Differential Diagnosis of Cartilaginous Lesions of Bone

David Suster, MD; Yin Pun Hung, MD, PhD; G. Petur Nielsen, MD

Context.—Cartilaginous tumors represent one of the most Data Sources.—PubMed (US National Library of Med- common tumors of bone. Management of these tumors icine, Bethesda, Maryland) literature review, case review includes observation, curettage, and surgical excision or of archival cases at the Massachusetts General Hospital, resection, depending on their locations and whether they are and personal experience of the authors. benign or malignant. They can be diagnostically challenging, Conclusions.—This review has examined primary well- particularly in small biopsies. In rare cases, benign tumors differentiated cartilaginous lesions of bone, including their may undergo malignant transformation. differential diagnosis and approach to management. Objective.—To review common cartilaginous tumors, Because of the frequent overlap in histologic features, including in patients with multiple hereditary exostosis, particularly between low-grade chondrosarcoma and Ollier disease, and Maffucci syndrome, and to discuss enchondroma, evaluation of well-differentiated cartilagi- problems in the interpretation of well-differentiated nous lesions should be undertaken in conjunction with cartilaginous neoplasms of bone. Additionally, the concept thorough review of the imaging studies. of atypical cartilaginous tumor/chondrosarcoma grade 1 (Arch Pathol Lab Med. 2020;144:71–82; doi: 10.5858/ will be discussed and its use clarified. arpa.2019-0441-RA)

artilage-forming tumors comprise one of the most are symptomatic or cause functional impairment, such as C common bone tumors, with enchondroma and osteo- restricted movement or complications from fractures. The chondroma encompassing the overwhelming majority of clinical management and prognosis depend heavily on the benign cartilaginous lesions and low-grade chondrosarcoma location and the pathologic diagnosis.2 With limited tissue, being the most common malignant cartilaginous tumor.1 the differential diagnosis may be problematic, particularly These tumors are characterized by the formation of a with regard to distinguishing enchondroma from low-grade cartilaginous matrix and can sometimes display overlapping chondrosarcoma. These tumors may display characteristic histologic features, which may pose a problem for diagnosis, clinical and radiologic features that allow for this distinction; especially in cases where histologic material is limited. however, the histologic overlap in the well-differentiated In the World Health Organization (WHO) fourth edition lesions can preclude a definitive diagnosis, and some studies 1 (2013) classification, cartilaginous tumors were classified have shown significant interobserver variability even among as either benign (such as osteochondroma and enchon- orthopedic pathologists.3 In a study by Eefting et al4 droma), intermediate (locally aggressive/rarely metastasiz- assessing interobserver variability, considerable variation in ing, such as chondromyxoid fibroma, chondroblastoma, the histologic assessment of cartilaginous tumors was and atypical cartilaginous tumor/chondrosarcoma grade 1), demonstrated (j coefficient ¼ 0.78). The greatest variability or malignant (chondrosarcoma grades 2 and 3 and other occurred in the distinction between enchondroma and grade high-grade chondrosarcomas). In the upcoming WHO 1 chondrosarcoma (j coefficient ¼ 0.54).4 classification, chondroblastoma and chondromyxoid fibro- This review discusses some of the more common benign ma have been moved into the benign category. No cartilaginous tumor belongs to the intermediate category. and malignant cartilaginous tumors as listed above. Additionally, the use of the term atypical cartilaginous tumor Furthermore, relevant clinical syndromes, including multiple is further delineated. hereditary exostosis (MHE), Ollier disease, and Maffucci Overall, benign cartilaginous lesions behave in an syndrome, are discussed, as the risks of malignant indolent fashion and do not require treatment, unless they transformation of benign cartilage tumors in these patients are increased.

Accepted for publication September 10, 2019. OSTEOCHONDROMA From the Department of Pathology, Massachusetts General Osteochondroma is a benign cartilage-capped tumor Hospital and Harvard Medical School, Boston. The authors have no relevant financial interest in the products or arising on the surface of bones and is the most common companies described in this article. benign cartilage tumor of bone. More than 80% of Presented in part at the 11th Annual Midwestern Conference: osteochondromas are solitary; they are usually diagnosed Update Course in Surgical Pathology; September 14–16, 2018; by the second decade of life. There is a slight male Milwaukee, Wisconsin. Corresponding author: G. Petur Nielsen, MD, Department of predominance. They typically arise in the area of the Pathology, Massachusetts General Hospital, 55 Fruit St, Boston, MA metaphysis of long bones derived from endochondral 02114 (email: [email protected]). ossification, most commonly the distal femur, proximal Arch Pathol Lab Med—Vol 144, January 2020 Differential Diagnosis of Cartilage Lesions—Suster et al 71 Table 1. Comparison of Features Distinguishing Osteochondroma From Secondary Chondrosarcoma Arising in Osteochondroma Features Osteochondroma Secondary Chondrosarcoma Size Average 3–6 cm, although may grow larger than Often larger, although smaller lesions (,10 cm) 20 cm have been identified Symptoms Usually asymptomatic or related to mechanical Pain unrelated to movement or nocturnal pain symptoms/fracture Growth May display growth until growth plates close, Continued growth after skeletal maturity; then should remain stable sudden acceleration in growth of bone and cartilage cap components Cartilage cap thickness Usually less than 2–3 cm Generally thicker cartilage cap of more than 3– 4cm Microscopic findings Endochondral ossification with overlying mature Large lobulated cartilaginous nodules separated hyaline cartilage and a relatively well- by fibrous septa, increased cellularity, nuclear demarcated fibrous sheath. Chondrocytes atypia, mitotic activity, and overt infiltration show minimal atypia. No infiltration of soft into soft tissue or through the medullary tissue or infiltration of underlying bony connection into the underlying bone with trabeculae encasement of bony trabeculae tibia, and proximal humerus, but they can also arise on the thick cartilage cap with prominent calcifications, soft tissue surface of flat bones, such as the ilium or scapula.1,2,5–7 invasion, infiltration of the stalk, erosion of bone, and tumor Although initially believed to be a developmental invasion of the underlying bone are features of malignant anomaly, it has been shown subsequently that sporadic transformation (Table 1).1,2,9,11,16,17 osteochondromas harbor homozygous EXT1 and EXT2 Osteochondromas are usually observed or resected in deletions within a subset of chondrocytes within the symptomatic patients. Symptoms may be due to mechanical cartilaginous cap, indicating that it is a neoplastic process.3 issues, impingement on adjacent nerves, development of a Additionally, families with MHE have been shown to harbor bursa on the surface of the cap, or a pathologic fracture germline mutations in the EXT1 or EXT2 genes.8,9 through the stalk. Radiographic findings in osteochondroma show that osteochondroma arises from the surface of the bone with MHE (OSTEOCHONDROMATOSIS) continuity of the cortices and of the medullary cavities Multiple hereditary exostosis is an autosomal dominant (Figure 1, A and B), often pointing away from the nearest condition in which patients develop multiple osteochon- joint. Rarely, osteochondroma is sessile with a broad-based dromas by the second decade of life. Approximately 60% of stalk.10 Magnetic resonance imaging (MRI) is the most patients have a family history. Multiple hereditary exostosis useful imaging modality for assessing the thickness of the has an incidence of approximately 1 in 50 000 and, in rare cartilaginous cap, which can be variable.11,12 patients, presents as part of a separate genetic syndrome, Grossly, osteochondroma contains a cartilaginous cap and such as trichorhinophalangeal syndrome or Potocki-Shaffer an underlying stalk. The outer layer consists of a thin fibrous syndrome.1 It is now known that germline alterations in the sheath overlying the bluish gray cartilaginous cap (Figure 1, EXT1 (8q24) or EXT2 (11p11-p12) gene drive the disease. C). It is important to document the maximum thickness of this cap. Microscopically, this outer fibrous layer is the Similar to nonhereditary osteochondromas, aberrations of perichondrium. The cartilage cap is of variable thickness and the EXT genes lead to dysfunctional proteins exostosin 1 at the base undergoes endochondral ossification (Figure 1, and exostosin 2 and the subsequent failure of heparin sulfate 1,2,11 polymerization required for normal cartilaginous develop- D). The chondrocytes within the cap are usually 4,5,9,18 organized in a similar fashion to the normal growth plate. ment. Both the cellularity of the cartilage and the size of the From an early age, these patients present with multiple chondrocytes increase within the deeper layers of the cap, osteochondromas, which continue to grow in size until with the chondrocytes arranged in a vaguely columnar skeletal maturity with the closure of the growth plates. fashion. The cartilaginous matrix at the base of the cap often Similar to solitary osteochondromas, the majority of these shows calcifications with residual columns of cartilage upon tumors are asymptomatic; however, patients with increased which new bone deposition occurs.2 numbers of osteochondromas can develop various bone The pathologic diagnosis of osteochondroma is generally deformities, leading to functional impairment that may 19 straightforward, with a differential diagnosis that includes require surgical correction. bizarre parosteal osteochondromatous proliferation, surface Radiographically, the presence of multiple osteochondro- chondroma, and parosteal osteosarcoma. None of these mas can be confirmed with conventional radiographs lesions have a medullary connection to underlying bone; (Figure 2, A), and the size of the cartilage cap can be thus, radiologic correlation can differentiate among these assessed with MRI. Grossly and microscopically, the tumors.13–15 osteochondromas of MHE are identical to solitary osteo- The rate of malignant transformation of an osteochon- chondromas, only more numerous. droma into a low-grade chondrosarcoma is very low (,2%). Multiple hereditary exostosis carries an increased risk of Some authors consider an increased size of the cartilaginous malignant transformation reportedly ranging from 0.2% to cap a worrisome feature of malignancy; however, a 25% (Figure 2, B).9,19,20 As with solitary osteochondromas, thickened cartilage cap alone is not sufficient for the the same clinicopathologic features are used to evaluate diagnosis of a malignant transformation. In addition to a patients for possible malignant transformation (Table 1). 72 Arch Pathol Lab Med—Vol 144, January 2020 Differential Diagnosis of Cartilage Lesions—Suster et al

Figure 1. A, Plain film radiograph demonstrating a well-defined exostosis in continuity with the marrow cavity, extending from the cortex of the distal tibial diaphysis and growing away from the nearby joint. B, Axial computed tomography scan of the distal tibia shows an osteochondroma with a pedunculated shape, thin stalk, and marrow space and cortical continuity. C, Gross photograph of an osteochondroma demonstrates a well-formed hyaline cartilage cap with underlying newly formed cancellous bone. D, Microscopic image of an osteochondroma showing a dome-shaped cartilaginous cap with underlying endochondral ossification. A thin fibrous sheath of periosteum overlying the cartilaginous cap can be seen (hematoxylin-eosin, original magnification 320 [D]).

Studies have shown that there is significant interobserver ENCHONDROMA variability in the histologic diagnosis of cartilaginous Enchondroma is the second most common benign tumors,21 especially grade 1 chondrosarcoma, in patients with MHE. A multidisciplinary approach to the manage- primary hyaline cartilage–forming tumor of bone, account- ment of these patients with clinical and radiologic correla- ing for 12% to 24% of primary bone tumors. These tumors tion is recommended, especially in cases in which malignant typically present during the third to fourth decade of life and transformation is suspected. are most frequently located within the distal appendicular Arch Pathol Lab Med—Vol 144, January 2020 Differential Diagnosis of Cartilage Lesions—Suster et al 73 Figure 2. A, Plain film radiograph demon- strating numerous osteochondromas centered about the distal femur and proximal tibia in a patient with multiple hereditary exostoses. B, Gross photograph demonstrating a secondary chondrosarcoma arising in association with a preexisting osteochondroma of the ilium in a patient with multiple hereditary exostoses. The residual osteochondroma is difficult to identify as it has been replaced by a large lobulated cartilaginous lesion bulging into the surrounding soft tissue.

skeleton. They arise in bones that form by endochondral Immunohistochemistry is largely unhelpful in the diag- ossification. Approximately 90% of enchondromas are nosis of cartilaginous tumors, as most are positive for S100 solitary; they are frequently detected as incidental findings protein and ERG. The diagnosis relies mainly on histologic during radiologic workup for pain associated with other examination with close clinical and radiologic correlation. adjacent lesions such as osteoarthritis or tendon/ligamental IDH1 and IDH2 mutations represent by far the most tears.1,2,22 Most enchondromas are asymptomatic; however, common genetic aberrations in enchondromas, a finding they may be associated with pain in the setting of a gross or that is shared with chondrosarcomas, thus preventing these microscopic pathologic fracture.23 If they are painful, the alterations from being used diagnostically as a discriminator possibility of a chondrosarcoma should be considered and among these differential diagnoses. The main differential excluded. diagnosis is low-grade chondrosarcoma. In our experience, Genetic aberrations described in enchondromas include the most useful approach for the diagnosis of enchondroma mutations in isocitrate dehydrogenase IDH1 (R132C; even in problematic cases is strict radiologic correlation in

R132H) or IDH2 (R172S), which are found in approximately conjunction with the histologic assessment, with a perme- 40% of solitary lesions, with even higher rates in patients ative growth pattern seen in chondrosarcoma but not in with multiple enchondromas.5,24 Rare cases have been enchondroma. described to harbor aberrations in PTHR1; cytogenetic ENCHONDROMATOSIS abnormalities involving chromosomes 5, 6, 7, 12, and 17 have also been reported.25–27 Multiple enchondromas present typically as a manifesta- Radiographically, x-rays show spherical or oblong, some- tion of either of 2 related clinical syndromes, Ollier disease times elongated, well-circumscribed lucent lesions with or Maffucci syndrome, or as part of an unrelated syndrome, scattered radiodensities, which represent irregular calcifica- metachondromatosis. These disorders are rare; although the tumors developed by these patients are benign, there is an tions of the cartilage matrix. These calcifications are 28,29 sometimes present at the periphery of the lobules and are increased risk of malignant transformation. In all 3 syndromes, patients present at an early age, frequently seen as rings or arches (Figure 3, A and B). Scalloping and being diagnosed with multiple enchondromas during early thinning of the cortex may be present, especially in small childhood. tubular bones; however, extension into soft tissues or overt Ollier disease and Maffucci syndrome are 2 related bone destruction is not seen. Computed tomography scan sporadic disorders that are characterized by the presence often shows a well-circumscribed, lobulated lesion with of multiple enchondromas from a young age. Maffucci similar calcifications to those seen on the x-rays. On MRI, 2,7 syndrome differs from Ollier disease by the presence of enchondromas are hyperintense on T2-weighted images. vascular lesions, most commonly spindle cell hemangio- Grossly, enchondromas are composed of well-circum- mas.30 Both disorders are caused by somatic mosaic scribed, gray, glistening nodules (Figure 3, C). Microscop- mutations of IDH1 or IDH2.31,32 The short tubular bones of ically, the tumors are composed of variably sized nodules of the hands and feet are frequently involved, although the hyaline-type cartilage, which are well circumscribed, sharply tumors may be found within long bones, scapulae, pelvis, or demarcated from the surrounding bone, and often encased some flat bones.2 The large number of lesions can lead to by reactive bone formation (corresponding to the rings and deformation and functional impairment. arches seen radiographically). Variable numbers of benign- Radiographically, patients with Ollier disease and Maf- appearing chondrocytes are present, with frequent scattered fucci syndrome present with multiple enchondromas, and calcifications of the hyaline matrix and associated necrosis of the severely affected bones will appear shortened and chondrocytes in these areas (Figure 3, D). Rare binucleated deformed (Figure 4, A). In long bones, columns of dysplastic chondrocytes may be present. Enchondromas in the digits cartilage that originate in the growth plate produce linear or in patients with multiple enchondromatosis may dem- radiolucencies that extend from the metaphysis into the onstrate increased cellularity and cytologic atypia (Figure 3, diaphysis; this radiologic finding is characteristic for both E).2 Ollier disease and Maffucci syndrome.2 74 Arch Pathol Lab Med—Vol 144, January 2020 Differential Diagnosis of Cartilage Lesions—Suster et al

Figure 3. A, Plain film radiograph of the distal femur showing an enchondroma with a uniform distribution of calcifications and well-formed arclike pattern. B, Plain film radiograph of the right hand showing a well-circumscribed ovoid lesion with a ring-and-arc pattern, corresponding to reactive bone rimming individual nodules of cartilage. A small fracture can be seen associated with the tumor. C, Gross photograph of an enchondroma shows a tan-white cartilaginous lesion with clear demarcation from the residual normal cortex. There is focal thinning of the cortex overlying the lesion. D, Microscopic image showing a variable number of benign-appearing chondrocytes, with focal areas of scattered calcifications and bone deposition on the periphery of the nodule. E, Microscopic image of an enchondroma of the finger demonstrating increased cellularity with prominent variation in the size of the chondrocytes (hematoxylin-eosin, original magnifications 320 [D] and 3200 [E]). Arch Pathol Lab Med—Vol 144, January 2020 Differential Diagnosis of Cartilage Lesions—Suster et al 75 Malignant transformation has been reported to occur in up to 40% of patients. The most common malignant tumor is conventional-type chondrosarcoma (Figure 4, B and C); however, rarely patients can develop dedifferentiated chondrosarcoma.33,34 In addition, both Ollier disease and Maffucci syndrome have been associated with the develop- ment of other tumor types, such as ovarian juvenile granulosa cell tumors.2,35 Metachondromatosis is an inherited autosomal dominant disease caused by loss of function mutations in the PTPN11 gene.36 Patients with metachondromatosis present early with the development of numerous enchondromas as well as osteochondromas. Unlike patients with Ollier disease or Maffucci syndrome, patients with metachondromatosis do not appear to have an increased risk of malignant transformation, though it has rarely been reported.37 Although pathologic assessment may play a limited role in the initial diagnosis of these syndromes, as they are primarily diagnosed on clinical-radiologic grounds, it can be crucial to guide clinical management, particularly in patients for whom there is a concern for malignant transformation. When evaluating biopsies from these patients, it is important to remember that enchondromas in Ollier disease and Maffucci syndrome can show increased cellularity and cytologic atypia, histologically mimicking chondrosarcoma. Given the propensity for malignant transformation as well as the association with other rare nonskeletal tumor types, these patients are closely followed by imaging and screened for any signs of malignant transformation.38,39

CHONDROMYXOID FIBROMA

Chondromyxoid fibroma is a rare cartilaginous tumor (,1% of primary bone tumors)40 that was previously classified as an intermediate biologic potential (locally aggressive) tumor,1 but will be reclassified as a benign neoplasm in the upcoming WHO classification of bone tumors. Microscopically, it is characterized by lobulated chondromyxoid areas, multinucleated giant cells, and, in approximately 25% of tumors, scattered coarse calcifica- tions. These tumors usually arise in the second to third decade of life, show a slight male predilection, and typically involve the long bones but also occasionally flat bones including the ilium, ribs, vertebral bodies, scapula, and the small bones of the foot. Patients often present with pain, which may be of long duration. The treatment is surgical with curettage or conservative resection. Local recurrence rate is 10% to 20%.1,2,41–44 Clonal rearrangements of chromosome 6 including t(6;9)(q25;q22) and inv(6)(p25q13) have been described as either an isolated genetic aberration or in concert with other karyotypic abnormalities including deletions of 6q24.25,45–48 Recurrent fusions of the GRM1 gene have been implicated in the pathogenesis of chondromyxoid fibroma; upregu- lation of the glutamate metabotropic receptor 1 (GRM1) through promoter swapping and gene fusion events has been shown to be a specific driver event in the development 49 Figure 4. A, Plain film radiograph of the bilateral feet in a patient with of these tumors. DNA microarray studies comparing Ollier disease showing multiple enchondromas with prominent chondromyxoid fibroma to chondroblastoma did not show deformation of the digits. B, Gross photograph from a patient with any differential gene expression in cartilage-related genes; Ollier disease showing a secondary chondrosarcoma arising in however, higher expression levels of CD166, cyclin D1, and association with multiple enchondromas within the medullary cavity. The larger nodules of gray-white hyaline type cartilage have eroded through the cortex into the surrounding soft tissue. C, Microscopic image showing a secondary chondrosarcoma arising in a patient with shows a permeative growth pattern that entraps preexisting bony Ollier disease. There is increased chondrocyte cellularity, and the tumor trabeculae (hematoxylin-eosin, original magnification 340 [C]). 76 Arch Pathol Lab Med—Vol 144, January 2020 Differential Diagnosis of Cartilage Lesions—Suster et al tions and sharply demarcated sclerotic borders (Figure 5, A). When they arise in long bones, they are often eccentrically located. Some cases show prominent calcifications that are evident on imaging modalities, particularly computed tomography scans. Geographic bone destruction and scalloped borders can be seen as well. On MRI, chondro- myxoid fibromas are hypointense on T1- and hyperintense on T2-weighted images.45 Grossly, chondromyxoid fibromas are solid, lobulated, and well circumscribed, with a gelatinous cut surface that may have gritty calcifications. Histologically, the tumor displays a lobulated architecture, with central areas com- posed of a chondromyxoid matrix with bland-appearing spindle- and stellate-shaped cells. The cells tend to become more condensed near the periphery of the lobules and are often cuffed by areas of bland round or spindle-shaped cells with osteoclast-type giant cells and prominent hemangio- pericytoma-like staghorn vessels (Figure 5, B). Coarse calcifications and degenerative changes can be seen within the areas of chondromyxoid stroma (Figure 5, C).1,2 The tumor may undergo secondary cystic changes (aneurysmal bone cyst–like). The tumors may show areas with pseudomalignant cells with enlarged hyperchromatic nuclei, which resemble the degenerative atypia seen in benign peripheral nerve sheath tumors; mitotic activity, however, should be absent. In small core biopsies, a distinguishing feature for chondromyxoid fibroma from other cartilaginous lesions is the character of the chondroid matrix, which is usually less well formed and has a more myxoid quality than the mature hyaline matrix present in other cartilage tumors.

Immunohistochemistry is unhelpful, as the chondrocytic cells in chondromyxoid fibroma are positive for markers such as S100 protein, Sox9, and ERG, similar to other cartilaginous lesions. The peripheral myofibroblastic areas stain diffusely for smooth muscle actin, whereas desmin, h- caldesmon, and calponin show negative staining. CD34 immunohistochemical stain strongly highlights the periph- erally located blood vessels.51–53 The diagnosis of chondromyxoid fibroma can be a challenge, because of its variegated morphology as well as the rarity of the lesion itself. The differential diagnosis includes chondroblastoma, enchondroma, low-grade chon- drosarcoma, and the exceedingly rare chondromyxoid fibroma–like osteosarcoma.54 Given the broad differential diagnosis, careful clinical and radiologic correlation is required (Table 2).

CHONDROBLASTOMA Chondroblastoma is a rare tumor with chondrogenic Figure 5. A, Plain film radiograph of chondromyxoid fibroma of the differentiation and was previously classified as having ulna, showing an eccentric, expansile, radiolucent, and multilobulated intermediate biologic potential (rarely metastasizing)1; lesion with internal septations and sharply demarcated borders. B, Microscopic image of chondromyxoid fibroma showing a bland- however, in the upcoming WHO classification, it is appearing population of stellate to spindled cells that are embedded reclassified as benign. It typically affects young, skeletally within a gray chondromyxoid stroma. Focal lobular areas of chondroid immature individuals. Among the well-differentiated carti- tissue are present with an area of adjacent increased cellularity. A few laginous lesions, chondroblastoma can show the least small, irregularly shaped vessels are present within the lesion. C, amount of apparent cartilaginous differentiation. Chondro- Microscopic image showing a chondromyxoid fibroma with character- blastomas are more common in males and typically arise in istic coarse purple calcifications within the chondroid tissue (hematox- 2 ylin-eosin, original magnification 3100 [B and C]). the epiphysis of long tubular bones. The peak incidence is during the second decade of life. Although chondroblasto- p16INK4A were seen in these tumors as compared to high- ma can occur in adults, primarily in flat bones and short grade central chondrosarcoma.50 tubular bones of the foot, it is rare to see a chondroblastoma Radiographically, chondromyxoid fibromas are expansile, in patients older than 30 years.55 Chondroblastomas follow a lytic, radiolucent, and multilobulated, with internal septa- benign course and are generally cured with curettage or Arch Pathol Lab Med—Vol 144, January 2020 Differential Diagnosis of Cartilage Lesions—Suster et al 77 Table 2. Useful Distinguishing Features for the Differential Diagnosis of Chondromyxoid Fibroma, Chondroblastoma, and Other Low-Grade Chondroid Lesions Low-Grade Features Chondromyxoid Fibroma Chondroblastoma Enchondroma Chondrosarcoma Age (general ,30 (50% of patients), ,30 .30 (younger in syndromic .30 (usually fifth–seventh guideline), y ,40 (72% of patients) patients) decade of life) Radiologic Well-demarcated, Well-demarcated, central or Well-demarcated, May be well-demarcated, lobulated, central or eccentric, epiphyseal, metaphyseal, usually radiolucent lesion, with eccentric, metaphyseal, lytic lesion central, radiodensities radiodensities (ring and lytic lesion (ring and arc arc calcifications); bone calcifications) destruction may be seen Architectural Well-circumscribed, Well-circumscribed lesion Well-circumscribed, May show infiltrative lobulated lesion with with eosinophilic pink lobulated, variably borders and soft tissue peripheral condensation matrix, fine pattern of hypocellular, can show invasion; infiltration of cells, associated calcifications (‘‘chicken degenerative changes around preexisting bony fibrous stroma with wire’’), scattered trabeculae is the most hemangiopericytoma-like multinucleated giant cells, important feature; lobules vessels, coarse commonly shows with fibrous septa calcifications secondary aneurysmal bone cyst–like changes Cytologic Stellate or spindle cell– Epithelioid chondroblastic Benign-appearing Variably increased shaped cells, oval dark cells with round nuclei chondrocytes with bland cellularity, mild nuclear nuclei, eosinophilic and nuclear grooves, no nuclei, occasional pleomorphism with cytoplasm, mitotic atypical mitoses seen binucleated cells, no sometimes deceptively activity usually absent mitotic activity bland chondrocytes ablative techniques; however, 5% to 12% of tumors locally expression of keratin and p63 and scattered strong recur.56,57 membranous DOG1 staining.52,62,63 K36M mutations of the H3F3B gene (and rarely of the Usually, the diagnosis of chondroblastoma is straightfor- H3F3A gene), which encodes for histone H3.3, have recently ward, with the differential diagnosis including other giant been described in chondroblastomas and can help distin- cell–rich tumors such as giant cell tumor of bone, guish these lesions among histologic mimics.58 Behjati et al59 aneurysmal bone cyst, chondromyxoid fibroma, and rarely reported the presence of histone H3.3 mutations in 73 of 77 chondroblastoma-like osteosarcoma. Radiologic and path- cases (95%); the H3.3 mutations in the 73 chondroblasto- ologic correlation can be particularly helpful in distinguish- mas were all K36M, with 68 identified in the H3F3B gene ing chondroblastoma-like osteosarcoma, as it shows and 5 in the H3F3A gene. A mutation-specific antibody aggressive radiologic and pathologic features such as cortical destruction, infiltration, and focal malignant osteoid depo- against the H3F3B K36M mutation as found in most 64 chondroblastomas has been shown to be diagnostically sition. Furthermore, immunohistochemistry for the H3F3B helpful in separating this lesion from other primary bone K36M mutation may be helpful in differentiating chondro- tumors.60,61 blastoma from other giant cell–rich lesions and cartilage- producing tumors. Radiologically, chondroblastoma appears as a radiolucent lesion that shows well-defined sclerotic borders and is LOW-GRADE CHONDROSARCOMA AND ATYPICAL centered about the epiphysis (Figure 6, A and B). Scattered CARTILAGINOUS TUMOR calcifications may be present. Chondroblastoma commonly undergoes secondary aneurysmal bone cyst–like changes Chondrosarcoma is defined as a malignant cartilage and can show fluid-fluid levels on MRI. These secondary matrix-producing tumor and comprises a heterogenous changes may cause a periosteal expansion that gives the family of tumors, which includes conventional chondro- sarcoma, secondary chondrosarcoma, periosteal chon- appearance of a more aggressive lesion.2 drosarcoma, clear cell chondrosarcoma, dedifferentiated Grossly, chondroblastoma is well circumscribed, red to chondrosarcoma, and mesenchymal chondrosarcoma.1 For white, and gritty and may have areas of hemorrhage and simplicity, this review will focus on the differential diagnosis cystic degeneration. Histologically, it is composed of an between benign cartilaginous lesions and low-grade con- admixture of mononuclear chondroblastic cells and multi- ventional or secondary chondrosarcoma. Conventional nucleated osteoclast-type giant cells, with associated calci- chondrosarcoma is a primary chondrosarcoma, which arises fications and deposition of poorly formed eosinophilic in the absence of a precursor lesion, whereas secondary 1,2 chondroid matrix. The mononuclear neoplastic cells tend chondrosarcoma is associated with a preexisting bone tumor, to grow in sheets and have eccentric eosinophilic cytoplasm such as enchondroma or osteochondroma.2 with well-demarcated cell borders; the nuclei frequently Since the fourth edition of the WHO classification1 in have prominent nuclear grooves (coffee bean–like) (Figure 2013, the term atypical cartilaginous tumor has emerged as a 6, C and D). The calcifications are characteristically present new concept that is used to denote a low-grade cartilagi- in a fine reticular pattern (‘‘chicken-wire’’ calcifications) nous neoplasm that is microscopically identical to a grade 1 surrounding individual mononuclear cells that may undergo chondrosarcoma and is located in the appendicular skele- necrosis. Rare mitotic figures may be seen. Immunohisto- ton. The concept of atypical cartilaginous tumor is akin to chemistry for chondroblastoma shows expression of carti- the concept of atypical lipomatous tumor used to denote laginous markers such as S100 and Sox9, as well as variable peripheral adipocytic tumors that are histologically identical 78 Arch Pathol Lab Med—Vol 144, January 2020 Differential Diagnosis of Cartilage Lesions—Suster et al

Figure 6. A, Plain film radiograph of chondroblastoma of the proximal tibia with a well-circumscribed lytic lesion with sclerotic margins. B, Corresponding coronal T1-weighted magnetic resonance imaging of the proximal tibia shows a small circular mass with low signal intensity, vaguely lobular architecture, and well-circumscribed margins that extend to the base of the articular surface. C, Microscopic image showing a monotonous cell population with admixed multinucleated giant cells and characteristic eosinophilic matrix. D, Microscopic image showing an epithelioid cell population with eosinophilic cytoplasm, scattered reniform nuclei, and prominent nuclear folds (hematoxylin-eosin, original magnifications 3200 [C] and 3400 [D]). to well-differentiated liposarcoma in deep-seated locations. seventh decade of life and shows a slight male predomi- As atypical cartilaginous tumors/low-grade chondrosarcoma nance. The tumors can arise in any bone that forms by are clinically relatively indolent as compared to other types endochondral ossification, with the most common locations of chondrosarcomas, they can be treated by surgical being the pelvis, followed by the proximal and distal femur, curettage for sufficient local control, rather than other more proximal humerus, and ribs. In rare cases, primary extensive/morbid procedures as were done in the past. The chondrosarcomas can arise in the small bones of the hands term atypical cartilaginous tumor should be used for tumors and feet.2 Patients typically present with pain and an of the appendicular skeleton, whereas the term chondrosar- enlarging mass. Radiographically, the tumors are lytic with coma grade 1 should be reserved for tumors of the axial scattered radiodensities and irregular spiculations, which skeleton, including the pelvis, scapula, and base of skull. can often show cortical changes including thinning and Primary central chondrosarcoma accounts for approxi- scalloping (Figure 7, A and B). Magnetic resonance imaging mately 20% of malignant bone tumors and is the most can be helpful in identifying the extent of the tumor.66,67 The common malignant cartilage-forming tumor of bone.65 histologic grading of chondrosarcoma is the most important Primary central chondrosarcoma makes up approximately prognostic factor; grade 1 lesions act in a locally aggressive 90% of all chondrosarcomas, with the other 10% being of manner, with a 5-year survival of ~80% and a very low (if the several histologic variants mentioned above. Primary any) rate of metastasis. The treatment for tumors in the central chondrosarcoma usually develops during the fifth to appendicular skeleton is by surgical curettage; however, for Arch Pathol Lab Med—Vol 144, January 2020 Differential Diagnosis of Cartilage Lesions—Suster et al 79

Figure 7. A, Plain film radiograph shows a central chondrosarcoma of the pelvis. There is a mixed lytic and sclerotic lesion of the right ileum with expansion of the bone and irregular borders. B, Corresponding coronal computed tomography image demonstrates the expansive lesion with thinning of the cortex and focal area of central mineralization. C, Gross photograph of the low-grade chondrosarcoma of the pelvis. There is a lobulated, gray- white, glistening tumor located within the medullary space with focal thinning of the adjacent cortical bone. D, Microscopic image showing the infiltrative appearance of a low-grade chondrosarcoma with encasement of preexisting bony trabeculae and focal extension through the cortex into the surrounding soft tissue (bottom of image) (hematoxylin-eosin, original magnification 320 [D]). tumors located in some deep-seated sites such as the pelvis, Radiologically, secondary chondrosarcoma displays similar wide resection is needed, as recurrences are common and characteristics to primary chondrosarcoma; furthermore, the can be difficult to control.2,68,69 primary underlying associated lesion may be apparent Secondary chondrosarcoma is subdivided into secondary radiographically or histologically.2,70 The tumors are usually central chondrosarcoma (which arises from an enchondro- low grade, although rarely higher-grade chondrosarcomas ma) and secondary peripheral chondrosarcoma (which (grades 2 and 3) and dedifferentiated chondrosarcoma can arises from the cartilaginous cap of an osteochondroma).1,2 arise in association with an underlying benign cartilage Secondary chondrosarcomas have a bimodal age distribu- lesion. Secondary chondrosarcomas are treated in the same tion, as they can arise at an earlier age in syndromic patients fashion as primary chondrosarcomas; when the lesions are with Ollier disease, Maffucci syndrome, or MHE, but can low grade, they have a very good prognosis. also occur later.2 As mentioned previously, syndromic Genetically, chondrosarcomas of primary and secondary patients have a higher incidence of malignant transforma- types are characterized by mutations in the isocitrate tion, as noted in up to 40% in patients with Ollier disease or dehydrogenase isoforms IDH1 and IDH2, which have been Maffucci syndrome and up to 25% of patients with MHE.28,32 detected in approximately 50% to 60% of primary and 80 Arch Pathol Lab Med—Vol 144, January 2020 Differential Diagnosis of Cartilage Lesions—Suster et al secondary central chondrosarcomas.71,72 Peripheral chon- 8. Hameetman L, Szuhai K, Yavas A, et al. The role of EXT1 in nonhereditary osteochondroma: identification of homozygous deletions. J Natl Cancer Inst. drosarcomas appear to show similar EXT1 and EXT2 2007;99(5):396–406. 73 aberrations to solitary and hereditary osteochondromas. 9. Bovee´ JV. Multiple osteochondromas. Orphanet J Rare Dis. 2008;3(1):3. The genetic underpinnings mediating the transformation 10. Kumar CY, Shervegar S, Gadi D, Rahul P. Solitary sessile osteochondroma of scapula, a rare case report. J Clin Diagn Res. 2014;8(3):174–175. from benign cartilaginous lesions to malignant lesions are 11. Kitsoulis P, Galani V, Stefanaki K, et al. Osteochondromas: review of the not entirely elucidated; however, complex karyotypic clinical, radiological and pathological features. In Vivo. 2008;22(5):633–646. abnormalities, mutations in TP53, and defects in the RB1 12. Bernard SA, Murphey MD, Flemming DJ, Kransdorf MJ. Improved pathway have been described in these lesions as they differentiation of benign osteochondromas from secondary chondrosarcomas 74 with standardized measurement of cartilage cap at CT and MR imaging. transform into higher-grade chondrosarcomas. Radiology. 2010;255(3):857–865. Grossly, these tumors are often large and composed of 13. Michelsen H, Abramovici L, Steiner G, Posner MA. Bizarre parosteal gray, glistening lobules of cartilage. They often fill the osteochondromatous proliferation (Nora’s lesion) in the hand. J Hand Surg Am. 2004;29(3):520–525. medullary cavity, showing changes in the overlying cortical 14. Ruengwanichayakun P, Gambarotti M, Frisoni T, et al. PAROSTEAL bone such as scalloping or thinning and extension into osteosarcoma: a monocentric retrospective analysis of 195 patients. Hum Pathol. adjacent soft tissue (Figure 7, C). In secondary lesions 2019;91:11–18. 15. Gholamrezanezhad A, Basques K, Kosmas C. 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