—  SPECIALTY CONFERENCE  —

Bone and Soft Tissue Pathology

Case 4 - Chondrosarcoma of the Skull Base

Andrew E. Rosenberg
Department of Pathology
James Homer Wright Laboratories
Massachusetts General Hospital
Harvard Medical School
Boston, MA.


Click on each slide thumbnail image for an enlarged view
Clinical History
A 64 year old woman presented to her physician complaining of a 1 year history of headaches and diplopia. The symptoms had become progressively more severe during this time period. Radiographic imaging studies revealed a focally calcified, well circumscribed mass in the region of the clivus that impinged upon the brain stem. A biopsy was performed.


Case 4 - Figure 1 - Lobular growth pattern of tumor.
Case 4 - Figure 2 - Periphery of lobules are hypercelluar.
Case 4 - Figure 3 - Myxoid component of tumor composed of bipolar and stellate cells arranged in interconnecting cords.


Case 4 - Figure 4 - Neoplastic cells in myxoid component have round to elongate nuclei with somewhat irregular contours. Small nucleoli are present in some nuclei.
Case 4 - Figure 5 - Chondroid areas composed of more homogenous solid appearing matrix with tumor cells located in lacunar spaces.


Case 4 - Figure 6 - Tumor cells stain strongly for S-100.
Case 4 - Figure 7 - Tumor cells are negative for keratin cocktail (AE1,3)

Pathology
The biopsy specimen consists of a moderately cellular neoplasm composed of round, stellate and elongate cells enmeshed in a matrix that varied from frothy and myxoid to solid and cartilaginous. The cells are moderate in size, contain central, mildly enlarged, somewhat irregular round to oval nuclei that are either dark staining or have a fine chromatin pattern with small nucleoli. The cytoplasm of most cells is eosinophilic, but, in some cells the cytoplasm contains small round clear vacuoles, which impinge upon and scallop the nuclei. In the myxoid regions, the cells grow in cords and strands forming a complex interconnecting network and in the cartilaginous appearing areas, the cells are single and isolated within the matrix where they reside within lacunar spaces. Mitoses are very rare.

Immunohistochemistry on the formalin fixed tissue shows that the tumor cells are positive for S-100 and negative for keratin and epithelial membrane antigen.

Diagnosis
Chondrosarcoma, mixed hyaline and myxoid type, Grade 1-2/3.

Discussion

Introduction
The skull base is composed of a variety of tissues, including bone, hyaline cartilage, notochord, fat, blood vessels, smooth muscle cells, fibroblasts, and hematopoietic elements. Neoplasms of the skull base may recapitulate any of these components, however, the types of primary tumors that arise in this region tend to be restricted in their phenotype. The most common primary bone tumors of the skull base are chordoma and chondrosarcoma.

Chondrosarcoma was officially recognized as a sarcoma distinct from osteosarcoma in the medical community of the United States in 1939. Since that time, chondrosarcoma has become recognized as the second most common primary malignancy of bone. However, only 5% of chondrosarcomas arise in the head and neck region where they account for 0.1% of head and neck cancers and only 1% originate in the skull base. Based on the number of cases reported in the literature chondrosarcoma follows chordoma as the most frequent primary sarcoma in the skull base.

Epidemiology
Approximately 600 chondrosarcomas of the base of the skull are reported in the literature with the largest series of well-documented cases accounting for 200 cases. The patients range in age from children to the elderly, however most are middle aged with the mean age being in the end of the 4th decade of life. There is a slight female predominance with a female to male ratio of 1.1-1.3:1. The majority of skull base chondrosarcomas arise in the vicinity of the clivus with 66% centered in the tempero-occipital junction, 28% in the spheno-occiput, and 6% in the sphenoethmoid complex (63). Almost all skull base chondrosarcomas arise de novo as only 2.5% of patients have a pre-existing condition such as Ollier's disease, Maffuci's syndrome or multiple hereditary exostoses, which predisposes them to the development of chondrosarcoma.

Symptomatology and Radiographic Features
Patients with skull base chondrosarcoma typically present with symptoms related to the central nervous system including headaches, cranial nerve palsies, hearing deficits, and disturbances in gait. The duration of symptoms prior to diagnosis is relatively long and is reported to range from 18-60 months.

Regardless of site of origin, chondrosarcoma usually manifests as a destructive and mineralized mass that may extend into the soft tissues. The mineralized component is frequently multifocal, dense and spiculated.

Classification and Pathology
Almost all chondrosarcomas of the skull base are of the conventional type. Clear cell chondrosarcoma, dedifferentiated chondrosarcoma and mesenchymal chondrosarcoma rarely arise in the skull base and therefore, are not further discussed. Conventional chondrosarcoma is composed solely of hyaline or myxoid cartilage, or an admixture of these components. Grossly, conventional chondrosarcomas are bulky, consisting of nodules of gray to tan-white tissue that rang from firm and gritty to mucinous. They typically grow with an infiltrative pattern, replacing the normal marrow elements, surrounding pre-existing cancellous bone, and permeating the vascular channels within the cortical bone. It is by this mechanism that they frequently transgress the cortex and form a well-delineated soft tissue masses.

In hyaline chondrosarcoma, the neoplastic chondrocytes reside within lacunar spaces and are surrounded by hyaline matrix. The chondrocyte nuclei have a variable appearance, ranging from small and round with smooth borders to medium size with fine chromatin and small nucleoli or even very large, and hyperchromatic, with irregular borders. Bi- or multinucleate tumor cells are commonly present. The cytoplasm of the cells may be clear or eosinophilic and is usually scant and retracted around the nucleus, however, in a minority of cases it may be more abundant. It is important to note that it is not uncommon for the cytoplasm of the tumor cells to have a bubbly or vacuolated appearance mimicking physaliphorous cells of chordoma. Mitotic activity is usually limited except in the more poorly differentiated tumors, and foci of necrosis may be present. The matrix of hyaline chondrosarcoma frequently mineralizes and this manifests as irregular purple granules and, in some tumors, focal enchondral ossification also occurs.

Neoplastic cells that appear to float in a frothy mucinous matrix characterize myxoid chondrosarcoma. The tumor cells are bipolar or stellate with elongate cytoplasmic processes that approach closely or directly contact the processes of neighboring cells. This architectural arrangement produces a honeycomb network of interconnecting strands and cords of cells. In all areas, including the more cellular portions of neoplastic lobules, matrix surrounds individual chondrocytes so that cohesive clusters or nests of tightly opposed cells, characteristic of chordoma, are not present. The myxoid matrix occasionally mineralizes and in these regions enchondral ossification is common.

Mixed hyaline and myxoid chondrosarcoma contains variable amounts of both matrices, which either merges imperceptibly with or are sharply demarcated from one another. The morphology of the chondrocytes and their arrangement in the matrix is not different from purely hyaline or myxoid tumors.

Conventional chondrosarcoma is graded according to the degree of its cellularity, cytologic atypia and mitotic activity. Most grading systems use a three or four tier scheme and the vast majority of conventional chondrosarcomas are well or moderately differentiated. In a series of 200 skull base chondrosarcomas that were graded based on a three tier system, 50.5% were grade 1, 28.5% had areas of grade 1 and 2, and 21% were purely grade 2 tumors. None of the neoplasms were grade 3. This is not surprising, as in all anatomic sites, poorly differentiated conventional chondrosarcomas are distinctly uncommon. The presence of aggressive appearing cartilage characteristic of poorly differentiated conventional chondrosarcoma should always raise the possibility of chondroblastic osteosarcoma, because this type of cartilage is more commonly a component of high-grade osteosarcoma than a pure chondrosarcoma.

Differential Diagnosis The most important tumor in the differential diagnosis is conventional and chondroid chordoma.

Histologically, conventional chordoma is composed of lobules of large cells arranged in cords and cohesive nests. Within the nests one commonly finds one cell wrapped around its neighbor as if one cell is "hugging" the other. The cohesion of the neoplastic cells and the "hugging " phenomenon, reflect the presence of epithelial type intercellular junctions, and is an architectural growth pattern not present in conventional chondrosarcoma, as normal and neoplastic chondrocytes lack these cell-to-cell attachments. Chordoma cells are generally large, larger than the tumor cells in chondrosarcoma, and are polyhedral, and epithelial in appearance and vary little in size and shape; however, they may occasionally exhibit significant pleomorphism or a spindle cell morphology. The nuclei are of moderate size, darkly staining, and may contain small nucleoli or pseudoinclusions. The tumor cells have abundant pink cytoplasm and some contain single, large or multiple, small, round, clear cytoplasmic vacuoles that impart a 'bubbly' appearance to the cytoplasm. These vacuolated cells are known as physaliphorous cells, a term coined by Virchow in 1857, and have since become the sine qua non of chordoma. However, the diagnostic significance of physaliphorous cells is limited, as they are not always present and chondrosarcoma, may have similar appearing cells. Chordoma cells generally show limited mitotic activity and areas of necrosis are commonplace, especially in large tumors. The stroma in conventional chordoma is usually abundant, mucinous, and typically appears frothy and basophilic as it enmeshes the cords and nests of tumor cells.

Immunohistochemically, conventional chordoma typically expresses the epithelial markers keratin and epithelial membrane antigen and the vast majority also stain with antibodies to the calcium binding protein S-100. This profile can be very helpful in distinguishing chondrosarcoma from chordoma, in that chondrosarcomas are negative for epithelial markers, especially, keratin.

The histologic features that define chondroid chordoma include an admixture of conventional chordoma and regions that mimic hyaline-type chondrosarcoma. The two elements may either merge with or be sharply demarcated from one another. The chondroid component is made up of neoplastic cells arranged individually in lacunar spaces and surrounded by a solid, hyalinized matrix morphologically similar to the matrix in hyaline cartilage. The quantity of the chondroid component is variable and in some cases it may be abundant, causing diagnostic confusion with chondrosarcoma. Ultrastructurally, the tumor cells in the chondroid areas have the same features as those of conventional chordoma. Similarly, the cells in the chondroid regions have the same immunohistochemical profile as those in the conventional areas in that they both express epithelial markers. Accordingly, the chondroid appearance in these tumors represents a morphologic change in the extracellular matrix and cell distribution and does not represent the presence of hyaline cartilage in a chordoma.

Cytogenetics
Cytogenetic analysis of conventional chondrosarcoma has been performed on a small number of tumors that have arisen mainly in the appendicular skeleton. Studies have documented that the most frequent structural abnormalities affect chromosomes 1,6,9,12 and 1. A chromosomal abnormality specific for conventional chondrosarcoma has yet to be identified.

Treatment and Prognosis
Potentially fatal progressive enlargement and subsequent compression or invasion of important neighboring structures such as the brain, brainstem, optic pathway, cranial nerves and pituitary gland characterizes the biologic behavior of chondrosarcoma of the skull base. The critical location of these tumors precludes complete surgical resection, therefore, most of these neoplasms are treated with a combination of surgery and irradiation. The outcome of skull base chondrosarcoma has varied according to the therapy employed. In patients treated with surgery alone the local recurrence rate was reported in a literature review to be 53%. When proton beam irradiation was used in conjunction with biopsy only or varying degrees of neurosurgical resection in a group of 200 patients, the 5 and 10 year local control rates were 99% and 98% respectively and the 5 and 10 year disease specific survival rates were both 99%. In other recent series treating smaller numbers of patients with surgery and irradiation, the local control rates have varied from 90-100%. The control rates are so good that in most situations, surgical treatment, other than biopsy is not indicated. This outcome is significantly better than that for chordoma for which radiation and surgical resection is currently the recommended therapy; in a large series in which patients with chordoma of the skull base were treated with surgery and radiation, 46% of patients developed local progression at a median of 69 months follow-up. Other investigators found that the 5 year local control rate was 59%, in another analysis, the 5 year recurrence free survival was 65% and lastly, the 5 and 10 year estimated overall survival rates in another study were 51% and 35, respectively. This difference in prognosis and treatment emphasizes the importance of accurately distinguishing chondrosarcoma from chordoma.

Prognostic Markers
Conventional chondrosarcoma of the peripheral skeleton has been evaluated by a variety of techniques to determine if any correlation between biological markers and outcome exists. Ploidy studies of tumors arising in the appendicular skeleton have provided limited prognostic information. In one study, cell proliferation as measured by the expression of Ki67 (MIB-1) using an immunohistochemical detection method, in conventional chondrosarcomas of the appendicular skeleton, showed a correlation between proliferation index and tumor grade. Otherwise, no biologic marker that reliably predicts the clinical behavior of chondrosarcoma exists.

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