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Conventional chondrosarcoma: old controversies and new insights
MINI-SYMPOSIUM: PATHOLOGY OF CARTILAGINOUS TUMOURS
Conventional chondrosarcoma: old controversies and new insights
decades of life, and very rarely in children and young adults. While central chondrosarcomas can involve any bone, more than two-thirds arise either in the trunk (including shoulder girdle) or proximal ends of the femora and humeri. They only rarely occur in the spine, craniofacial bones and small bones of the distal extremities. The histologic diagnosis of chondrosarcoma endures as one of the most challenging areas of bone pathology, particularly when trying to distinguish benign enchondroma from low-grade chondrosarcoma. As aptly stated by Lichenstein and Jaffe in 194, “ .the histologic picture of a particular lesion does not have to be crudely and obviously malignant to indicate chondrosarcoma.”2 Likewise, in 1956, Dahlin acknowledged the problem by stating, “.the criteria that separate a low-grade chondrosarcoma from a chondroma are very subtle.”.3 Over the past several decades, numerous publications have attempted to address this diagnostic dilemma, albeit with limited success. Moreover, the difficulties associated with distinguishing benign from malignant cartilaginous tumors are compounded by confusing terminology. There are also on-going issues with histologic grading of chondrosarcoma. These challenges have important clinical implications since benign and malignant cartilaginous tumors are treated differently and the histologic grade of chondrosarcoma is an important prognosticator. This review will highlight longstanding controversies in the diagnosis of chondrosarcoma and explore the impact of new insights on both the diagnosis and management of chondrosarcoma. The focus will be on central chondrosarcoma involving the long bones and axial skeleton; tumors of the small bones and syndrome-associated cartilaginous tumors will not be discussed.
Jodi M Carter Carrie Y Inwards
Abstract Conventional chondrosarcomas comprise the largest group of malignant cartilaginous tumors. The distinction enchondroma and low-grade chondrosarcoma remains among the most challenging diagnoses for bone pathologists. Although numerous histologic criteria have been proposed to distinguish them, significant interobserver variability still exists. Fortunately, advances in diagnostic imaging and novel surgical approaches to low-grade tumors have lessened the need for definitive histologic diagnosis on biopsy material. In addition, the current WHO classification atypical or borderline cartilaginous tumors with Grade 1 chondrosarcoma in an attempt to facilitate diagnosis and treatment. While histologic grade remains the most important prognosticator in chondrosarcoma, the criteria for grading remain controversial. Finally, despite numerous insights into the pathobiology of cartilaginous tumors, targeted therapies remain elusive. However, there is an emerging role for isocitrate dehydrogenase mutational testing in the clinically important distinction between chondrosarcoma and chondroblastic osteosarcoma.
Keywords atypical cartilaginous tumor; cartilage; central; chondrosarcoma; enchondroma; grading; isocitrate dehydrogenase
The evolving concept of low-grade cartilaginous tumors Hyaline cartilage tumors arising within the intramedullary cavity are traditionally classified as enchondroma on the benign end of the spectrum, and chondrosarcoma on the malignant end. Chondrosarcoma has been further classified by histologic grade using a scale of Grades 1e3. These diagnoses require a combination of clinical, radiologic and histologic information, particularly in the recognition of low-grade tumors. Nevertheless, we have applied histologic criteria over the years that are paramount in defining these tumors.
Introduction Chondrosarcomas are malignant tumors, defined by their cartilaginous matrix-producing constituent cells. They comprise an estimated 20% of primary malignant bone tumors, second only to osteosarcoma.1 Chondrosarcomas are generally categorized by their location within the parent bone. Central chondrosarcomas arise de novo within the intramedullary cavity of bone, whereas peripheral chondrosarcomas arise on the surface of cortical bone, most commonly within a pre-existing osteochondroma. Conventional chondrosarcomas are the most common subtype of malignant cartilage-forming tumors, comprising an estimated 75 e85% of tumors. Less common subtypes include clear cell chondrosarcoma, dedifferentiated chondrosarcoma and mesenchymal chondrosarcoma. Conventional chondrosarcomas occur primarily in adults, most often in the fourth through sixth
Microscopic assessment The classic microscopic features of enchondroma are those of a well-circumscribed and relatively hypocellular tumor, composed of cartilaginous lobules containing chondrocytes with small dark nuclei within lacunae. Permeation of host lamellar and cortical bone is absent in enchondromas. In contrast, chondrosarcomas demonstrate an overall greater degree of cellularity and cytologic atypia than enchondroma. They have a permeative growth pattern characterized by total engulfment of host bone trabeculae and cortical destruction oftentimes associated with extension into soft tissue. The histologic features of higher grade chondrosarcoma (Grades 2 and 3) are usually readily discernable, in large part due to obvious cytologic atypia. In addition, the radiologic appearance usually reflects an aggressive behavior corresponding to the malignant histologic findings. The diagnostic dilemma rests with
Jodi M Carter M.D. Ph.D. Bone and Soft Tissue Pathology Fellow, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. Conflicts of interest: none declared. Carrie Y Inwards M.D. Associate Professor of Laboratory Medicine, College of Medicine, Mayo Clinic, Rochester, MN, USA. Conflicts of interest: none declared.
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remains a useful criterion in the distinction of benign and malignant cartilaginous tumors. However, the descriptive heterogeneity of “myxoid” stroma, including stellate cells embedded in an acid mucopolysaccharide-rich matrix rich; mucoid matrix degeneration; myxoid, frothy/bubbly, intercellular substance partially dissolved into strings or cords separated by amorphous partially basophilic mucus, and lack of defined quantitative parameters hinder its application. In 1980, Sanerkin, highlighted invasion or permeation into host bone by neoplastic cells as another important histologic criterion.6 In fact, there is now general agreement that permeation of host bone is the most important histologic criterion separating enchondroma from chondrosarcoma Figure 1. This concept was expanded by Mirra and colleagues with the introduction of a new histologic approach to differentiating enchondroma and low-grade chondrosarcoma based on lowmagnification tissue patterns.7 In this approach, enchondromas are characterized as multiple nodules of hyaline cartilage separated by normal marrow in conjunction with partial to complete encompassing plates of lamellar bone that conform to the irregular shapes of the cartilage nodules Figure 2. In contrast, chondrosarcomatous patterns include a single confluent mass of cartilage, with frequent marrow permeation, trapping of host lamellar bone on all sides and bands of fibrosis between confluent cartilage nodules. These criteria proved to be a valuable addition to the literature. However, as the authors noted, two important caveats apply: permeation may be missed due to sampling error, and excessive fragmentation of an enchondroma may create artifactual disruption of the cancellous bone, resulting in juxtaposition of neoplastic cartilage to bony trabeculae in a pattern that is misinterpreted as permeation. Furthermore, a generous amount of tissue is required when a diagnosis is based on low-magnification growth patterns rather than cytologic features. With the emergence of limited tissue procurement by image-guided, needle core biopsies, the separation of enchondroma from low-grade chondrosarcoma by this approach became next to impossible. Over the past two decades, histologic features used in the diagnosis of chondrosarcoma have combined any number of the above criteria. Unfortunately, as highlighted in two recent publications, considerable interobserver variability still exists, even
separating enchondroma from low-grade (Grade 1) chondrosarcoma. Difficulties stem from histologic heterogeneity within, and overlap between, these tumors compounded by the subjectivity inherent in assessing a lower degree of cytological atypia. As a result, there have been numerous studies aimed at simplifying the problem. Lichtenstein and Jaffe published one of the earliest descriptions of chondrosarcoma, a diagnosis they based on cytologic features of the neoplastic cells. They maintained that a cartilage tumor should no longer be considered benign if, in viable areas, it shows: 1) many cells with plump nuclei; 2) more than an occasional cell with two such nuclei; and 3) giant cartilage cells with large single or multiple nuclei or with clumps of chromatin. When referring to difficult cases at the low-grade end of the spectrum, they commented, “.even in the early stages of the evolution of a chondrosarcoma, one will find, at least in scattered fields, if adequate material is examined, subtle but tell-tale evidences of cytologic atypism of the cartilage cells which will betray the malignant character of the lesion”. Thus, they recognized the problems that can occur when dealing with microscopic heterogeneity, a lower degree of cytologic atypia, and lack of sufficient diagnostic tissue. Over the ensuing years, it became apparent that histologic tools beyond cytologic atypia were required to separate enchondroma from low-grade chondrosarcoma. In part, this was due to interobserver variability in the interpretation of the aforementioned terms “many”, “more than occasional”, and “plump”. Furthermore, binucleated cells can be found in benign and malignant cartilage tumors. Attention turned to exploring other features such as cellularity, mitotic activity, growth pattern, and changes in the matrix that might serve as helpful diagnostic tools. In 1959, Jaffe stated that a solitary cartilage tumor should be suspect of being a chondrosarcoma if it shows, even in scattered fields, hypercellularity of the tissue. In 1977, Evans et al added cellularity and mitotic activity to the histologic criteria for diagnosis and grading of chondrosarcoma.4 In this schema, cellularity increased from low to high with increasing tumor grade. With regard to mitotic activity, mitoses were scarce in the majority (53 of 71) of tumors (<2/10 high power fields) and absent in Grade 1 tumors. Thus, mitotic activity was not helpful in the most difficult diagnostic situation, namely distinguishing Grade 1 chondrosarcoma from enchondroma. Subsequent studies confirmed the very low mitotic count in low-grade chondrosarcomas. While mitoses can often be appreciated in highgrade tumors, they also show obvious features of malignancy. In a large series of chondrosarcoma of the long bones and pelvis, Bjornsson et al reported that only 8% (27 of 233) of tumors contained mitotic figures, e begging the question of their utility in either the diagnosis or grading of chondrosarcoma.5 Evans et al also added the “character of intercellular background” to their histologic criteria for chondrosarcoma, wherein a predominantly chondroid component was associated with benignity and myxoid stroma was associated with malignant tumors.4 While myxoid change and degenerative necrosis may be focally present in an enchondroma, extensive myxoid change is usually indicative of malignancy. Indeed, myxoid matrix was the most common histologic feature (87% of 233 cases) in a Mayo Clinic study of chondrosarcoma.5 Currently, stromal assessment
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Figure 1 Host bone entrapment by chondrosarcoma.
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chondrosarcoma, and no value in mitotic count, a criterion also discarded in the grading scheme used by Unni.1 In short, the degree of cellularity and cytologic atypia form the foundation of almost all current grading schemes. The systems that include mitotic activity usually reference the scheme proposed by Evans and colleagues.4 In this system, mitotic figures are absent in Grade 1 tumors, “occasionally” seen in Grade 2 tumors and a count of 2 per 10 high power fields is indicative of a Grade 3 tumor. Therefore, mitotic activity is, for the most part, a feature of Grade 3 tumors, a group that represents only a small percentage of chondrosarcomas. In larger series, the distribution of chondrosarcomas by histologic grade varies, ranging from 13% to 60% for Grade 1, and 35%e67% for Grade 2 tumors.5,12,13 This range reflects the subjectivity inherent in the grading schema and hampers comparisons of clinical data and survival rates. However, generally Grade 1 tumors comprise closer to 60% of tumors and Grade 2 tumors account for just over 30%. In most series, Grade 3 chondrosarcomas comprise fewer than 10% of tumors, but rates ranging to 25% have been reported. Difficulties separating chondroblastic osteosarcoma from Grade 3 chondrosarcoma and inclusion of dedifferentiated chondrosarcomas likely contribute to the higher end of this range. As early as 1956, Dahlin reported the diagnostic difficulty of cartilaginous tumors with “borderline” malignant histologic features – a long-standing source of frustration for pathologists. Over time, these “borderline” tumors have known a number of names including Grade 0 chondrosarcoma, Grade ½ chondrosarcoma, borderline chondrosarcoma, cartilage tumor of undetermined malignant potential (CLUMP), low-grade cartilaginous tumor, atypical cartilage tumor, atypical enchondroma and active enchondroma. The lack of consistent terminology further confuses an already challenging task. In general, this category is reserved for tumors involving the long bones with worrisome radiologic features, but unconvincing histologic features of malignancy. However, the histologic criteria for this category have never been well defined. In an attempt to standardize terminology, the current WHO classification of bone tumors merges the term atypical cartilaginous lesion with Grade 1 chondrosarcoma, an approach that is similar to the WHO classification of atypical lipomatous tumor/ well-differentiated liposarcoma.14 This modification places atypical cartilaginous lesion/Grade 1 chondrosarcoma into an intermediate (locally aggressive) category Figures 3e5. This strategy acknowledges atypical tumors with low malignant potential within a widely accepted and respected classification scheme. However, it remains to be seen whether this will clarify the issue or create confusion by the assignment of malignant terminology (Grade 1 chondrosarcoma) to a borderline category. In addition, although Grade 1 chondrosarcomas have a low propensity for metastasis, documented examples exist in the literature.
Figure 2 Enchondroma involving the proximal femur of a 54-year-old male. A nodule of hyaline cartilage surrounded by normal bone marrow and partially encased by a plate of lamellar bone.
among experienced musculoskeletal pathologists.8,9 Not surprisingly, the distinction between enchondroma and Grade 1 chondrosarcoma is the most discordant diagnosis in cartilaginous tumors, reflecting the lack of significant progress since Jaffe introduced the histologic dilemma several decades ago. Accordingly, among these studies addressing interobserver variability, Eefting and colleagues found high cellularity, presence of host bone entrapment, open chromatin, and myxoid matrix to be the most helpful histologic parameters in the distinction between enchondroma and low-grade chondrosarcoma - all features echoing what has been said in the past.9 Histologic grading of chondrosarcoma Dahlin was the first to apply histologic grading to chondrosarcomas.3 In a 1956 review of 212 cases, he used Broder’s method of grading based on the cytologic features described by Lichtenstein and Jaffe. As no chondrosarcoma qualified as a Grade 4 tumor, the series was graded with histologic Grades 1 to 3. This grading scale was widely accepted and its use continues to the present time. Most authors group Grade 1 tumors as lowgrade and Grade 2 and 3 tumors as high-grade. However, in a study of 109 patients with chondrosarcoma, Reith and colleagues found that Grade 2 tumors were more appropriately grouped with Grade 1 tumors.10 In large part, the differences likely reflect a lack of uniform and reproducible histologic criteria for Grade 1 chondrosarcoma, a problem that can lead to significant therapeutic consequences. Dahlin found histologic grade to correlate with biologic behavior, and today it remains the most important independent predictor of local recurrence and metastasis. Nevertheless, methods of histologic grading remain a controversial issue, fraught with poor interobserver reproducibility. All grading schemes are based on the assessment of cytologic features (binucleate cells, nuclear size, hyperchromasia and pleomorphism) but controversy exists regarding the required number of features. Cellularity and mitotic activity are included in some, but not all, schemes. For instance, Welkerling et al propose a system based solely on nuclear size and nuclear hyperchromatism.11 Similar to Mirra, they found an overlap in the frequency of binucleated cells in enchondromas and low-grade
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Radiologic assessment Radiologic correlation is essential in the classification of all bone tumors, but its role is particularly critical when dealing with cartilage tumors, especially in the context of enchondroma vs. lowgrade chondrosarcoma. Early studies recognized helpful diagnostic features of chondrosarcoma afforded by roentgenograms.3 These included cortical destruction, mottled or fuzzy
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Figure 3 Histologic heterogeneity within an “atypical cartilaginous tumor/grade 1 chondrosarcoma” (per WHO classification) involving the distal femur (a) Some fields demonstrate paucicellular hyaline cartilage containing chondrocytes with small nuclei. (b) Other fields are more cellular, showing chondrocytes with nuclear enlargement.
calcification, fusiform expansion and thickening of the cortex. While these features remain useful, subsequent studies have shown that conventional radiology alone is not reliable in differentiating benign from low-grade malignant cartilaginous tumors. The advent of advanced imaging modalities significantly improved the amount of information provided by radiologic evaluation Figure 6. Currently, the combination of radiographs, CT and MR imaging allows radiologists to play a key role in assessing the biologic behavior, and thus treatment, of cartilage tumors. The radiologic features of Grades 2 and 3 chondrosarcoma, including moth-eaten and permeative patterns of bone lysis often associated with large soft tissue masses, reflect the aggressive behavior of higher grade tumors. Thus, their distinction from enchondroma, a tumor with an indolent radiologic appearance, is usually not a difficult task Figure 7. Radiologic imaging is also useful in determining the size of tumors, a feature shown to be helpful in predicting biologic behavior. In general, tumors <5 cm in size behave in a benign fashion. In 1999, Murphey et al published one of the largest and most comprehensive studies addressing the clinical and radiologic
features used in the distinction of enchondroma and chondrosarcoma of the appendicular skeleton.15 They found a clinical presentation of tumoral pain combined with the radiologic findings of deep endosteal scalloping (greater than two-thirds of the cortical thickness), cortical destruction and soft-tissue mass on CT or MR imaging, periosteal reaction and marked uptake of radionuclide at bone scintigraphy facilitated the diagnosis of approximately 90% of tumors in their series. Popcorn-like calcifications and MR imaging findings including abnormal peritumoral marrow and soft tissue signals, and fast contrast-enhanced MR imaging have also been reported to facilitate the distinction of enchondroma from low-grade chondrosarcoma.16 One study showed early uptake of gadolinium with an exponential curve on dynamic MRI was associated with malignant cartilaginous tumors. Moreover, two studies of fluorodeoxyglucose positron emission tomography (PET) in cartilaginous tumors found the standard uptake value correlated with the grade of malignancy. Given interobserver variability in the histologic diagnosis of these tumors, one must be cognizant of this limitation when interpreting studies aimed at defining radiologic criteria.
Figure 4 (a) Enchondromas abutting the cortical bone. (b) “Atypical cartilaginous tumor/grade 1 chondrosarcoma” (per WHO classification) eroding, but not extending through, the cortical bone.
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extremities, whereas chondrosarcomas comprise only 1% of hyaline tumors at this anatomic site. Moreover, the radiographic features of enchondromas arising in the small bones, such as deep endosteal scalloping, cortical expansion and thickening, overlap with those of biologically more aggressive cartilaginous tumors located in the long tubular bones, namely those considered to be atypical enchondroma/low-grade cartilaginous tumor. Also, enchondromas of the small bones show histologic features, including increased cellularity and cytologic atypia, that would be worrisome for malignancy in cartilaginous tumors of other skeletal sites. Thus, the consensus criteria for diagnosis of chondrosarcoma of the small bones differ from those of other sites and focus primarily on radiologic and/or histologic evidence of host bone permeation/cortical destruction with or without soft tissue extension. In contrast to the small bones, the vast majority of cartilaginous tumors arising within the flat bones are malignant. Accordingly, enchondromas of these sites are exceedingly uncommon, a phenomenon that is reflected in the lack of literature on the topic. Thus, a diagnosis of enchondroma should be entertained with great caution with cartilaginous tumors of the pelvic bones, ribs, sternum, scapula and vertebrae. Arguably, the paucity of enchondromas at these sites may be a self-fulfilling prophecy. In any event, tumors of the flat bones are treated by en bloc surgical resection due to the significant surgical complexity associated with subsequent recurrence at these sites. Once again, the term “atypical cartilaginous tumor/low-grade chondrosarcoma” in chondrosarcomas of the flat bones may be controversial if it implies that conservative surgery (i.e. intralesional curettage with adjuvant therapy) is adequate management. In addition to anatomic site, clinical presentation plays a role in the diagnosis of benign and malignant cartilaginous tumors. Pain is the most common presenting symptom of patients with chondrosarcoma, and is traditionally considered a worrisome sign for malignancy. However, recent studies have shown that the presence or absence of local pain does not reliably discriminate between benign and malignant cartilaginous tumors. In these series, pain is also a presenting symptom in approximately 40%e80% of enchondromas. Moreover, a recent study by Levy et al, found 88% of 57 humeral enchondromas presented with pain; however, careful clinical and radiographic correlation showed that in the vast majority of cases, pain was due to nontumoral causes.17 Thus, careful consideration should be paid to isolating the source of pain as it is likely tumor-related in chondrosarcoma, but not in those with enchondroma. Figure 5 (a & b) AP and lateral radiographs of the forearm show an atypical cartilaginous tumor involving a long segment of the radial diaphysis. There are regions of focal lucency with associated significant endosteal scalloping/erosion in the lesion distally along with cortical thickening about the entire lesion. (c & d) Coronal T1 and T2 weighted MR images show that the lesion occupies the entire diameter of the medullary canal and confirm the presence of significant endosteal scalloping/ erosion.
Treatment Surgery is the mainstay of treatment for chondrosarcoma. The vast majority of tumors are slow-growing and poorly vascularized, rendering them largely resistant to radiotherapy, with the notable exception of proton-beam irradiation for chondrosarcomas of the skull base. Similar to radiotherapy, cytotoxic chemotherapy plays little role in the current management of central chondrosarcomas, whether in the setting of unresectable primary disease or metastatic disease.18 In addition to the intrinsically low cell turnover in chondrosarcomas, particularly in low-grade tumors, along with their abundant hyaline matrix, the expression of anti-apoptotic Bcl-2 family members and multi-
Clinical considerations It is important to pay attention to the anatomic location of a cartilage tumor when formulating a diagnosis. Approximately 40% of enchondromas affect the small tubular bones of the distal
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Figure 6 AP radiograph (a) left hip and femur shows a predominantly lytic destructive lesion involving the a long segment of the proximal femur with scattered chondroid matrix, endosteal scalloping, diffuse cortical thickening and areas of indolent periosteal new bone formation. The imaging features are classic for chondrosarcoma. The coronal T1 (b) and T2 (c) weighted MR images show that the lesion extends from the femoral neck to the distal femoral diaphysis.
frees the pathologist from facing histologic difficulties associated with separating enchondroma from low-grade chondrosarcoma on pre-operative biopsy tissue. Microscopic evaluation of the curetted tissue is still essential to confirm the diagnosis and identify the rare case with an unexpected higher histologic grade. Moreover, occasionally a pre-operative biopsy is obtained in order to confirm the radiologic impression of a cartilage tumor. En bloc resection remains the preferred surgical approach for all chondrosarcomas involving the pelvis and higher grade (2 and 3) tumors of the long bones; the latter are identified by their aggressive radiologic features (cortical destruction, soft tissue mass), typically accompanied by a pre-operative tissue diagnosis.22
drug resistance pumps such as p-glycoprotein may contribute to chemoresistance.19 While a number of clinical trials with targeted therapies, including Hedgehog pathway inhibitors, have been initiated, definitive therapeutic targets remain elusive in the management of chondrosarcoma. Historically, the surgical management of all chondrosarcomas, regardless of histologic grade or anatomic location, was en bloc resection with wide surgical margins. In recent years, the use of this surgical approach, with its associated morbidity has come into question for low-grade chondrosarcoma of the long bones. These tumors have very little proclivity for local recurrence or metastasis. Intra-lesional curettage with adjuvant local therapy (i.e. intra-lesional cryotherapy, phenol, liquid nitrogen or argon-beam laser) has emerged as an effective treatment for tumors of the long bones classified as Grade 1 chondrosarcomas or atypical/borderline tumors, provided the tumors show no radiologic evidence of aggression i.e. cortical permeation or soft tissue extension20,21 Figure 7. This approach
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Prognosis Histologic grade of conventional chondrosarcoma remains the single most important predictor of local recurrence and metastasis. Fortunately, the assignment of higher histologic grades is typically not a diagnostic challenge for pathologists. And while
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Figure 7 AP radiograph (a), coronal T1 (b) and T2 (c) weighted MR images of the left shoulder demonstrate classic features of a benign enchondroma in the proximal humeral metaphysis with stippled chondroid matrix.
has shown that enchondromas and low-grade central chondrosarcomas are typically near diploid whereas complex karyotypes can occur in higher grade tumors, but contain few consistent genetic aberrations. In the developing growth plate, Indian hedgehog (IHH) and parathyroid hormone-like hormone (PTHLH) coordinate the
the distinction of enchondroma and low-grade chondrosarcoma is difficult, it doesn’t carry the prognostic significance attached to separating Grade 1 from Grade 2 tumors. Historically, reported local recurrence rates for Grade 1 chondrosarcoma varied widely, ranging from 0% to 50%. Recent studies report local recurrence rates for low-grade tumors of approximately 15%. Predictably, recurrence rates are influenced by factors that affect surgical accessibility, such as skeletal location (axial vs. appendicular skeleton) and adequacy of resection. Metastases are rare in low-grade tumors, with published rates ranging between 0% and 10%. Survival rates for patients with Grade 1 chondrosarcoma throughout the skeleton range from 88% to 100% at 5 years and 79%ew100% at 10 years. The outcome of patients with pelvic chondrosarcoma is usually worse than that reported for patients with extremity chondrosarcoma.22 Not surprisingly, survival rates decrease with higher grade tumors. Recent reports on survival rates for Grade 2 tumors range from 62 to 95% at 5 years and 53e90% at 10 years. Survival for patients with Grade 3 chondrosarcoma range from 62% to 77% at 5 years, and 29%e55% at 10 years.4,5,12,13,23 While the prognosis for high-grade bone sarcomas, such as osteosarcoma, has significantly improved with the implementation of adjuvant therapies, these strategies have not been as successful in the treatment of chondrosarcoma. As expected, local recurrence portends a poorer prognosis in high-grade chondrosarcoma. Interestingly, recent data suggest that local recurrence also impacts survival in low-grade chondrosarcoma of the long bones. Schwab and colleagues reported that progression of tumor grade, multiple recurrences and metastases were frequently observed in patients with locally recurrent Grade 1 chondrosarcoma. Accordingly, these events negatively impacted overall long-term survival, particularly at 10 years.24 Thus, aggressive surgical management is the preferred approach in the setting of locally recurrent disease, irrespective of the initial histologic grade.
Figure 8 Common IDH mutations in cartilaginous tumors. Automated DNA sequencing electropherograms illustrate the most common IDH1 single nucleotide substitutions in cartilaginous tumors. IDH1: R132C (CGT > TGT) and R132H (CGT > CAT) (arrowheads).
Molecular genetics The pathogenetic mechanisms of cartilage-forming tumors remain poorly understood. Conventional cytogenetic analysis
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surface osteosarcoma.28 Thus, additional study of IDH1/2 mutational status in osteosarcoma is required to clarify its utility in the distinction of chondrosarcoma from chondroblastic osteosarcoma.
regulation of chondrocyte proliferation and differentiation. Predictably, aberrant signaling of the IHH-PTHLH pathway has been implicated in both benign and malignant cartilaginous tumors25 Activated Src and Akt kinase signaling, alterations in pRB and derangements in the hypoxic and glycolytic pathways among others, have all been observed in chondrosarcoma. Acquisition of mutations in tumor suppressors such as p53 and CDKN2A/ p16/INK4A may herald tumoral progression to higher grade. Also, genomic analysis of central and variant chondrosarcomas has revealed frequent, complex mutations in COL2A1, encoding the predominant collagen in articular cartilage. Finally, histone deacetylase inhibitors impair growth and promote differentiation of chondrosarcoma cells in vitro. Together, these seemingly disparate genetic and epigenetic alterations highlight the pathogenetic complexity in chondrosarcomas. One of the most important and intriguing molecular genetic insights into cartilaginous tumors hinged on the observation that gliomas and acute myeloid leukemia (AML) occasionally occur in patients with syndromic enchondromatosis (Ollier syndrome and Maffucci syndrome). Both gliomas and AML are associated with mutations in IDH1 and IDH2, encoding isocitrate dehydrogenase, a key enzyme in the tricarboxylic acid cycle. Mutated IDH produces D-2-hydroxyglutarate, an oncometabolite which is thought to impair DNA demethylation. In 2011, Amary and colleagues tested a large series of syndromic and sporadic enchondromas, central (low and highgrade) chondrosarcomas, perisoteal chondrosarcomas, dedifferentiated chondrosarcomas and other cartilage-forming tumors for IDH mutations. They discovered that heterozygous, somatic IDH mutations are frequent events in both syndromic and sporadic enchondromas and central as well as periosteal chondrosarcomas, including central tumors with dedifferentiation.26 Subsequent studies have confirmed these findings. In cartilaginous tumors, hotspot IDH mutations occur as single nucleotide substitutions within codons for arginine residues within either IDH1 (R132) or IDH2 (R172). Among these, IDH1 R132C is the most common mutation, with frequencies ranging from 40 to 80%; IDH1 R132H is the second most common mutation, detected in approximately 15% of tumors. Mutations in IDH2 R172 are uncommon Figure 8. Although IDH mutations in gliomas occur within the same codons, the predominant nucleotide substitutions differ. Unfortunately, commercially available antibodies to mutated IDH1 protein recognize the common IDH mutations in gliomas, IDH1 R132 H/S, and are currently of little use in the diagnosis of cartilaginous tumors. As IDH mutations occur in approximately 50% of sporadic enchondromas and central chondrosarcomas, IDH mutational testing has no role in the distinction of enchondroma and lowgrade chondrosarcoma. However, in the two largest series to date, Amary et al and Kerr and colleagues reported no IDH mutations in chondroblastic osteosarcomas (0/46 and 0/36 respectively), raising the possibility that IDH mutational testing could be a valuable adjunct in the distinction of chondroblastic osteosarcoma from chondrosarcoma.26,27 This would have particular value in the setting of limited biopsy material. Furthermore, the differing prognoses and therapeutic strategies for osteosarcoma and chondrosarcoma underscore the clinical importance of this distinction. Of note, very recently IDH2 (R172S) mutations were reported in two osteoblastic osteosarcomas and one high-grade
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Summary The diagnosis and treatment of chondrosarcoma requires a multidisciplinary team consisting of pathologists, radiologists and surgeons. For the past several decades, the biggest diagnostic challenge for pathologists and radiologists has been the distinction between enchondroma and Grade 1 chondrosarcoma involving the long bones. Interobserver variability among radiologists has improved with the advent of advanced imaging modalities. However, subjective histologic criteria and tumoral heterogeneity continue to hinder the pathologic diagnosis, particularly with limited biopsy tissue. Fortunately, the past few years have seen a paradigm shift to intra-lesional curettage (with adjuvant local therapy) for the subset of atypical cartilaginous tumors/low-grade chondrosarcomas of the long bones that show no radiologic evidence of extension through cortical bone (Stage 1A). Thus, careful radiologic assessment of tumoral behavior has markedly diminished the need for a definitive, pre-operative histologic diagnosis in this setting. However, as histologic grade remains the most important prognosticator of chondrosarcomas, pathologists still play an important role in evaluating curetted tissue and resected tumors with more aggressive radiologic features. Unlike conventional osteosarcoma, chondrosarcomas are highly resistant to chemoradiation and as a result, (neo)adjuvant therapies have little role in their management. Despite numerous advances in our understanding of the biology of cartilageforming tumors, targeted therapies also remain elusive. The detection of IDH mutations in cartilage-forming tumors has been one of the most important genetic insights with direct clinical application. While IDH mutations frequently occur in both benign and malignant cartilaginous tumors, chondroblastic osteosarcomas appear to lack IDH mutations. Thus, IDH mutational testing shows promise as an emerging genetic tool in the clinically important distinction of chondrosarcoma and chondroblastic osteosarcoma. A REFERENCES 1 Unni KK, Inwards CY. Dahlin’s bone tumors. 6th edn. Philadelphia: Lippincott Williams & Wilkins, 2010. 2 Lichtenstein L, Jaffe HL. Chondrosarcoma of bone. Am J Pathol 1943 Jul; 19: 553e89. 3 Dahlin DC, Henderson ED. Chondrosarcoma, a surgical and pathological problem; review of 212 cases [Case Reports]. J Bone Joint Surg Am 1956 Oct; 38-A: 1025e38. passim. 4 Evans HL, Ayala AG, Romsdahl MM. Prognostic factors in chondrosarcoma of bone: a clinicopathologic analysis with emphasis on histologic grading. Cancer 1977 Aug; 40: 818e31. 5 Bjornsson J, McLeod RA, Unni KK, Ilstrup DM, Pritchard DJ. Primary chondrosarcoma of long bones and limb girdles. Cancer 1998 Nov 15; 83: 2105e19. 6 Sanerkin NG. The diagnosis and grading of chondrosarcoma of bone: a combined cytologic and histologic approach [Comparative Study]. Cancer 1980 Feb; 45: 582e94.
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18 Italiano A, Mir O, Cioffi A, et al. Advanced chondrosarcomas: role of chemotherapy and survival. Ann Oncol 2013 Nov; 24: 2916e22. 19 van Oosterwijk JG, Herpers B, Meijer D, et al. Restoration of chemosensitivity for doxorubicin and cisplatin in chondrosarcoma in vitro: BCL-2 family members cause chemoresistance. official journal of the European Society for Medical Oncology/ESMO. [Research Support, Non-U.S. Gov’t]. Ann Oncol 2012 Jun; 23: 1617e26. 20 Leerapun T, Hugate RR, Inwards CY, Scully SP, Sim FH. Surgical management of conventional grade I chondrosarcoma of long bones. Clin Orthop Relat Res 2007 Oct; 463: 166e72. 21 Meftah M, Schult P, Henshaw RM. Long-term results of intralesional curettage and cryosurgery for treatment of low-grade chondrosarcoma. J Bone Joint Surg Am 2013 Aug 7; 95: 1358e64. 22 Pring ME, Weber KL, Unni KK, Sim FH. Chondrosarcoma of the pelvis. A review of sixty-four cases [Review]. J Bone Joint Surg Am 2001 Nov; 83-A: 1630e42. 23 Angelini A, Guerra G, Mavrogenis AF, Pala E, Picci P, Ruggieri P. Clinical outcome of central conventional chondrosarcoma. J Surg Oncol 2012 Dec; 106: 929e37. 24 Schwab JH, Wenger D, Unni K, Sim FH. Does local recurrence impact survival in low-grade chondrosarcoma of the long bones? Clin Orthop Relat Res 2007 Sep; 462: 175e80. 25 Tiet TD, Hopyan S, Nadesan P, et al. Constitutive hedgehog signaling in chondrosarcoma up-regulates tumor cell proliferation [Research Support, Non-U.S. Gov’t]. Am J Pathol 2006 Jan; 168: 321e30. 26 Amary MF, Bacsi K, Maggiani F, et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours [Research Support, Non-U.S. Gov’t]. J Pathol 2011 Jul; 224: 334e43. 27 Kerr DA, Lopez HU, Deshpande V, et al. Molecular distinction of chondrosarcoma from chondroblastic osteosarcoma through IDH1/2 mutations [Research Support, Non-U.S. Gov’t]. Am J Surg Pathol 2013 Jun; 37: 787e95. 28 Liu X, Kato Y, Kaneko MK, et al. Isocitrate dehydrogenase 2 mutation is a frequent event in osteosarcoma detected by a multispecific monoclonal antibody MsMab-1. Cancer Med 2013 Dec; 2: 803e14.
7 Mirra JM, Gold R, Downs J, Eckardt JJ. A new histologic approach to the differentiation of enchondroma and chondrosarcoma of the bones. A clinicopathologic analysis of 51 cases [Comparative Study]. Clin Orthop Relat Res 1985 Dec; 214e37. 8 Reliability of histopathologic and radiologic grading of cartilaginous neoplasms in long bones. J Bone Joint Surg Am 2007 Oct; 89: 2113e23. 9 Eefting D, Schrage YM, Geirnaerdt MJ, et al. Assessment of interobserver variability and histologic parameters to improve reliability in classification and grading of central cartilaginous tumors [Research Support, Non-U.S. Gov’t]. Am J Surg Pathol 2009 Jan; 33: 50e7. 10 Reith JD, Horodyski MB, Scarborough MT. Grade 2 chondrosarcoma: stage I or stage II tumor? [Validation Studies]. Clin Orthop Relat Res 2003 Oct; 45e51. 11 Welkerling H, Kratz S, Ewerbeck V, Delling G. A reproducible and simple grading system for classical chondrosarcomas. Analysis of 35 chondrosarcomas and 16 enchondromas with emphasis on recurrence rate and radiological and clinical data. an international journal of pathology. Virchows Arch 2003 Dec; 443: 725e33. 12 Gitelis S, Bertoni F, Picci P, Campanacci M. Chondrosarcoma of bone. The experience at the Istituto Ortopedico Rizzoli. J Bone Joint Surg Am 1981 Oct; 63: 1248e57. 13 Lee FY, Mankin HJ, Fondren G, et al. Chondrosarcoma of bone: an assessment of outcome. J Bone Joint Surg Am 1999 Mar; 81: 326e38. 14 Fletcher CD, Bridge JA, Hogendoorn PCW, Mertens F, eds. WHO classification of tumours of soft tissue and bone. Lyon: IARC, 2013. 15 Murphey MD, Flemming DJ, Boyea SR, Bojescul JA, Sweet DE, Temple HT. Enchondroma versus chondrosarcoma in the appendicular skeleton: differentiating features. a review publication of the Radiological Society of North America, Inc. [Comparative Study]. Radiographics 1998 SepeOct; 18: 1213e37. quiz 44e5. 16 Choi BB, Jee WH, Sunwoo HJ, et al. MR differentiation of low-grade chondrosarcoma from enchondroma. Clin Imaging 2013 MayeJun; 37: 542e7. 17 Levy JC, Temple HT, Mollabashy A, Sanders J, Kransdorf M. The causes of pain in benign solitary enchondromas of the proximal humerus. Clin Orthop Relat Res 2005 Feb; 181e6.
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Conventional chondrosarcoma: old controversies and new insights
decades of life, and very rarely in children and young adults. While central chondrosarcomas can involve any bone, more than two-thirds arise either in the trunk (including shoulder girdle) or proximal ends of the femora and humeri. They only rarely occur in the spine, craniofacial bones and small bones of the distal extremities. The histologic diagnosis of chondrosarcoma endures as one of the most challenging areas of bone pathology, particularly when trying to distinguish benign enchondroma from low-grade chondrosarcoma. As aptly stated by Lichenstein and Jaffe in 194, “ .the histologic picture of a particular lesion does not have to be crudely and obviously malignant to indicate chondrosarcoma.”2 Likewise, in 1956, Dahlin acknowledged the problem by stating, “.the criteria that separate a low-grade chondrosarcoma from a chondroma are very subtle.”.3 Over the past several decades, numerous publications have attempted to address this diagnostic dilemma, albeit with limited success. Moreover, the difficulties associated with distinguishing benign from malignant cartilaginous tumors are compounded by confusing terminology. There are also on-going issues with histologic grading of chondrosarcoma. These challenges have important clinical implications since benign and malignant cartilaginous tumors are treated differently and the histologic grade of chondrosarcoma is an important prognosticator. This review will highlight longstanding controversies in the diagnosis of chondrosarcoma and explore the impact of new insights on both the diagnosis and management of chondrosarcoma. The focus will be on central chondrosarcoma involving the long bones and axial skeleton; tumors of the small bones and syndrome-associated cartilaginous tumors will not be discussed.
Jodi M Carter Carrie Y Inwards
Abstract Conventional chondrosarcomas comprise the largest group of malignant cartilaginous tumors. The distinction enchondroma and low-grade chondrosarcoma remains among the most challenging diagnoses for bone pathologists. Although numerous histologic criteria have been proposed to distinguish them, significant interobserver variability still exists. Fortunately, advances in diagnostic imaging and novel surgical approaches to low-grade tumors have lessened the need for definitive histologic diagnosis on biopsy material. In addition, the current WHO classification atypical or borderline cartilaginous tumors with Grade 1 chondrosarcoma in an attempt to facilitate diagnosis and treatment. While histologic grade remains the most important prognosticator in chondrosarcoma, the criteria for grading remain controversial. Finally, despite numerous insights into the pathobiology of cartilaginous tumors, targeted therapies remain elusive. However, there is an emerging role for isocitrate dehydrogenase mutational testing in the clinically important distinction between chondrosarcoma and chondroblastic osteosarcoma.
Keywords atypical cartilaginous tumor; cartilage; central; chondrosarcoma; enchondroma; grading; isocitrate dehydrogenase
The evolving concept of low-grade cartilaginous tumors Hyaline cartilage tumors arising within the intramedullary cavity are traditionally classified as enchondroma on the benign end of the spectrum, and chondrosarcoma on the malignant end. Chondrosarcoma has been further classified by histologic grade using a scale of Grades 1e3. These diagnoses require a combination of clinical, radiologic and histologic information, particularly in the recognition of low-grade tumors. Nevertheless, we have applied histologic criteria over the years that are paramount in defining these tumors.
Introduction Chondrosarcomas are malignant tumors, defined by their cartilaginous matrix-producing constituent cells. They comprise an estimated 20% of primary malignant bone tumors, second only to osteosarcoma.1 Chondrosarcomas are generally categorized by their location within the parent bone. Central chondrosarcomas arise de novo within the intramedullary cavity of bone, whereas peripheral chondrosarcomas arise on the surface of cortical bone, most commonly within a pre-existing osteochondroma. Conventional chondrosarcomas are the most common subtype of malignant cartilage-forming tumors, comprising an estimated 75 e85% of tumors. Less common subtypes include clear cell chondrosarcoma, dedifferentiated chondrosarcoma and mesenchymal chondrosarcoma. Conventional chondrosarcomas occur primarily in adults, most often in the fourth through sixth
Microscopic assessment The classic microscopic features of enchondroma are those of a well-circumscribed and relatively hypocellular tumor, composed of cartilaginous lobules containing chondrocytes with small dark nuclei within lacunae. Permeation of host lamellar and cortical bone is absent in enchondromas. In contrast, chondrosarcomas demonstrate an overall greater degree of cellularity and cytologic atypia than enchondroma. They have a permeative growth pattern characterized by total engulfment of host bone trabeculae and cortical destruction oftentimes associated with extension into soft tissue. The histologic features of higher grade chondrosarcoma (Grades 2 and 3) are usually readily discernable, in large part due to obvious cytologic atypia. In addition, the radiologic appearance usually reflects an aggressive behavior corresponding to the malignant histologic findings. The diagnostic dilemma rests with
Jodi M Carter M.D. Ph.D. Bone and Soft Tissue Pathology Fellow, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. Conflicts of interest: none declared. Carrie Y Inwards M.D. Associate Professor of Laboratory Medicine, College of Medicine, Mayo Clinic, Rochester, MN, USA. Conflicts of interest: none declared.
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remains a useful criterion in the distinction of benign and malignant cartilaginous tumors. However, the descriptive heterogeneity of “myxoid” stroma, including stellate cells embedded in an acid mucopolysaccharide-rich matrix rich; mucoid matrix degeneration; myxoid, frothy/bubbly, intercellular substance partially dissolved into strings or cords separated by amorphous partially basophilic mucus, and lack of defined quantitative parameters hinder its application. In 1980, Sanerkin, highlighted invasion or permeation into host bone by neoplastic cells as another important histologic criterion.6 In fact, there is now general agreement that permeation of host bone is the most important histologic criterion separating enchondroma from chondrosarcoma Figure 1. This concept was expanded by Mirra and colleagues with the introduction of a new histologic approach to differentiating enchondroma and low-grade chondrosarcoma based on lowmagnification tissue patterns.7 In this approach, enchondromas are characterized as multiple nodules of hyaline cartilage separated by normal marrow in conjunction with partial to complete encompassing plates of lamellar bone that conform to the irregular shapes of the cartilage nodules Figure 2. In contrast, chondrosarcomatous patterns include a single confluent mass of cartilage, with frequent marrow permeation, trapping of host lamellar bone on all sides and bands of fibrosis between confluent cartilage nodules. These criteria proved to be a valuable addition to the literature. However, as the authors noted, two important caveats apply: permeation may be missed due to sampling error, and excessive fragmentation of an enchondroma may create artifactual disruption of the cancellous bone, resulting in juxtaposition of neoplastic cartilage to bony trabeculae in a pattern that is misinterpreted as permeation. Furthermore, a generous amount of tissue is required when a diagnosis is based on low-magnification growth patterns rather than cytologic features. With the emergence of limited tissue procurement by image-guided, needle core biopsies, the separation of enchondroma from low-grade chondrosarcoma by this approach became next to impossible. Over the past two decades, histologic features used in the diagnosis of chondrosarcoma have combined any number of the above criteria. Unfortunately, as highlighted in two recent publications, considerable interobserver variability still exists, even
separating enchondroma from low-grade (Grade 1) chondrosarcoma. Difficulties stem from histologic heterogeneity within, and overlap between, these tumors compounded by the subjectivity inherent in assessing a lower degree of cytological atypia. As a result, there have been numerous studies aimed at simplifying the problem. Lichtenstein and Jaffe published one of the earliest descriptions of chondrosarcoma, a diagnosis they based on cytologic features of the neoplastic cells. They maintained that a cartilage tumor should no longer be considered benign if, in viable areas, it shows: 1) many cells with plump nuclei; 2) more than an occasional cell with two such nuclei; and 3) giant cartilage cells with large single or multiple nuclei or with clumps of chromatin. When referring to difficult cases at the low-grade end of the spectrum, they commented, “.even in the early stages of the evolution of a chondrosarcoma, one will find, at least in scattered fields, if adequate material is examined, subtle but tell-tale evidences of cytologic atypism of the cartilage cells which will betray the malignant character of the lesion”. Thus, they recognized the problems that can occur when dealing with microscopic heterogeneity, a lower degree of cytologic atypia, and lack of sufficient diagnostic tissue. Over the ensuing years, it became apparent that histologic tools beyond cytologic atypia were required to separate enchondroma from low-grade chondrosarcoma. In part, this was due to interobserver variability in the interpretation of the aforementioned terms “many”, “more than occasional”, and “plump”. Furthermore, binucleated cells can be found in benign and malignant cartilage tumors. Attention turned to exploring other features such as cellularity, mitotic activity, growth pattern, and changes in the matrix that might serve as helpful diagnostic tools. In 1959, Jaffe stated that a solitary cartilage tumor should be suspect of being a chondrosarcoma if it shows, even in scattered fields, hypercellularity of the tissue. In 1977, Evans et al added cellularity and mitotic activity to the histologic criteria for diagnosis and grading of chondrosarcoma.4 In this schema, cellularity increased from low to high with increasing tumor grade. With regard to mitotic activity, mitoses were scarce in the majority (53 of 71) of tumors (<2/10 high power fields) and absent in Grade 1 tumors. Thus, mitotic activity was not helpful in the most difficult diagnostic situation, namely distinguishing Grade 1 chondrosarcoma from enchondroma. Subsequent studies confirmed the very low mitotic count in low-grade chondrosarcomas. While mitoses can often be appreciated in highgrade tumors, they also show obvious features of malignancy. In a large series of chondrosarcoma of the long bones and pelvis, Bjornsson et al reported that only 8% (27 of 233) of tumors contained mitotic figures, e begging the question of their utility in either the diagnosis or grading of chondrosarcoma.5 Evans et al also added the “character of intercellular background” to their histologic criteria for chondrosarcoma, wherein a predominantly chondroid component was associated with benignity and myxoid stroma was associated with malignant tumors.4 While myxoid change and degenerative necrosis may be focally present in an enchondroma, extensive myxoid change is usually indicative of malignancy. Indeed, myxoid matrix was the most common histologic feature (87% of 233 cases) in a Mayo Clinic study of chondrosarcoma.5 Currently, stromal assessment
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Figure 1 Host bone entrapment by chondrosarcoma.
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chondrosarcoma, and no value in mitotic count, a criterion also discarded in the grading scheme used by Unni.1 In short, the degree of cellularity and cytologic atypia form the foundation of almost all current grading schemes. The systems that include mitotic activity usually reference the scheme proposed by Evans and colleagues.4 In this system, mitotic figures are absent in Grade 1 tumors, “occasionally” seen in Grade 2 tumors and a count of 2 per 10 high power fields is indicative of a Grade 3 tumor. Therefore, mitotic activity is, for the most part, a feature of Grade 3 tumors, a group that represents only a small percentage of chondrosarcomas. In larger series, the distribution of chondrosarcomas by histologic grade varies, ranging from 13% to 60% for Grade 1, and 35%e67% for Grade 2 tumors.5,12,13 This range reflects the subjectivity inherent in the grading schema and hampers comparisons of clinical data and survival rates. However, generally Grade 1 tumors comprise closer to 60% of tumors and Grade 2 tumors account for just over 30%. In most series, Grade 3 chondrosarcomas comprise fewer than 10% of tumors, but rates ranging to 25% have been reported. Difficulties separating chondroblastic osteosarcoma from Grade 3 chondrosarcoma and inclusion of dedifferentiated chondrosarcomas likely contribute to the higher end of this range. As early as 1956, Dahlin reported the diagnostic difficulty of cartilaginous tumors with “borderline” malignant histologic features – a long-standing source of frustration for pathologists. Over time, these “borderline” tumors have known a number of names including Grade 0 chondrosarcoma, Grade ½ chondrosarcoma, borderline chondrosarcoma, cartilage tumor of undetermined malignant potential (CLUMP), low-grade cartilaginous tumor, atypical cartilage tumor, atypical enchondroma and active enchondroma. The lack of consistent terminology further confuses an already challenging task. In general, this category is reserved for tumors involving the long bones with worrisome radiologic features, but unconvincing histologic features of malignancy. However, the histologic criteria for this category have never been well defined. In an attempt to standardize terminology, the current WHO classification of bone tumors merges the term atypical cartilaginous lesion with Grade 1 chondrosarcoma, an approach that is similar to the WHO classification of atypical lipomatous tumor/ well-differentiated liposarcoma.14 This modification places atypical cartilaginous lesion/Grade 1 chondrosarcoma into an intermediate (locally aggressive) category Figures 3e5. This strategy acknowledges atypical tumors with low malignant potential within a widely accepted and respected classification scheme. However, it remains to be seen whether this will clarify the issue or create confusion by the assignment of malignant terminology (Grade 1 chondrosarcoma) to a borderline category. In addition, although Grade 1 chondrosarcomas have a low propensity for metastasis, documented examples exist in the literature.
Figure 2 Enchondroma involving the proximal femur of a 54-year-old male. A nodule of hyaline cartilage surrounded by normal bone marrow and partially encased by a plate of lamellar bone.
among experienced musculoskeletal pathologists.8,9 Not surprisingly, the distinction between enchondroma and Grade 1 chondrosarcoma is the most discordant diagnosis in cartilaginous tumors, reflecting the lack of significant progress since Jaffe introduced the histologic dilemma several decades ago. Accordingly, among these studies addressing interobserver variability, Eefting and colleagues found high cellularity, presence of host bone entrapment, open chromatin, and myxoid matrix to be the most helpful histologic parameters in the distinction between enchondroma and low-grade chondrosarcoma - all features echoing what has been said in the past.9 Histologic grading of chondrosarcoma Dahlin was the first to apply histologic grading to chondrosarcomas.3 In a 1956 review of 212 cases, he used Broder’s method of grading based on the cytologic features described by Lichtenstein and Jaffe. As no chondrosarcoma qualified as a Grade 4 tumor, the series was graded with histologic Grades 1 to 3. This grading scale was widely accepted and its use continues to the present time. Most authors group Grade 1 tumors as lowgrade and Grade 2 and 3 tumors as high-grade. However, in a study of 109 patients with chondrosarcoma, Reith and colleagues found that Grade 2 tumors were more appropriately grouped with Grade 1 tumors.10 In large part, the differences likely reflect a lack of uniform and reproducible histologic criteria for Grade 1 chondrosarcoma, a problem that can lead to significant therapeutic consequences. Dahlin found histologic grade to correlate with biologic behavior, and today it remains the most important independent predictor of local recurrence and metastasis. Nevertheless, methods of histologic grading remain a controversial issue, fraught with poor interobserver reproducibility. All grading schemes are based on the assessment of cytologic features (binucleate cells, nuclear size, hyperchromasia and pleomorphism) but controversy exists regarding the required number of features. Cellularity and mitotic activity are included in some, but not all, schemes. For instance, Welkerling et al propose a system based solely on nuclear size and nuclear hyperchromatism.11 Similar to Mirra, they found an overlap in the frequency of binucleated cells in enchondromas and low-grade
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Radiologic assessment Radiologic correlation is essential in the classification of all bone tumors, but its role is particularly critical when dealing with cartilage tumors, especially in the context of enchondroma vs. lowgrade chondrosarcoma. Early studies recognized helpful diagnostic features of chondrosarcoma afforded by roentgenograms.3 These included cortical destruction, mottled or fuzzy
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Figure 3 Histologic heterogeneity within an “atypical cartilaginous tumor/grade 1 chondrosarcoma” (per WHO classification) involving the distal femur (a) Some fields demonstrate paucicellular hyaline cartilage containing chondrocytes with small nuclei. (b) Other fields are more cellular, showing chondrocytes with nuclear enlargement.
calcification, fusiform expansion and thickening of the cortex. While these features remain useful, subsequent studies have shown that conventional radiology alone is not reliable in differentiating benign from low-grade malignant cartilaginous tumors. The advent of advanced imaging modalities significantly improved the amount of information provided by radiologic evaluation Figure 6. Currently, the combination of radiographs, CT and MR imaging allows radiologists to play a key role in assessing the biologic behavior, and thus treatment, of cartilage tumors. The radiologic features of Grades 2 and 3 chondrosarcoma, including moth-eaten and permeative patterns of bone lysis often associated with large soft tissue masses, reflect the aggressive behavior of higher grade tumors. Thus, their distinction from enchondroma, a tumor with an indolent radiologic appearance, is usually not a difficult task Figure 7. Radiologic imaging is also useful in determining the size of tumors, a feature shown to be helpful in predicting biologic behavior. In general, tumors <5 cm in size behave in a benign fashion. In 1999, Murphey et al published one of the largest and most comprehensive studies addressing the clinical and radiologic
features used in the distinction of enchondroma and chondrosarcoma of the appendicular skeleton.15 They found a clinical presentation of tumoral pain combined with the radiologic findings of deep endosteal scalloping (greater than two-thirds of the cortical thickness), cortical destruction and soft-tissue mass on CT or MR imaging, periosteal reaction and marked uptake of radionuclide at bone scintigraphy facilitated the diagnosis of approximately 90% of tumors in their series. Popcorn-like calcifications and MR imaging findings including abnormal peritumoral marrow and soft tissue signals, and fast contrast-enhanced MR imaging have also been reported to facilitate the distinction of enchondroma from low-grade chondrosarcoma.16 One study showed early uptake of gadolinium with an exponential curve on dynamic MRI was associated with malignant cartilaginous tumors. Moreover, two studies of fluorodeoxyglucose positron emission tomography (PET) in cartilaginous tumors found the standard uptake value correlated with the grade of malignancy. Given interobserver variability in the histologic diagnosis of these tumors, one must be cognizant of this limitation when interpreting studies aimed at defining radiologic criteria.
Figure 4 (a) Enchondromas abutting the cortical bone. (b) “Atypical cartilaginous tumor/grade 1 chondrosarcoma” (per WHO classification) eroding, but not extending through, the cortical bone.
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extremities, whereas chondrosarcomas comprise only 1% of hyaline tumors at this anatomic site. Moreover, the radiographic features of enchondromas arising in the small bones, such as deep endosteal scalloping, cortical expansion and thickening, overlap with those of biologically more aggressive cartilaginous tumors located in the long tubular bones, namely those considered to be atypical enchondroma/low-grade cartilaginous tumor. Also, enchondromas of the small bones show histologic features, including increased cellularity and cytologic atypia, that would be worrisome for malignancy in cartilaginous tumors of other skeletal sites. Thus, the consensus criteria for diagnosis of chondrosarcoma of the small bones differ from those of other sites and focus primarily on radiologic and/or histologic evidence of host bone permeation/cortical destruction with or without soft tissue extension. In contrast to the small bones, the vast majority of cartilaginous tumors arising within the flat bones are malignant. Accordingly, enchondromas of these sites are exceedingly uncommon, a phenomenon that is reflected in the lack of literature on the topic. Thus, a diagnosis of enchondroma should be entertained with great caution with cartilaginous tumors of the pelvic bones, ribs, sternum, scapula and vertebrae. Arguably, the paucity of enchondromas at these sites may be a self-fulfilling prophecy. In any event, tumors of the flat bones are treated by en bloc surgical resection due to the significant surgical complexity associated with subsequent recurrence at these sites. Once again, the term “atypical cartilaginous tumor/low-grade chondrosarcoma” in chondrosarcomas of the flat bones may be controversial if it implies that conservative surgery (i.e. intralesional curettage with adjuvant therapy) is adequate management. In addition to anatomic site, clinical presentation plays a role in the diagnosis of benign and malignant cartilaginous tumors. Pain is the most common presenting symptom of patients with chondrosarcoma, and is traditionally considered a worrisome sign for malignancy. However, recent studies have shown that the presence or absence of local pain does not reliably discriminate between benign and malignant cartilaginous tumors. In these series, pain is also a presenting symptom in approximately 40%e80% of enchondromas. Moreover, a recent study by Levy et al, found 88% of 57 humeral enchondromas presented with pain; however, careful clinical and radiographic correlation showed that in the vast majority of cases, pain was due to nontumoral causes.17 Thus, careful consideration should be paid to isolating the source of pain as it is likely tumor-related in chondrosarcoma, but not in those with enchondroma. Figure 5 (a & b) AP and lateral radiographs of the forearm show an atypical cartilaginous tumor involving a long segment of the radial diaphysis. There are regions of focal lucency with associated significant endosteal scalloping/erosion in the lesion distally along with cortical thickening about the entire lesion. (c & d) Coronal T1 and T2 weighted MR images show that the lesion occupies the entire diameter of the medullary canal and confirm the presence of significant endosteal scalloping/ erosion.
Treatment Surgery is the mainstay of treatment for chondrosarcoma. The vast majority of tumors are slow-growing and poorly vascularized, rendering them largely resistant to radiotherapy, with the notable exception of proton-beam irradiation for chondrosarcomas of the skull base. Similar to radiotherapy, cytotoxic chemotherapy plays little role in the current management of central chondrosarcomas, whether in the setting of unresectable primary disease or metastatic disease.18 In addition to the intrinsically low cell turnover in chondrosarcomas, particularly in low-grade tumors, along with their abundant hyaline matrix, the expression of anti-apoptotic Bcl-2 family members and multi-
Clinical considerations It is important to pay attention to the anatomic location of a cartilage tumor when formulating a diagnosis. Approximately 40% of enchondromas affect the small tubular bones of the distal
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Figure 6 AP radiograph (a) left hip and femur shows a predominantly lytic destructive lesion involving the a long segment of the proximal femur with scattered chondroid matrix, endosteal scalloping, diffuse cortical thickening and areas of indolent periosteal new bone formation. The imaging features are classic for chondrosarcoma. The coronal T1 (b) and T2 (c) weighted MR images show that the lesion extends from the femoral neck to the distal femoral diaphysis.
frees the pathologist from facing histologic difficulties associated with separating enchondroma from low-grade chondrosarcoma on pre-operative biopsy tissue. Microscopic evaluation of the curetted tissue is still essential to confirm the diagnosis and identify the rare case with an unexpected higher histologic grade. Moreover, occasionally a pre-operative biopsy is obtained in order to confirm the radiologic impression of a cartilage tumor. En bloc resection remains the preferred surgical approach for all chondrosarcomas involving the pelvis and higher grade (2 and 3) tumors of the long bones; the latter are identified by their aggressive radiologic features (cortical destruction, soft tissue mass), typically accompanied by a pre-operative tissue diagnosis.22
drug resistance pumps such as p-glycoprotein may contribute to chemoresistance.19 While a number of clinical trials with targeted therapies, including Hedgehog pathway inhibitors, have been initiated, definitive therapeutic targets remain elusive in the management of chondrosarcoma. Historically, the surgical management of all chondrosarcomas, regardless of histologic grade or anatomic location, was en bloc resection with wide surgical margins. In recent years, the use of this surgical approach, with its associated morbidity has come into question for low-grade chondrosarcoma of the long bones. These tumors have very little proclivity for local recurrence or metastasis. Intra-lesional curettage with adjuvant local therapy (i.e. intra-lesional cryotherapy, phenol, liquid nitrogen or argon-beam laser) has emerged as an effective treatment for tumors of the long bones classified as Grade 1 chondrosarcomas or atypical/borderline tumors, provided the tumors show no radiologic evidence of aggression i.e. cortical permeation or soft tissue extension20,21 Figure 7. This approach
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Prognosis Histologic grade of conventional chondrosarcoma remains the single most important predictor of local recurrence and metastasis. Fortunately, the assignment of higher histologic grades is typically not a diagnostic challenge for pathologists. And while
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Figure 7 AP radiograph (a), coronal T1 (b) and T2 (c) weighted MR images of the left shoulder demonstrate classic features of a benign enchondroma in the proximal humeral metaphysis with stippled chondroid matrix.
has shown that enchondromas and low-grade central chondrosarcomas are typically near diploid whereas complex karyotypes can occur in higher grade tumors, but contain few consistent genetic aberrations. In the developing growth plate, Indian hedgehog (IHH) and parathyroid hormone-like hormone (PTHLH) coordinate the
the distinction of enchondroma and low-grade chondrosarcoma is difficult, it doesn’t carry the prognostic significance attached to separating Grade 1 from Grade 2 tumors. Historically, reported local recurrence rates for Grade 1 chondrosarcoma varied widely, ranging from 0% to 50%. Recent studies report local recurrence rates for low-grade tumors of approximately 15%. Predictably, recurrence rates are influenced by factors that affect surgical accessibility, such as skeletal location (axial vs. appendicular skeleton) and adequacy of resection. Metastases are rare in low-grade tumors, with published rates ranging between 0% and 10%. Survival rates for patients with Grade 1 chondrosarcoma throughout the skeleton range from 88% to 100% at 5 years and 79%ew100% at 10 years. The outcome of patients with pelvic chondrosarcoma is usually worse than that reported for patients with extremity chondrosarcoma.22 Not surprisingly, survival rates decrease with higher grade tumors. Recent reports on survival rates for Grade 2 tumors range from 62 to 95% at 5 years and 53e90% at 10 years. Survival for patients with Grade 3 chondrosarcoma range from 62% to 77% at 5 years, and 29%e55% at 10 years.4,5,12,13,23 While the prognosis for high-grade bone sarcomas, such as osteosarcoma, has significantly improved with the implementation of adjuvant therapies, these strategies have not been as successful in the treatment of chondrosarcoma. As expected, local recurrence portends a poorer prognosis in high-grade chondrosarcoma. Interestingly, recent data suggest that local recurrence also impacts survival in low-grade chondrosarcoma of the long bones. Schwab and colleagues reported that progression of tumor grade, multiple recurrences and metastases were frequently observed in patients with locally recurrent Grade 1 chondrosarcoma. Accordingly, these events negatively impacted overall long-term survival, particularly at 10 years.24 Thus, aggressive surgical management is the preferred approach in the setting of locally recurrent disease, irrespective of the initial histologic grade.
Figure 8 Common IDH mutations in cartilaginous tumors. Automated DNA sequencing electropherograms illustrate the most common IDH1 single nucleotide substitutions in cartilaginous tumors. IDH1: R132C (CGT > TGT) and R132H (CGT > CAT) (arrowheads).
Molecular genetics The pathogenetic mechanisms of cartilage-forming tumors remain poorly understood. Conventional cytogenetic analysis
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surface osteosarcoma.28 Thus, additional study of IDH1/2 mutational status in osteosarcoma is required to clarify its utility in the distinction of chondrosarcoma from chondroblastic osteosarcoma.
regulation of chondrocyte proliferation and differentiation. Predictably, aberrant signaling of the IHH-PTHLH pathway has been implicated in both benign and malignant cartilaginous tumors25 Activated Src and Akt kinase signaling, alterations in pRB and derangements in the hypoxic and glycolytic pathways among others, have all been observed in chondrosarcoma. Acquisition of mutations in tumor suppressors such as p53 and CDKN2A/ p16/INK4A may herald tumoral progression to higher grade. Also, genomic analysis of central and variant chondrosarcomas has revealed frequent, complex mutations in COL2A1, encoding the predominant collagen in articular cartilage. Finally, histone deacetylase inhibitors impair growth and promote differentiation of chondrosarcoma cells in vitro. Together, these seemingly disparate genetic and epigenetic alterations highlight the pathogenetic complexity in chondrosarcomas. One of the most important and intriguing molecular genetic insights into cartilaginous tumors hinged on the observation that gliomas and acute myeloid leukemia (AML) occasionally occur in patients with syndromic enchondromatosis (Ollier syndrome and Maffucci syndrome). Both gliomas and AML are associated with mutations in IDH1 and IDH2, encoding isocitrate dehydrogenase, a key enzyme in the tricarboxylic acid cycle. Mutated IDH produces D-2-hydroxyglutarate, an oncometabolite which is thought to impair DNA demethylation. In 2011, Amary and colleagues tested a large series of syndromic and sporadic enchondromas, central (low and highgrade) chondrosarcomas, perisoteal chondrosarcomas, dedifferentiated chondrosarcomas and other cartilage-forming tumors for IDH mutations. They discovered that heterozygous, somatic IDH mutations are frequent events in both syndromic and sporadic enchondromas and central as well as periosteal chondrosarcomas, including central tumors with dedifferentiation.26 Subsequent studies have confirmed these findings. In cartilaginous tumors, hotspot IDH mutations occur as single nucleotide substitutions within codons for arginine residues within either IDH1 (R132) or IDH2 (R172). Among these, IDH1 R132C is the most common mutation, with frequencies ranging from 40 to 80%; IDH1 R132H is the second most common mutation, detected in approximately 15% of tumors. Mutations in IDH2 R172 are uncommon Figure 8. Although IDH mutations in gliomas occur within the same codons, the predominant nucleotide substitutions differ. Unfortunately, commercially available antibodies to mutated IDH1 protein recognize the common IDH mutations in gliomas, IDH1 R132 H/S, and are currently of little use in the diagnosis of cartilaginous tumors. As IDH mutations occur in approximately 50% of sporadic enchondromas and central chondrosarcomas, IDH mutational testing has no role in the distinction of enchondroma and lowgrade chondrosarcoma. However, in the two largest series to date, Amary et al and Kerr and colleagues reported no IDH mutations in chondroblastic osteosarcomas (0/46 and 0/36 respectively), raising the possibility that IDH mutational testing could be a valuable adjunct in the distinction of chondroblastic osteosarcoma from chondrosarcoma.26,27 This would have particular value in the setting of limited biopsy material. Furthermore, the differing prognoses and therapeutic strategies for osteosarcoma and chondrosarcoma underscore the clinical importance of this distinction. Of note, very recently IDH2 (R172S) mutations were reported in two osteoblastic osteosarcomas and one high-grade
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Summary The diagnosis and treatment of chondrosarcoma requires a multidisciplinary team consisting of pathologists, radiologists and surgeons. For the past several decades, the biggest diagnostic challenge for pathologists and radiologists has been the distinction between enchondroma and Grade 1 chondrosarcoma involving the long bones. Interobserver variability among radiologists has improved with the advent of advanced imaging modalities. However, subjective histologic criteria and tumoral heterogeneity continue to hinder the pathologic diagnosis, particularly with limited biopsy tissue. Fortunately, the past few years have seen a paradigm shift to intra-lesional curettage (with adjuvant local therapy) for the subset of atypical cartilaginous tumors/low-grade chondrosarcomas of the long bones that show no radiologic evidence of extension through cortical bone (Stage 1A). Thus, careful radiologic assessment of tumoral behavior has markedly diminished the need for a definitive, pre-operative histologic diagnosis in this setting. However, as histologic grade remains the most important prognosticator of chondrosarcomas, pathologists still play an important role in evaluating curetted tissue and resected tumors with more aggressive radiologic features. Unlike conventional osteosarcoma, chondrosarcomas are highly resistant to chemoradiation and as a result, (neo)adjuvant therapies have little role in their management. Despite numerous advances in our understanding of the biology of cartilageforming tumors, targeted therapies also remain elusive. The detection of IDH mutations in cartilage-forming tumors has been one of the most important genetic insights with direct clinical application. While IDH mutations frequently occur in both benign and malignant cartilaginous tumors, chondroblastic osteosarcomas appear to lack IDH mutations. Thus, IDH mutational testing shows promise as an emerging genetic tool in the clinically important distinction of chondrosarcoma and chondroblastic osteosarcoma. A REFERENCES 1 Unni KK, Inwards CY. Dahlin’s bone tumors. 6th edn. Philadelphia: Lippincott Williams & Wilkins, 2010. 2 Lichtenstein L, Jaffe HL. Chondrosarcoma of bone. Am J Pathol 1943 Jul; 19: 553e89. 3 Dahlin DC, Henderson ED. Chondrosarcoma, a surgical and pathological problem; review of 212 cases [Case Reports]. J Bone Joint Surg Am 1956 Oct; 38-A: 1025e38. passim. 4 Evans HL, Ayala AG, Romsdahl MM. Prognostic factors in chondrosarcoma of bone: a clinicopathologic analysis with emphasis on histologic grading. Cancer 1977 Aug; 40: 818e31. 5 Bjornsson J, McLeod RA, Unni KK, Ilstrup DM, Pritchard DJ. Primary chondrosarcoma of long bones and limb girdles. Cancer 1998 Nov 15; 83: 2105e19. 6 Sanerkin NG. The diagnosis and grading of chondrosarcoma of bone: a combined cytologic and histologic approach [Comparative Study]. Cancer 1980 Feb; 45: 582e94.
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