy The clear cells (Fig.. London. little indented nucleus. 4A) had an irregularly outlined cytoplasm. 2002 . Molecular Genetic Analysis All nine exons of the MMAC/PTEN gene and both exons of the p16 gene could be amplified from tumor DNA. Microsatellite Analysis Of the nine loci investigated for this tumor six were informative (D9S162.2% of all laryngeal neoplasms. 254 cases had been reported in the literature until 1997. Other cells showed more irregular. a few small mitochondria and rough endoplasmic reticulum cisternae were seen.19 According to Gripp FIG. DISCUSSION Cartilaginous tumors comprise 0. and a nucleolus (original magnification ×15. Am J Surg Pathol. Nose and Ear Hospital. D11S910. D18S58.CLEAR CELL CHONDROSARCOMA OF THE LARYNX 389 et al. No. whereas the two other loci on chromosome 9p21 and one other locus on chromosome 13q12 were not informative.27 The cricoid cartilage (70–83%) is FIG. 26. convoluted nuclei. Furthermore.1–0. (B) Another cell with deeply indented nucleus and dilated rough endoplasmic reticulum cisternae (original magnification ×30. Rough endoplasmic reticulum of these cells was very well developed and presented remarkable dilatation of the cisternae (Fig. 29 laryngeal chondrosarcomas were documented: 17 in case reports and 12 in a retrospective study of the Royal National Throat. In contrast. 4. and D13S263).

Furthermore. the diagnosis of laryngeal clear cell chondrosarcoma has to be confirmed. predominately clear cytoplasm with sparse intervening matrix. indented nuclei. Vol. which could be caused by the special processing of initially formalinfixed tissue for the electron-microscopic examination. It accounts for about 2% of all chondrosarcomas.29 Within the 16 cases of a recent study of clear cell chondrosarcomas.10. Clear cell feature in an osteosarcoma was described only once in the literature. reported to be the most common site of involvement.10 Since the first description of this entity in 1976. bone trabeculae. followed by the thyroid cartilage (20%). 3.18 At the electron-microscopic level the tumor cells showed an irregularly outlined cytoplasm. The distinction between chondrosarcoma and metastatic clear cell carcinoma.27 Most of the laryngeal chondrosarcomas considered in the literature are of the uniform conventional type. 5. the arytenoids. especially renal cell carcinoma. FIG. there was no evidence of tumoral osteoid. KLEIST ET AL. Additional evidence of cartilaginous differentiation was provided by immunohistochemically demonstrated collagen type II expression. The differential diagnoses of a malignant laryngeal neoplasm include squamous cell carcinoma and metastatic clear cell carcinoma. Although clear cell chondrosarcoma is generally considered to be a variant of chondrosarcoma. but not specific features because they can occur in developing and aging cartilage as well as in different chondroid tumors. Electropherogram of the normal DNA (above)/tumor DNA (below) pair. there are some variants of squamous cell carcinoma that may have associated chondrosarcomatous metaplastic foci and can thereby be mistaken for chondrosarcoma.33 approximately 150 cases have been reported in the literature. aneurysmal bone cyst-like areas. and large dilated rough endoplasmic reticulum cisternae.8 More helpful in distinguishing these entities are collagen type II expression as mentioned above and conventional staining methods such as PAS and Sudan-Red: the cells in clear cell metastatic lesions contain glycogen and fat.33 some reports suggest this tumor to be an independent histologic type between chon- . and by additional criteria as scattered osteoclast-like giant cells. No. like the chondrosarcoma described here.20 The clear cell type we describe here is an uncommon and rare variant of chondrosarcoma. in the actual case this diagnosis was considered unlikely in view of the predominating clear cells.18 In accordance with these authors. is more difficult because even immunohistochemical results have to be interpreted with caution. 26.9 In contrast to our PAS staining presenting intracellular glycogen. not only in the larynx but also in general. Recent data suggest that clear cell chondrosarcoma has a higher growth activity and thereby a different biologic behavior compared with benign chondroblastoma. The diagnosis of squamous cell carcinoma was rejected on the basis of histology and the absence of cytokeratin immunoreactivity.25 Chondroblastoma was recently reported as a difficult differential diagnosis because it shares several histologic characteristics with clear cell chondrosarcoma. there was no certain evidence of glycogen in our ultrastructural investigation. presented predominately clear cell features. Many important questions concerning the histogenesis of clear cell chondrosarcomas have not been fully investigated and remain controversial. These findings have already Am J Surg Pathol.390 B. given that about two thirds of renal cell carcinomas express S-100 protein10 and some cases of clear cell chondrosarcoma are found to be positive for cytokeratins. The arrows mark the lost allele. and epiglottis.8 whereas all tumors of an earlier analysis.8 Clear cell chondrosarcoma is mainly characterized by rounded cells having conspicuous. the portion of the diagnostic clear cell component varied between 20% and 80% of the entire tumor area. 2002 been reported in another ultrastructural study of clear cell chondrosarcoma and were defined there as characteristic. vocal cords.32 Chondroblastic osteosarcoma was also considered as a differential diagnosis but was readily excluded because severe nuclear polymorphism and atypical mitosis were absent. which is typical for osteosarcoma. The y-axis represents the peak height in fluorescence units. and also foci of conventional chondrosarcoma.5. which do not occur in such high percentages in chondroblastoma. we could demonstrate a PCNA expression at a relatively high level.2.16 Because of its rarity. which could be found only in cartilage and in very small amounts in the eye and which has already been described as a characteristic for clear cell chondrosarcoma. In uncertain cases the immunohistochemical determination of the PCNA index could facilitate the differential diagnosis. However.7. The lightmicroscopic appearance and the presence of glycogen and S-100 protein are consistent with this diagnosis but not specific parameters of a clear cell chondrosarcoma.18 However. whereas those of clear cell chondrosarcoma are rich only in glycogen.16.

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