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Surface tumours of bone
MINI-SYMPOSIUM: OSTEOARTICULAR PATHOLOGY
Surface tumours of bone
penetrate cortex and soft tissue tumours that have arisen from tissues other than periosteum and have come to erode or invade the bone surface. It is now proposed to deal comprehensively with all lesions given in the classification. Emphasis will be placed on potential diagnostic difficulties and the features of less well known entities will be described. There are three lesions in the group of reactive conditions. There may be some debate about these being true reactive as opposed to benign neoplastic conditions but for the purposes of this discussion the description ‘reactive’ is retained. The first condition is ossifying periostitis or ossifying periosteal fasciitis. The majority of affected patients are below the age of 40, the male:female ratio is 2:1 and the lower limb is most commonly involved (50%). Other sites include cranium, ribs, vertebral column and pelvis. Histologically there is a background appearance akin to nodular fasciitis with the added focal component of membrane type bone. Surgical excision may be followed by a local recurrence rate of up to 50% (Figure 2). Bizarre periosteal ossifying periostitis is more usually know by its acronym BPOP and is also called Nora’s lesion (FE Nora with others described the condition in 1983). It is a rare condition and is an exophytic outgrowth from the cortical bone surface comprising bone, cartilage and fibrous tissue. It affects proximal and middle phalanges and metacarpal and metatarsal bones. In some 70% cases the hand is involved. There is no sex preference and patient are generally young (majority less than 40 years). The lesion is benign but must be distinguished from parosteal osteosarcoma. The site and absence of cellular atypism is helpful in this context although the mixture of tissue types can be confusing. Osteochondroma is also very common in the hands and feet and its continuity with the medullary canal is said to distinguish if from BPOP. Although BPOP can be regarded as a reactive lesion there is a high rate of local recurrence (up to 55%) and a balanced chromosomal translocation (t(1; 17) (q32; q32; q21)) has been described suggesting that it may be a benign neoplastic process. Symptomatic BPOP requires excision although intra lesional excision is associated with a high recurrence rate. En bloc excision with removal of any pseudocapsule and subjacent periosteum reduces the rate of local recurrence (Figure 3). Reactive osteochondroma or subungual exostosis (also known as Dupuytren’s exostosis) most commonly arises in the dorsal aspect of the distal phalanx of the great toe. A smaller number of cases involve the hand. Patients are young (majority less than 30 years) although the clinical history may be quite long. The male:female ratio is 1:1. These lesions are often painful due to pressure on the nail bed and plate and can cause destruction of the former. Surgical excision if usually curative. The above three ‘reactive’ conditions are benign in overall behaviour although local recurrence may occur. They reflect the proliferative capacity of the periosteumand its three lines of possible differentiation (fibrogenic, chondrogenic and osteogenic). As stated above there is evidence that some may be benign neoplasms. There are five entities which are surface tumours of bone and which are true benign neoplasms. These are 1. Osteochondroma
John McClure D Chas Mangham Tony Freemont
Abstract Surface tumours of bone may be a cause of confusion and diagnostic difficulty. Confusion may arise from the several descriptive adjectives used e parosteal, periosteal and juxtacortical. Diagnostic difficulties may arise from the lack of awareness of less common entities, insufficient biopsy sampling and a failure to understand the precise relationship of a lesion and the bone surface. In this review we define and classify the important lesions and indicate imaging, macroscopic and microscopic features which are useful for diagnosis.
Keywords bone; chondroma; chondrosarcoma; juxtacortical; parosteal; periosteal; periosteum
Surface tumours of bone have a close association with the external surface of bone and commonly present as a soft tissue swelling or mass. The usual descriptions applied to these tumours are parosteal (near/alongside/beside the periosteum), periosteal (of the periosteum) and juxtacortical which is a more general adjective meaning next to the bone cortex. The spectrum of periosteum-associated neoplasms is very similar to that of neoplasms arising within the medullary cavity. This is hardly surprising as, like the marrow, the inner, cambium layer of the periosteum contains mesenchymal stem cells, is dynamically loaded, and is a source of soluble and insoluble molecules that regulate cell function. It is also vascular. It therefore has all the functionality for reactive proliferation and tumorigenesis (Figure 1). The outer fibrous layer of the periosteum is in continuity with tendon, ligaments and joint capsules and some collagen fibres (Sharpey’s fibres) traverse the periosteum to insert into bone. A conventional but useful classification of surface tumours of bone is shown in Box 1. Apart from osteochondroma all of the lesions, initially at least, leave the underlying cortex intact. Because of the nature of the mesenchymal stem cell any “soft tissue tumour” or “bone tumour” can arise de novo in this site. A distinction needs to be drawn between tumours arising from periosteum and bone tumours which arising the medulla and
John McClure MD FRCPath Formerly Consultant Pathologist in the Department of Musculoskeletal Pathology at Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust, Shropshire, UK. Conflicts of interest: none declared. D Chas Mangham BSc MB ChB FRCPath is Professor of Applied Molecular Pathology at the University of Manchester, Manchester, UK. Conflicts of interest: none declared. Tony Freemont BSc MD FRCP FRCPath is Professor of Osteoarticular Pathology and Director of the MRC/EPSRC Molecular Pathology Node at the University of Manchester, and the Manchester NIHR BRC, Manchester, UK. Conflicts of interest: none declared.
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Figure 1 (a) Normal periosteum with the fibrous component superiorly and cortical bone below. The cambium layer intervenes. In (b) the periosteum is activated. The cambium layer has proliferated and new woven bone formation is present.
2. Periosteal chondroma 3. Surface osteoma of long bones 4. Ivory exostosis 5. Melorheostosis. Osteochondroma (cartilage e capped exostosis) is a benign tumour composed of cartilage (undergoing varying degrees of endochondral ossification), subjacent bone and marrow tissues. The lesion represents the peripheral end of an epiphyseal (growth) plate left in-situ as the bone elongates in growth. Fifty per cent of patients (M:F 4:3) are aged 10e20 years and the commonest site (40%) is around the knee joint. Other sites which may be involved are the proximal femur and humerus and the scapula. The lesion projects from the bone surface and may be symptomatic because of pressure on adjacent soft tissues and impingement on blood vessels and nerves. The cartilage cap may be joined to the anatomical bone by a ‘neck’ of cortex (pedunculated) or there may be a flatter (sessile) disposition. Solitary lesions may be managed conservatively or, if symptomatic, may be excised aiming to completely remove the cartilage cap (Figure 4). Osteochondromatosis is the condition in which there are multiple osteochondromas and synonyms for the condition are diaphyseal aclasia/aclasis, multiple osteochondromas, multiple cartilaginous exostoses and hereditary multiple exostoses. Solitary osteochondroma is six times more common that the multiple disorder. The prevalence of the latter is 1:50,000 and the male/ female ratio is 3:2. Approximately 60% have a positive family history with genetic abnormalities (EXT1 (8q24), EXT2 (11p11p12), ? EXT 3(linkage to 19p)).
Surface tumours of bone e classification C
Reactive (or ? benign neoplastic) Ossifying periostitis / ossifying periosteal fasciitis Bizarre periosteal ossifying periostitis (BPOP, Nora’s lesion) Reactive osteochondroma (subungual exostosis)
C
Benign Cartilaginous e Osteochondroma e Periosteal chondroma Osseous e Surface osteoma of long bones e Ivory osteoma e Melorheostosis
C
Malignant Cartilaginous e Periosteal chondrosarcoma Osseous e Parosteal osteosarcoma e Periosteal (juxtacortical) osteosarcoma e High grade surface osteosarcoma
C
Miscellaneous (see Figure 15 below)
Box 1
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Figure 2 This is periostitis ossificans. In (a) there is new bone formation in which the deeply basophilic material is mineralized. (b) The formation of mineralized trabecular bone with covering osteoid and a surface monolayer of osteoblasts. There is zonal maturation. In (c) there is the spindled cell component. The lesion is essentially due to a proliferation of myofibroblasts. (d) Positive staining for smooth muscle antigen (SMA). In (e) the Ki67 mitotic index is low but can be higher depending on proliferative activity and the maturation of the lesion.
Importantly between 1 and 3% of cases of osteochondromatosis develop a secondary chondrosarcoma. This complication may arise in solitary osteochondroma but is much rarer. Malignant change usually occurs in axial, larger lesions and may be presaged by thickening of the cartilage cap, increased cellularity and cellular atypism but the true index of malignancy is permeative invasive growth (Figure 5). This point is highlighted by periosteal chondroma. The majority (75%) of patients are in the age range 10e40 years and the male/female ratio is 3:2. The most common skeletal location is the proximal humerus (30%) followed by the bones of the hand (20%), proximal and distal femur (15% each) and proximal tibia (5%). It is emphasized that periosteal chondroma is a rare lesion (1% or less of chondromas) but may cause significant diagnostic difficulties by virtue of being very cellular. The lesion is generally less than 5 cm in diameter but sometimes may be larger. The important feature is that the bone cortex subjacent to the lesion is intact and there is no permeative growth at the base (Figure 6). Therefore, it may be necessary to perform an en bloc excision to fully establish the histological diagnosis. Such excision is curative whilst curettage is followed by a high local recurrence rate. The benign neoplasms which show osseous differentiation are surface osteoma of long bones, ivory exostosis and melorheostosis.
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The majority (80%) of cases of surface osteoma of long bones occur in the age range 10e40 years (M:F 2:1). The most common skeletal site is the proximal femur (30%) followed by distal femur (15%), clavicle (15%), bones of the hand (5%) and proximal tibia (5%). The tumours are usually composed of cortical type Haversian bone. Surface osteomas of long bones may be associated with Gardner’s syndrome (although lesions of the mandible and calvarium are more commonly associated). Usually considered to be hamartomatous in nature the lesion does not recur after complete excision and there is no evidence of malignant transformation. The importance of this lesion does, however, lie in its accurate distinction from parosteal osteosarcoma. Ivory osteoma is a benign lesion of flat bones (viz those arising by intra membranous ossification) and usually involves the bones of the skull. It is composed of dense cortical e type bone. Tumours on the external surface of the skull present as a hard painful mass. Tumours on the inner skull table and those protruding into the sinuses have effects depending on their precise location. Melorheostosis is a rare genetic (LMEN3) developmental abnormality originally described in 1922 and of unknown aetiology. Patients may present at any age and there is no sex preference. There is irregular surface cortical thickening of one
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Figure 3 (a) A radiograph of a BPOP lesion of the fourth metatarsal bone and in (b) there is the cross-sectional scan. The lesion is on the bone surface and the cortex is not involved although it is substantially enveloped by the lesion. (c) Demonstrates that the actual physical connection with the cortex can be a narrow isthmus. Above is the anatomical bone and below is the BPOP lesion. The latter is composed of trabecular bone and overlaid with a mixture of cartilage and fibrous tissue in a disorganized arrangement. In superficial biopsies this architectural disarray may be confusing. An awareness of the entity and the absence of cellular atypism facilitates diagnosis.
Figure 4 In (a) there is a typical lobulated cartilage covered osteochondroma. In (b) the lesion has been sliced and a contact radiograph prepared. This illustrates the discontinuity in the cortex due to the osteochondroma with the margins forming cortical ‘shoulders’ and ‘neck’. This also shown histologically in (c). Here the continuity of the marrow space within the tumour and the bone medulla is clearly demonstrated and this is considered a feature of osteochondroma. However this ‘rule’ is not invariate. In (d) the cortex is bifid superiorly with one ‘arm’ continuing across the base of the lesion. This cortical bone is however, well cancellized and there is effective marrow space continuity. In both (c) and (d) the cartilage cap is not excessively thickened although the thickness in (d) is more variable. The cartilage is the neoplastic tissue can, rarely, undergo malignant transformation.
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Figure 5 This illustrates malignant transformation in an osteochondroma of the scapula. The scan (a) shows ‘upswing’ of the flared cortices forming a stalk indicating the original underlying osteochondroma. (b)e(d) show that there is a lobulated cartilage tumour which has not only grown in an exophytic fashion but has also filled the medullary space of the scapula reaching the contralateral endosteal surface with at least superficial erosion of that surface. The ipsilateral cortex is thicker and there is horizontal erosion of the left side.
aspect of a bone such that the macroscopic appearance resembles melted wax which has dripped down the side of a candle. This somewhat fanciful analogy provides the Greek roots (melos e limb; rhein e flow) for the name of this condition.
Melorheostosis can affect the long bones of the upper and lower limbs, hands, feet and sometimes the axial skeleton. Accompanying lesions may be osteopoikilosis and osteopathia striata and tumours or malformations of blood vessels and lymphatics. Limited lesions may clinically and radiologically mimic myositis ossificans, osteoma and parosteal osteosarcoma. Although most sarcomas have been described as arising from periosteum, in clinical practice there are four of importance. 1. Periosteal chondrosarcoma 2. Parosteal osteosarcoma 3. Periosteal (juxtacortical) osteosarcoma and 4. High grade surface osteosarcoma. The majority (70%) of periosteal chondrosarcoma patients are in the age range 20e50 years a somewhat younger age group than conventional chondrosarcoma. The male/female ratio is 3:2. Some 55% of cases involve the proximal femur. Other sites of involvement are the humerus (20%) tibia (10%) and pelvis (10%). Treatment is by complete en bloc excision since the 5year local recurrence-free survival is less in patients treated with intra lesional or marginal excision (25%) than for patients treated with the wide resections (93%). The overall 5-year metastasis e free survival is of the order of 80% although this is influenced adversely by increasing grade. The diagnostic challenges are to distinguish periosteal chondrosarcoma from periosteal chondroma (as stated above) and from periosteal osteosarcoma which usually requires chemotherapy (Figures 7 and 8). Parosteal osteosarcoma is an uncommon (5% of osteosarcomas), usually slowly growing malignant tumour frequently
Figure 6 This is an example of a periosteal chondroma. The important feature is the bone cortex seen inferiorly. It is of uniform thickness and there is no permeation by tumour. The deeply basophilic lobules on the right close to the cortex with a thin band of fibrous tissue between the cartilage and bone and which extends up over the proliferation. Superiorly the cartilage lobules are quite cellular and the matrix more lightly stained. Limited sampling of a periosteal chondroma can produce tissue with worrying cellularity. Understanding the intra periosteal location facilitates accurate diagnosis.
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Figure 7 In this illustration of a periosteal chondrosarcoma. (a) The external surface. Superiorly there is skeletal muscle below which there is fibrous periosteum into which the tumour is pushing. (b) The cellularity to this part of the tumour and the insert shows bi-and trinucleated cells and a degree of nuclear pleomorphism. Deeply however in (c) the tumour has penetrated cortex and is permeating trabecular bone. (d) The cytological features of the tumour in this deep location. Now there is marked cellularity and pleomorphism indicating a high grade of tumour.
Figure 8 (a) A periosteal chondrosarcoma in the distal femur. In the histological preparation more recently proliferated tissue is deeply basophilic and there is superficial erosion and some permeation of the cortex. This is, therefore, a borderline case since the permeation is weak and penetration to the medulla has not occurred. In contrast to the more recently proliferated tissue the cartilage cap is older (paler matrix) and relatively less cellular.
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Figure 9 This is a parosteal osteosarcoma in a classical location e posteriorly in the lower end of femur. The radiographs show dense mineralisation which is a consequence of the relatively slow growth of this tumour. The macroscopic view in (c) has a cartilaginous cap e the pale white tissue. This feature is present in up to 50% of cases.
Figure 10 In (a) and (b) the cartilage cap of a parosteal osteosarcoma is present. (a) Cartilage in low power and its interface with deeper bone forming tissue. In (b) there is a higher power view of the cartilage cap and its limiting external fibrous tissue layer. In (c) are the many trabecular structures typical of this tumour and when mineralized cause the characteristic radiodensity. In (d) the trabecular structures are irregular in outline whilst the intervening neoplastic tissue is cellular.
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Figure 11 (a) Low grade parosteal osteosarcoma with the subjacent cortex (b). In (c) and (d) there has been progression to an intermediate grade. This is manifest as increased cellularity and cellular pleomorphism.
Figure 12 This is the radiograph (a) and macroscopic preparation (b) of a resected periosteal osteosarcoma. The radiograph has a classical ‘sunburst’ image e due to mineralized spicules. In the macroscopic preparation there is no evidence of a penetrative or intramedullary component. The tumour is therefore exclusive to the periosteal surface.
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Figure 13 In (a) the blue (basophilic) zones are the chondroblastic element of this periosteal osteosarcoma. In (b) there is osteosarcoma permeating (superiorly) the bone cortex. In this case penetration of the cortex had occurred and the penetrative tissue was of higher grade (insert).
Figure 14 There had been treatment of this case of high grade surface osteosarcoma with chemotherapy. The effects of this account for the macroscopic appearance (a). In (b)e(d) the neoplastic tissue appears myxoid and hypocellular. However, as showing in (d) viable pleomorphic cells are still present. The high grade surface tumour differs from periosteal osteosarcoma in lacking a significant cartilaginous component and having high grade rather than intermediate grade osteosarcomatous tissue.
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Figure 15 This is an example of a periosteal sarcoma complete lacking in chondroosseous differentiation. In fact the histological features (c and d) are of a leiomyosarcoma e confirmed by positive staining for smooth muscle antigen (SMA). As can be seen in (a and b) the tumour is aggressive and is permeating cortex.
displaying a high degree of histological differentiation. It has a significantly better prognosis than the more usual varieties of osteosarcoma with a low propensity to metastasise. Sixty five per cent of cases are in the 20e40 years age range and the male/ female ratio is 2:3. Some 90% of tumours occur around the knee joint (80% distal femur: 10% proximal tibia). Histologically a typical lesion shows well-formed bone trabecular structures set in a fibrous stroma. Usually the periphery of the tumour is more cellular and the osteoidal material less mature. Nearer the base of the tumour the trabeculae are thicker, more mature and the fibrous component more collagenous. The prognosis is dependent on tumour grade (of the spindle cell component) and adequate local excision. Low grade tumours require en bloc excision and intermediate grade lesions similar excision and possibly chemotherapy. Where there is dedifferentiation or progression to a high grade osteosarcoma then en bloc excision and chemotherapy are required. Some 50% of cases show cartilage differentiation either as cartilage nodules or a cartilaginous cap (Figures 9, 10 & 11). It is important to recognize this when considering the biopsy differential diagnosis of osteochondroma and periosteal osteosarcoma. Periosteal osteosarcoma is rare comprising about 2% of all osteosarcomas. 75% of are between 10 and 40 years old. The male:female ratio is 2:3. The majority of these tumours occur in the femur or tibia and a much smaller number in the humerus (Figure 12). Histologically, at first sight, these tumours are chondrosarcomatous but there is definitionally a minor
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osteosarcomatous component (Figure 13). Grade can vary but it is usually intermediate. Treatment is by wide, en bloc or radical resection usually accompanied by chemotherapy. Prognosis is not as good as parosteal osteosarcomas but better than conventional high-grade intramedullary or surface osteosarcoma. High grade surface osteosarcomas are rare comprising less than 1% of all osteosarcomas and 9% of surface osteosarcomas. By definition they are conventional osteosarcomas arising on the surface of bone and with no intramedullary involvement. The age range is 20e40 years for 70% of cases. The male/female ratio is 2:1. The distal femur is involved in 30%, proximal humerus (20%), and proximal femur (10%). The histological features are identical to conventional intramedullary osteosarcoma and treatment is similarly identical. The overall survival at 5 years is z45%. Marginal excision is associated with increased risk of local recurrence and increasing tumour grade adversely influences prognosis. Wide excision and effective systemic chemotherapy are associated with better outcomes (Figures 14 and 15). A
FURTHER READING Antonescu CR, Huvos AG. Low-grade osteogenic sarcoma arising in medullary and surface osseous locations. Am J Clin Pathol 2000 Nov;(114 suppl); S90e103. Brien EW, Mirra JM, Luck Jr JV. Benign and malignant cartilage tumors of bone and joint: their anatomic and theoretical basis with
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an emphasis on radiology, pathology and clinical biology. II. Juxtacortical cartilage tumors. Skeletal Radiol 1999 Jan; 28: 1e20. Kenan S, Abdelwahab IF, Klein MJ, Hermann G, Lewis MM. Lesions of juxtacortical origin (surface lesions of bone). Skeletal Radiol 1993; 22: 337e57. Miller-Breslow A, Dorfman HD. Dupuytren’s (subungual) exostosis. Am J Surg Pathol 1988 May; 12: 368e78. Oviedo A, Simmons T, Benya E, Gonzalez-Crussi F. Bizarre parosteal osteochondromatous proliferation: case report and review of the literature. Pediatr Dev Pathol 2001 SepeOct; 4: 496e500. Romeo S, Hogendoorn PC, Dei Tos AP. Benign cartilaginous tumors of bone: from morphology to somatic and germ-line genetics. Adv Anat Pathol 2009 Sep; 16: 307e15.
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Practice points C
C
C
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Cartilaginous surface tumours of bone must be carefully assessed for permeative growth into the cortex e both radiologically and pathologically (e.g. periosteal chondroma versus periosteal chondrosarcoma) Cartilaginous and cartilage-capped surface bone tumours are not always simply chondromatous/chondrosarcomatous e think periosteal osteosarcoma and parosteal osteosarcoma Periosteal osteosarcoma, high grade surface osteosarcoma and progressed (i.e. to higher grade) parosteal osteosarcoma will usually require chemotherapy and the lesion’s response should be assessed histologically
Ó 2017 Published by Elsevier Ltd.
Surface tumours of bone
penetrate cortex and soft tissue tumours that have arisen from tissues other than periosteum and have come to erode or invade the bone surface. It is now proposed to deal comprehensively with all lesions given in the classification. Emphasis will be placed on potential diagnostic difficulties and the features of less well known entities will be described. There are three lesions in the group of reactive conditions. There may be some debate about these being true reactive as opposed to benign neoplastic conditions but for the purposes of this discussion the description ‘reactive’ is retained. The first condition is ossifying periostitis or ossifying periosteal fasciitis. The majority of affected patients are below the age of 40, the male:female ratio is 2:1 and the lower limb is most commonly involved (50%). Other sites include cranium, ribs, vertebral column and pelvis. Histologically there is a background appearance akin to nodular fasciitis with the added focal component of membrane type bone. Surgical excision may be followed by a local recurrence rate of up to 50% (Figure 2). Bizarre periosteal ossifying periostitis is more usually know by its acronym BPOP and is also called Nora’s lesion (FE Nora with others described the condition in 1983). It is a rare condition and is an exophytic outgrowth from the cortical bone surface comprising bone, cartilage and fibrous tissue. It affects proximal and middle phalanges and metacarpal and metatarsal bones. In some 70% cases the hand is involved. There is no sex preference and patient are generally young (majority less than 40 years). The lesion is benign but must be distinguished from parosteal osteosarcoma. The site and absence of cellular atypism is helpful in this context although the mixture of tissue types can be confusing. Osteochondroma is also very common in the hands and feet and its continuity with the medullary canal is said to distinguish if from BPOP. Although BPOP can be regarded as a reactive lesion there is a high rate of local recurrence (up to 55%) and a balanced chromosomal translocation (t(1; 17) (q32; q32; q21)) has been described suggesting that it may be a benign neoplastic process. Symptomatic BPOP requires excision although intra lesional excision is associated with a high recurrence rate. En bloc excision with removal of any pseudocapsule and subjacent periosteum reduces the rate of local recurrence (Figure 3). Reactive osteochondroma or subungual exostosis (also known as Dupuytren’s exostosis) most commonly arises in the dorsal aspect of the distal phalanx of the great toe. A smaller number of cases involve the hand. Patients are young (majority less than 30 years) although the clinical history may be quite long. The male:female ratio is 1:1. These lesions are often painful due to pressure on the nail bed and plate and can cause destruction of the former. Surgical excision if usually curative. The above three ‘reactive’ conditions are benign in overall behaviour although local recurrence may occur. They reflect the proliferative capacity of the periosteumand its three lines of possible differentiation (fibrogenic, chondrogenic and osteogenic). As stated above there is evidence that some may be benign neoplasms. There are five entities which are surface tumours of bone and which are true benign neoplasms. These are 1. Osteochondroma
John McClure D Chas Mangham Tony Freemont
Abstract Surface tumours of bone may be a cause of confusion and diagnostic difficulty. Confusion may arise from the several descriptive adjectives used e parosteal, periosteal and juxtacortical. Diagnostic difficulties may arise from the lack of awareness of less common entities, insufficient biopsy sampling and a failure to understand the precise relationship of a lesion and the bone surface. In this review we define and classify the important lesions and indicate imaging, macroscopic and microscopic features which are useful for diagnosis.
Keywords bone; chondroma; chondrosarcoma; juxtacortical; parosteal; periosteal; periosteum
Surface tumours of bone have a close association with the external surface of bone and commonly present as a soft tissue swelling or mass. The usual descriptions applied to these tumours are parosteal (near/alongside/beside the periosteum), periosteal (of the periosteum) and juxtacortical which is a more general adjective meaning next to the bone cortex. The spectrum of periosteum-associated neoplasms is very similar to that of neoplasms arising within the medullary cavity. This is hardly surprising as, like the marrow, the inner, cambium layer of the periosteum contains mesenchymal stem cells, is dynamically loaded, and is a source of soluble and insoluble molecules that regulate cell function. It is also vascular. It therefore has all the functionality for reactive proliferation and tumorigenesis (Figure 1). The outer fibrous layer of the periosteum is in continuity with tendon, ligaments and joint capsules and some collagen fibres (Sharpey’s fibres) traverse the periosteum to insert into bone. A conventional but useful classification of surface tumours of bone is shown in Box 1. Apart from osteochondroma all of the lesions, initially at least, leave the underlying cortex intact. Because of the nature of the mesenchymal stem cell any “soft tissue tumour” or “bone tumour” can arise de novo in this site. A distinction needs to be drawn between tumours arising from periosteum and bone tumours which arising the medulla and
John McClure MD FRCPath Formerly Consultant Pathologist in the Department of Musculoskeletal Pathology at Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust, Shropshire, UK. Conflicts of interest: none declared. D Chas Mangham BSc MB ChB FRCPath is Professor of Applied Molecular Pathology at the University of Manchester, Manchester, UK. Conflicts of interest: none declared. Tony Freemont BSc MD FRCP FRCPath is Professor of Osteoarticular Pathology and Director of the MRC/EPSRC Molecular Pathology Node at the University of Manchester, and the Manchester NIHR BRC, Manchester, UK. Conflicts of interest: none declared.
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Figure 1 (a) Normal periosteum with the fibrous component superiorly and cortical bone below. The cambium layer intervenes. In (b) the periosteum is activated. The cambium layer has proliferated and new woven bone formation is present.
2. Periosteal chondroma 3. Surface osteoma of long bones 4. Ivory exostosis 5. Melorheostosis. Osteochondroma (cartilage e capped exostosis) is a benign tumour composed of cartilage (undergoing varying degrees of endochondral ossification), subjacent bone and marrow tissues. The lesion represents the peripheral end of an epiphyseal (growth) plate left in-situ as the bone elongates in growth. Fifty per cent of patients (M:F 4:3) are aged 10e20 years and the commonest site (40%) is around the knee joint. Other sites which may be involved are the proximal femur and humerus and the scapula. The lesion projects from the bone surface and may be symptomatic because of pressure on adjacent soft tissues and impingement on blood vessels and nerves. The cartilage cap may be joined to the anatomical bone by a ‘neck’ of cortex (pedunculated) or there may be a flatter (sessile) disposition. Solitary lesions may be managed conservatively or, if symptomatic, may be excised aiming to completely remove the cartilage cap (Figure 4). Osteochondromatosis is the condition in which there are multiple osteochondromas and synonyms for the condition are diaphyseal aclasia/aclasis, multiple osteochondromas, multiple cartilaginous exostoses and hereditary multiple exostoses. Solitary osteochondroma is six times more common that the multiple disorder. The prevalence of the latter is 1:50,000 and the male/ female ratio is 3:2. Approximately 60% have a positive family history with genetic abnormalities (EXT1 (8q24), EXT2 (11p11p12), ? EXT 3(linkage to 19p)).
Surface tumours of bone e classification C
Reactive (or ? benign neoplastic) Ossifying periostitis / ossifying periosteal fasciitis Bizarre periosteal ossifying periostitis (BPOP, Nora’s lesion) Reactive osteochondroma (subungual exostosis)
C
Benign Cartilaginous e Osteochondroma e Periosteal chondroma Osseous e Surface osteoma of long bones e Ivory osteoma e Melorheostosis
C
Malignant Cartilaginous e Periosteal chondrosarcoma Osseous e Parosteal osteosarcoma e Periosteal (juxtacortical) osteosarcoma e High grade surface osteosarcoma
C
Miscellaneous (see Figure 15 below)
Box 1
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Figure 2 This is periostitis ossificans. In (a) there is new bone formation in which the deeply basophilic material is mineralized. (b) The formation of mineralized trabecular bone with covering osteoid and a surface monolayer of osteoblasts. There is zonal maturation. In (c) there is the spindled cell component. The lesion is essentially due to a proliferation of myofibroblasts. (d) Positive staining for smooth muscle antigen (SMA). In (e) the Ki67 mitotic index is low but can be higher depending on proliferative activity and the maturation of the lesion.
Importantly between 1 and 3% of cases of osteochondromatosis develop a secondary chondrosarcoma. This complication may arise in solitary osteochondroma but is much rarer. Malignant change usually occurs in axial, larger lesions and may be presaged by thickening of the cartilage cap, increased cellularity and cellular atypism but the true index of malignancy is permeative invasive growth (Figure 5). This point is highlighted by periosteal chondroma. The majority (75%) of patients are in the age range 10e40 years and the male/female ratio is 3:2. The most common skeletal location is the proximal humerus (30%) followed by the bones of the hand (20%), proximal and distal femur (15% each) and proximal tibia (5%). It is emphasized that periosteal chondroma is a rare lesion (1% or less of chondromas) but may cause significant diagnostic difficulties by virtue of being very cellular. The lesion is generally less than 5 cm in diameter but sometimes may be larger. The important feature is that the bone cortex subjacent to the lesion is intact and there is no permeative growth at the base (Figure 6). Therefore, it may be necessary to perform an en bloc excision to fully establish the histological diagnosis. Such excision is curative whilst curettage is followed by a high local recurrence rate. The benign neoplasms which show osseous differentiation are surface osteoma of long bones, ivory exostosis and melorheostosis.
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The majority (80%) of cases of surface osteoma of long bones occur in the age range 10e40 years (M:F 2:1). The most common skeletal site is the proximal femur (30%) followed by distal femur (15%), clavicle (15%), bones of the hand (5%) and proximal tibia (5%). The tumours are usually composed of cortical type Haversian bone. Surface osteomas of long bones may be associated with Gardner’s syndrome (although lesions of the mandible and calvarium are more commonly associated). Usually considered to be hamartomatous in nature the lesion does not recur after complete excision and there is no evidence of malignant transformation. The importance of this lesion does, however, lie in its accurate distinction from parosteal osteosarcoma. Ivory osteoma is a benign lesion of flat bones (viz those arising by intra membranous ossification) and usually involves the bones of the skull. It is composed of dense cortical e type bone. Tumours on the external surface of the skull present as a hard painful mass. Tumours on the inner skull table and those protruding into the sinuses have effects depending on their precise location. Melorheostosis is a rare genetic (LMEN3) developmental abnormality originally described in 1922 and of unknown aetiology. Patients may present at any age and there is no sex preference. There is irregular surface cortical thickening of one
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Figure 3 (a) A radiograph of a BPOP lesion of the fourth metatarsal bone and in (b) there is the cross-sectional scan. The lesion is on the bone surface and the cortex is not involved although it is substantially enveloped by the lesion. (c) Demonstrates that the actual physical connection with the cortex can be a narrow isthmus. Above is the anatomical bone and below is the BPOP lesion. The latter is composed of trabecular bone and overlaid with a mixture of cartilage and fibrous tissue in a disorganized arrangement. In superficial biopsies this architectural disarray may be confusing. An awareness of the entity and the absence of cellular atypism facilitates diagnosis.
Figure 4 In (a) there is a typical lobulated cartilage covered osteochondroma. In (b) the lesion has been sliced and a contact radiograph prepared. This illustrates the discontinuity in the cortex due to the osteochondroma with the margins forming cortical ‘shoulders’ and ‘neck’. This also shown histologically in (c). Here the continuity of the marrow space within the tumour and the bone medulla is clearly demonstrated and this is considered a feature of osteochondroma. However this ‘rule’ is not invariate. In (d) the cortex is bifid superiorly with one ‘arm’ continuing across the base of the lesion. This cortical bone is however, well cancellized and there is effective marrow space continuity. In both (c) and (d) the cartilage cap is not excessively thickened although the thickness in (d) is more variable. The cartilage is the neoplastic tissue can, rarely, undergo malignant transformation.
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Figure 5 This illustrates malignant transformation in an osteochondroma of the scapula. The scan (a) shows ‘upswing’ of the flared cortices forming a stalk indicating the original underlying osteochondroma. (b)e(d) show that there is a lobulated cartilage tumour which has not only grown in an exophytic fashion but has also filled the medullary space of the scapula reaching the contralateral endosteal surface with at least superficial erosion of that surface. The ipsilateral cortex is thicker and there is horizontal erosion of the left side.
aspect of a bone such that the macroscopic appearance resembles melted wax which has dripped down the side of a candle. This somewhat fanciful analogy provides the Greek roots (melos e limb; rhein e flow) for the name of this condition.
Melorheostosis can affect the long bones of the upper and lower limbs, hands, feet and sometimes the axial skeleton. Accompanying lesions may be osteopoikilosis and osteopathia striata and tumours or malformations of blood vessels and lymphatics. Limited lesions may clinically and radiologically mimic myositis ossificans, osteoma and parosteal osteosarcoma. Although most sarcomas have been described as arising from periosteum, in clinical practice there are four of importance. 1. Periosteal chondrosarcoma 2. Parosteal osteosarcoma 3. Periosteal (juxtacortical) osteosarcoma and 4. High grade surface osteosarcoma. The majority (70%) of periosteal chondrosarcoma patients are in the age range 20e50 years a somewhat younger age group than conventional chondrosarcoma. The male/female ratio is 3:2. Some 55% of cases involve the proximal femur. Other sites of involvement are the humerus (20%) tibia (10%) and pelvis (10%). Treatment is by complete en bloc excision since the 5year local recurrence-free survival is less in patients treated with intra lesional or marginal excision (25%) than for patients treated with the wide resections (93%). The overall 5-year metastasis e free survival is of the order of 80% although this is influenced adversely by increasing grade. The diagnostic challenges are to distinguish periosteal chondrosarcoma from periosteal chondroma (as stated above) and from periosteal osteosarcoma which usually requires chemotherapy (Figures 7 and 8). Parosteal osteosarcoma is an uncommon (5% of osteosarcomas), usually slowly growing malignant tumour frequently
Figure 6 This is an example of a periosteal chondroma. The important feature is the bone cortex seen inferiorly. It is of uniform thickness and there is no permeation by tumour. The deeply basophilic lobules on the right close to the cortex with a thin band of fibrous tissue between the cartilage and bone and which extends up over the proliferation. Superiorly the cartilage lobules are quite cellular and the matrix more lightly stained. Limited sampling of a periosteal chondroma can produce tissue with worrying cellularity. Understanding the intra periosteal location facilitates accurate diagnosis.
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Figure 7 In this illustration of a periosteal chondrosarcoma. (a) The external surface. Superiorly there is skeletal muscle below which there is fibrous periosteum into which the tumour is pushing. (b) The cellularity to this part of the tumour and the insert shows bi-and trinucleated cells and a degree of nuclear pleomorphism. Deeply however in (c) the tumour has penetrated cortex and is permeating trabecular bone. (d) The cytological features of the tumour in this deep location. Now there is marked cellularity and pleomorphism indicating a high grade of tumour.
Figure 8 (a) A periosteal chondrosarcoma in the distal femur. In the histological preparation more recently proliferated tissue is deeply basophilic and there is superficial erosion and some permeation of the cortex. This is, therefore, a borderline case since the permeation is weak and penetration to the medulla has not occurred. In contrast to the more recently proliferated tissue the cartilage cap is older (paler matrix) and relatively less cellular.
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Figure 9 This is a parosteal osteosarcoma in a classical location e posteriorly in the lower end of femur. The radiographs show dense mineralisation which is a consequence of the relatively slow growth of this tumour. The macroscopic view in (c) has a cartilaginous cap e the pale white tissue. This feature is present in up to 50% of cases.
Figure 10 In (a) and (b) the cartilage cap of a parosteal osteosarcoma is present. (a) Cartilage in low power and its interface with deeper bone forming tissue. In (b) there is a higher power view of the cartilage cap and its limiting external fibrous tissue layer. In (c) are the many trabecular structures typical of this tumour and when mineralized cause the characteristic radiodensity. In (d) the trabecular structures are irregular in outline whilst the intervening neoplastic tissue is cellular.
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Figure 11 (a) Low grade parosteal osteosarcoma with the subjacent cortex (b). In (c) and (d) there has been progression to an intermediate grade. This is manifest as increased cellularity and cellular pleomorphism.
Figure 12 This is the radiograph (a) and macroscopic preparation (b) of a resected periosteal osteosarcoma. The radiograph has a classical ‘sunburst’ image e due to mineralized spicules. In the macroscopic preparation there is no evidence of a penetrative or intramedullary component. The tumour is therefore exclusive to the periosteal surface.
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Figure 13 In (a) the blue (basophilic) zones are the chondroblastic element of this periosteal osteosarcoma. In (b) there is osteosarcoma permeating (superiorly) the bone cortex. In this case penetration of the cortex had occurred and the penetrative tissue was of higher grade (insert).
Figure 14 There had been treatment of this case of high grade surface osteosarcoma with chemotherapy. The effects of this account for the macroscopic appearance (a). In (b)e(d) the neoplastic tissue appears myxoid and hypocellular. However, as showing in (d) viable pleomorphic cells are still present. The high grade surface tumour differs from periosteal osteosarcoma in lacking a significant cartilaginous component and having high grade rather than intermediate grade osteosarcomatous tissue.
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Figure 15 This is an example of a periosteal sarcoma complete lacking in chondroosseous differentiation. In fact the histological features (c and d) are of a leiomyosarcoma e confirmed by positive staining for smooth muscle antigen (SMA). As can be seen in (a and b) the tumour is aggressive and is permeating cortex.
displaying a high degree of histological differentiation. It has a significantly better prognosis than the more usual varieties of osteosarcoma with a low propensity to metastasise. Sixty five per cent of cases are in the 20e40 years age range and the male/ female ratio is 2:3. Some 90% of tumours occur around the knee joint (80% distal femur: 10% proximal tibia). Histologically a typical lesion shows well-formed bone trabecular structures set in a fibrous stroma. Usually the periphery of the tumour is more cellular and the osteoidal material less mature. Nearer the base of the tumour the trabeculae are thicker, more mature and the fibrous component more collagenous. The prognosis is dependent on tumour grade (of the spindle cell component) and adequate local excision. Low grade tumours require en bloc excision and intermediate grade lesions similar excision and possibly chemotherapy. Where there is dedifferentiation or progression to a high grade osteosarcoma then en bloc excision and chemotherapy are required. Some 50% of cases show cartilage differentiation either as cartilage nodules or a cartilaginous cap (Figures 9, 10 & 11). It is important to recognize this when considering the biopsy differential diagnosis of osteochondroma and periosteal osteosarcoma. Periosteal osteosarcoma is rare comprising about 2% of all osteosarcomas. 75% of are between 10 and 40 years old. The male:female ratio is 2:3. The majority of these tumours occur in the femur or tibia and a much smaller number in the humerus (Figure 12). Histologically, at first sight, these tumours are chondrosarcomatous but there is definitionally a minor
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osteosarcomatous component (Figure 13). Grade can vary but it is usually intermediate. Treatment is by wide, en bloc or radical resection usually accompanied by chemotherapy. Prognosis is not as good as parosteal osteosarcomas but better than conventional high-grade intramedullary or surface osteosarcoma. High grade surface osteosarcomas are rare comprising less than 1% of all osteosarcomas and 9% of surface osteosarcomas. By definition they are conventional osteosarcomas arising on the surface of bone and with no intramedullary involvement. The age range is 20e40 years for 70% of cases. The male/female ratio is 2:1. The distal femur is involved in 30%, proximal humerus (20%), and proximal femur (10%). The histological features are identical to conventional intramedullary osteosarcoma and treatment is similarly identical. The overall survival at 5 years is z45%. Marginal excision is associated with increased risk of local recurrence and increasing tumour grade adversely influences prognosis. Wide excision and effective systemic chemotherapy are associated with better outcomes (Figures 14 and 15). A
FURTHER READING Antonescu CR, Huvos AG. Low-grade osteogenic sarcoma arising in medullary and surface osseous locations. Am J Clin Pathol 2000 Nov;(114 suppl); S90e103. Brien EW, Mirra JM, Luck Jr JV. Benign and malignant cartilage tumors of bone and joint: their anatomic and theoretical basis with
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an emphasis on radiology, pathology and clinical biology. II. Juxtacortical cartilage tumors. Skeletal Radiol 1999 Jan; 28: 1e20. Kenan S, Abdelwahab IF, Klein MJ, Hermann G, Lewis MM. Lesions of juxtacortical origin (surface lesions of bone). Skeletal Radiol 1993; 22: 337e57. Miller-Breslow A, Dorfman HD. Dupuytren’s (subungual) exostosis. Am J Surg Pathol 1988 May; 12: 368e78. Oviedo A, Simmons T, Benya E, Gonzalez-Crussi F. Bizarre parosteal osteochondromatous proliferation: case report and review of the literature. Pediatr Dev Pathol 2001 SepeOct; 4: 496e500. Romeo S, Hogendoorn PC, Dei Tos AP. Benign cartilaginous tumors of bone: from morphology to somatic and germ-line genetics. Adv Anat Pathol 2009 Sep; 16: 307e15.
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Cartilaginous surface tumours of bone must be carefully assessed for permeative growth into the cortex e both radiologically and pathologically (e.g. periosteal chondroma versus periosteal chondrosarcoma) Cartilaginous and cartilage-capped surface bone tumours are not always simply chondromatous/chondrosarcomatous e think periosteal osteosarcoma and parosteal osteosarcoma Periosteal osteosarcoma, high grade surface osteosarcoma and progressed (i.e. to higher grade) parosteal osteosarcoma will usually require chemotherapy and the lesion’s response should be assessed histologically
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