Benign Osteoblastic Tumors


Chapter 4

Benign Osteoblastic Tumors


Benign osteoblastic tumors were first recognized as a distinct group by Jaffe and Mayer in 1932.54 The identification of osteoid osteoma as a separate entity came later in a 1935 report by Jaffe.52 Once osteoid osteoma had been established as a diagnostic category, other benign bone-forming lesions were recognized. The term benign osteoblastoma was introduced independently by Jaffe and Lichtenstein in 1956 to delineate a benign osteoblastic tumor that has greater growth potential than osteoid osteoma.53,70,71 Most authors now regard osteoid osteoma and osteoblastoma as separate, though related, entities.44,71 In the majority of cases, fairly consistent differences in size, location, degree of reactive sclerosis, and pain pattern are useful features for selecting the proper diagnostic category.46 However, there are cases with composite features that defy classification. Moreover, a few cases of transition from osteoid osteoma to osteoblastoma have been reported, supporting the concept of a close relationship between these two lesions.16,17,25,122 It is important to realize that osteoid osteomas and osteoblastomas have nearly identical microscopic features and must be distinguished from one another by some means other than microscopy. Several arbitrary but still useful diagnostic criteria have been proposed to resolve this diagnostic dilemma. Maximum diameters for the osteoid osteoma nidus of 1 and 2 cm have been proposed as criteria.110 McLeod et al.81 arbitrarily designated all lesions measuring less than 1 cm in diameter as osteoid osteomas and those larger than 2 cm in diameter as osteoblastomas. These authors also proposed an arbitrary dividing line of 1.5 cm for lesions with composite features.


More recent experience with benign osteoblastic tumors has indicated that some lesions may reach a considerable size, usually exceeding 4 cm in diameter. These lesions have a locally destructive growth pattern and a high recurrence rate after curettage. Although the basic histologic pattern of these tumors is similar to that of conventional osteoblastoma, the presence of so-called epithelioid osteoblasts is their distinct diagnostic feature.1,42,59,60 We have designated these tumors as aggressive osteoblastomas, a term tentatively proposed in 1973.39 The more definitive recognition of aggressive osteoblastoma as an entity was made in a 1984 report by Dorfman and Weiss.42 Such intermediate or borderline osteoblastic lesions have been referred to by a variety of terms, including aggressive osteoblastoma,42 malignant osteoblastoma,110 or even low-grade osteosarcoma.15,78,79,82,84,98 Therefore there are three main categories of benign osteoblastic tumors: osteoid osteoma, benign osteoblastoma, and aggressive osteoblastoma. However, benign osteoblastic tumors represent a continuum of lesions that have different growth potentials and different levels of extrinsic humoral activity. This results in a mosaic of lesions that vary considerably in size and in their ability to induce secondary changes in the adjacent tissue (Fig. 4-1). In such lesions, hemorrhage, secondary reparative changes, and bizarre degenerating nuclei can raise the suspicion of malignancy (“pseudoanaplasia”).9,83



Almost a century after the first conceptual identification of this group of bone forming tumors, relatively little is known about their biology. Cytogenetic studies on a few benign osteoblastic tumors have demonstrated clonal chromosomal alterations involving 22q in osteoid osteoma, benign osteoblastoma, and aggressive osteoblastoma.11,34 A single cytogenetic report on an aggressive osteoblastoma showed a distinct pseudodiploid clone with balanced translocations involving chromosomes 4, 7, and 14.10 The study of alterations in cell cycle regulator genes such as mutations in the TP53 and RAS genes, loss of heterozygosity at the p53, p16, and Rb-locus, and amplification of the MDM2 gene and the c-myc gene, as indicators of graded genetic instability in borderline osteoblastic tumors, may prove useful in their differential diagnosis.100 A recent study of genomic aberrations in several osteoblastomas and two examples of aggressive osteoblastoma disclosed multiple chromosomal rearrangements in aggressive osteoblastomas.93 Moreover, deletions of 22q were seen in several conventional osteoblastomas and in aggressive osteoblastomas, confirming the relationship between these two entities. The chromosomal alterations, especially those involving 22q, involve the genes controlling osteogenesis and are implicated to have a role in the development of several solid and hematopoietic malignancies. The genomic alterations point toward the involvement of MN1 and NF2 as well as ZNRF3 and KREMEN1, known inhibitors of the Wnt/beta-catenin signaling pathway. In line with these observations increased levels of beta-catenin were detected in osteoblastomas.93



Osteoid Osteoma


Definition


Osteoid osteoma is a benign tumor that consists of a well-demarcated osteoblastic mass called a nidus that is surrounded by a distinct zone of reactive bone sclerosis. The zone of sclerosis is not an integral part of the tumor and represents a secondary reversible change that gradually disappears after removal of the nidus. This zone should be specifically excluded in taking measurements of these lesions. The nidus tissue has a limited local growth potential and usually is less than 1 cm in diameter.



Incidence and Location


Osteoid osteomas are common lesions that account for about 10% to 12% of all benign bone tumors. They usually occur in teenagers and young adults. The male/female sex ratio is approximately 2 : 1. Familial occurrence has been reported rarely.55 More than 80% of patients are between age 5 and 25 years, and the peak incidence is in the second decade of life. About 50% of all osteoid osteomas occur in the long bones of the lower extremities, and the femoral neck is the single most frequent anatomic site. In the long bones, osteoid osteoma is usually located near the end of the shaft. Osteoid osteoma occurs less frequently in the long bones of the upper extremities, and the bones of the elbow are the most frequent anatomic site in the upper extremity. Osteoid osteomas are often present in the small bones of the hands and feet. They occur rarely in the axial skeleton but if present are usually found in the lumbar portion of the spine. In vertebrae, they are nearly exclusively located in the posterior arch. The primary location in the vertebral body is very rare. Osteoid osteomas occur very rarely in flat bones and almost never in craniofacial bones.13,36,110 The peak age incidence and the most frequent sites of skeletal involvement are shown in Figure 4-2. The skeletal and age distribution patterns of individual osteoid osteomas are shown in Figure 4-3.





Clinical Symptoms


Osteoid osteoma is associated with characteristic and quite often virtually diagnostic symptoms. The most frequently reported symptom is pain of increasing severity that is relieved by aspirin and other nonsteroidal anti-inflammatory agents. The typical clinical symptoms occur in approximately 80% of patients.5,13,48 The pain is frequently worse at night and is sometimes referred to the nearest joint. If the tumor is located in the proximity of a joint, the patient may have symptoms of arthritis. If the involved bone is superficial, painful swelling of the adjacent soft tissue may be present. This often occurs in the small bones of the hands and feet, where osteoid osteoma can be clinically mistaken for an inflammatory process. With vertebral involvement, there is often an associated painful scoliosis that results from a unilateral spasticity of spinal muscles. Some patients with vertebral lesions may have clinical symptoms suggestive of a neurologic disorder, lumbar disk disease, or both.8,62 Lesions of the extremities in young patients with open growth plates may produce significant length discrepancy, caused by the increased growth rate of the affected bone.95 In neglected cases, the patient may have severe dysfunction of the extremity and muscle atrophy. Some degree of muscle atrophy is present in nearly 20% of cases.


In the past, the presence of nerves within the nidus, documented by the axonal silver stain and electron microscopy, was thought to be the cause of the patient’s pain.113 More recently, high levels of prostaglandin E2 and prostacyclin have been found directly in the nidus tissue and its explants incubated in vitro.47,76,130 Large amounts of prostaglandin E2 and prostacyclin released from the nidus have since been implicated as being responsible for reactive sclerosis, nonspecific inflammatory changes of soft tissue, and pain in osteoid osteomas.47 Moreover, it has been documented that the urinary excretion rate of the major metabolite of prostacyclin (i.e., 2,3-dinor-6-keto-prostaglandin F) is significantly higher in patients with osteoid osteoma and returns to normal after the nidus is removed.30 Recent studies on the expression of the cyclooxygenases (COX-1 and COX-2), which were thought to be the source of the excess prostaglandins in osteoid osteomas, have shown that COX-2 is one of the main mediators of pain and inflammatory effects on surrounding tissues, including adjacent synovium.57,87



Radiographic Imaging


The radiographic features of osteoid osteoma are characteristic and diagnostic. Conventional radiographs reveal a well-demarcated lytic lesion (nidus) surrounded by a distinct zone of sclerosis. A zone of central opacity that represents a more sclerotic portion of the nidus and is surrounded by a lucent halo may be present within the nidus. The intracortical lesions of long bones produce extensive fusiform thickening of the cortex with dense radiopacity that sometimes obscures the nidus (Figs. 4-4 and 4-5). In such instances the nidus may not be visible on conventional radiographs, so additional imaging techniques, such as computed tomography, radioisotope scanning, and magnetic resonance imaging, may be necessary to document the lesion.18,49,50,75,123,129 Occasionally, several distinct foci of osteoid osteoma occur at the same anatomic site, giving the appearance of a multifocal nidus.7 The tumors may exhibit different levels of matrix mineralization and may have different degrees of radiographic density and scintigraphic activity.48 The adjacent periosteal reaction sometimes mimics a stress fracture. The intramedullary lesion and the lesion located in cancellous bone produce less distinctive sclerosis. However, such lesions may provoke a multilaminar, exuberant periosteal reaction that may involve long segments of the diaphysis (Fig. 4-5). Minimal or absent perilesional sclerosis is also a common feature of osteoid osteomas that are located near the end of bone (juxtaarticular) and in subperiosteal lesions. In vertebral locations, conventional radiographs show increased density of the pedicle, loss of a distinct contour, or both features. In vertebrae the nidus is often not seen on conventional radiographs. Exact anatomic localization of the nidus usually requires computed tomography (Figs. 4-6 and 4-7). Most frequently, the nidus is present in the area of the posterior arch or at the base of a pedicle. In very unusual instances, it is present within the transverse or spinous process.







Gross Findings


The nidus tissue, when examined intact in its anatomic setting, appears as a distinct oval or round, reddish area that can be easily separated from its bed (Fig. 4-8). This tissue varies in consistency from friable, soft, and granular to densely sclerotic. The central portion of the nidus is sometimes more sclerotic than its periphery. The nidus is usually surrounded by a large zone of dense sclerotic bone (Fig. 4-8). The surrounding sclerotic bone may be minimal or even completely absent. The nidus is rarely surrounded by normal cancellous bone with no evidence of sclerosis. Sometimes, it may be difficult to identify the nidus grossly, particularly in sclerotic intracortical lesions. Preoperative tetracycline labeling is therefore of great assistance because the nidus tissue stands out from the reactive bone when it is examined under ultraviolet light.6,68 Intraoperative scintillation probes after the administration of a radioisotope may be used to confirm identification.64,68,96,124




Microscopic Findings


At low magnification the nidus consists of an interlacing network of bone trabeculae with different levels of mineralization (Figs. 4-9 to 4-11). The trabeculae are usually thin and uniformly distributed in loose stromal vascular connective tissue. The size, thickness, and mineralization of the trabeculae can vary considerably in different lesions (Figs. 4-9 to 4-13). The trabeculae also may vary in different areas of the same nidus (Fig. 4-9). The entire nidus may be composed of densely sclerotic bone tissue with a disordered (pagetoid) pattern of cement lines. Prominent osteoblasts rim the osteoid trabeculae and are accompanied by numerous osteoclast-like, multinucleated giant cells. The nidus may have a clearly recognizable zonal architecture with a more completely ossified central portion (Fig. 4-9). The central portion, which is heavily ossified, is usually less cellular compared with the less mineralized and highly cellular peripheral zone. As a rule, cartilage is not an integral component of the nidus and should not be present in typical osteoid osteoma. In some exceptional cases, however, small foci of clearly recognizable cartilage with occasional myxoid features may be present within the nidus (Fig. 4-14).








The bone surrounding the nidus may be cancellous with thickened trabeculae and stroma consisting of rich vascular connective tissue and rarely small foci of mononuclear inflammatory cell infiltrate. Prominent large blood vessels may be present in the connective tissue surrounding the nidus and within enlarged haversian canals in the surrounding densely sclerotic cortical bone (Fig. 4-15). The adjacent synovium may be thickened, with prominent chronic inflammatory cell infiltrates that have lymphofollicular features. The changes in the synovial membrane occasionally simulate rheumatoid arthritis (Fig. 4-20). Special techniques such as immunohistochemistry and ultrastructural investigations are practically never used in the diagnosis of osteoid osteoma.3,120,121 Osteoid osteomas express master regulatory proteins involved in skeletal development, such as Runx2 and Osterix, confirming the osteoblastic nature of the lesion.36




Differential Diagnosis


Osteoid osteoma should be differentiated from chronic and acute osteomyelitis, bone abscess, intracortical hemangioma, bone island, stress fracture, Ewing’s sarcoma, and intracortical osteosarcoma. This long list of diverse entities indicates that in some instances the differential diagnosis of this well-known lesion can be very complex and difficult.


Radiographically and clinically, osteoid osteoma can be confused with inflammatory conditions, such as bone abscess and osteomyelitis of acute or chronic sclerosing types. This problem is most evident in osteoid osteomas affecting the small bones of the hands and feet. In juxtaarticular locations, monoarticular rheumatoid arthritis can be simulated microscopically and radiographically because of the associated prominent lymphoproliferative synovitis. In each of these cases, histologic identification of the nidus tissue disposes of the diagnostic difficulty.


Lesions that present as intracortical lucencies resembling osteoid osteoma include abscesses, hemangiomas and, in very unusual circumstances, intracortical osteosarcomas. In all these entities, positive findings on bone scans can be anticipated; therefore bone scans are of limited diagnostic usefulness in discriminating between osteoid osteoma and the other lesions. In most cases, enostoses, or small bone islands, can be separated from osteoid osteomas by the absence of clinical symptoms, lack of perilesional sclerosis, and usually negative bone isotope scans.


Periosteal new bone formation associated with osteoid osteomas can simulate stress fractures and even avulsion injuries on radiographs when the nidus is not clearly discernible on plain films.


Exuberant periosteal reactions also can mimic Ewing’s sarcoma or acute osteomyelitis on plain radiographs. This problem may be accentuated by the associated prominent swelling of surrounding soft tissue.


Rarely, accessory growth centers can be confused radiologically with osteoid osteoma. Such growth centers are most likely to occur in tarsal or carpal bones.


The histologic appearance of osteoid osteoma nidus tissue is usually so distinctive that differential diagnostic problems on this level rarely occur. However, when taken out of clinical and radiologic context, it can be confused with osteosarcoma. Reactive new bone formation usually can be distinguished by its parallel or radially oriented bone trabeculae, which often show gradual peripheral maturation to lamellar bone. These can be easily distinguished from the random disorderly pattern of osteoid and woven bone trabeculae in nidus tissue. In curetted material, sclerotic nidus tissue may present special problems in microscopic recognition.



Treatment and Behavior


Osteoid osteomas have limited growth potential and rarely exceed 1 cm. The majority of lesions are about 0.5 cm in diameter. Some tumors may even spontaneously regress.51,116 The primary treatment is surgical removal of the nidus and some of the surrounding bone by en bloc excision after precise localization of the nidus.99,128 Curettage with bone grafting is an acceptable modality of treatment in anatomic sites where en bloc excision cannot be performed. However, this approach is generally discouraged because of the risk of incomplete removal of the nidus and recurrence of symptoms. Recurrence may occasionally happen many years after removal of the primary lesion.103 In some cases, no nidus tissue can be found in the resected specimen. According to Mayo Clinic data, this occurs in nearly 20% of patients with osteoid osteomas that have a radiologically documented nidus.117 It is important to consider whether the lesion was missed at surgery or the pathologist failed to identify it. The persistence of symptoms suggests that the nidus was not removed. Such patients need reevaluation and further surgery if there is evidence of a nidus. The nidus tissue can be found in a relatively high proportion of patients who undergo further surgery.117 Still, in some patients whose symptoms are relieved, no nidus tissue or other abnormality can be documented in the resected specimen other than bone sclerosis.


Although en bloc excision is the preferred treatment, in some cases a lesion may be inaccessible to the surgeon. In such instances, its complete removal may cause more disability than that associated with the original disease. Some of these patients can be managed with prolonged treatment with nonsteroidal anti-inflammatory drugs. As reported by Kneisl and Simon,65 prolonged anti-inflammatory treatment (30-40 months) can induce permanent relief of symptoms, and regression of the nidus may be seen on radiographs. Ablation of the nidus with a percutaneously placed radiofrequency electrode that produces thermocoagulation has become widely accepted. This technique may be of value in anatomic sites where it is difficult to surgically remove the tumor.4,5,20,22,31,80,81,106,107 Osteoid osteomas of the vertebrae present special problems with this type of treatment because of the risk of nerve root damage, but to date, a number of tumors at this site have been treated successfully without nerve root or spinal cord injury. Reported success rates for treatment by thermocoagulation with radiofrequency electrodes have ranged between 80% and 90% (no need for additional procedures or medications for 2 years). A needle biopsy guided by computed tomography should be performed before introducing the electrode with percutaneous thermocoagulation therapy of osteoid osteomas, because other intracortical or subperiosteal lesions can mimic their radiologic appearance. Among these are intracortical abscess and intracortical chondroma.



Osteoid Osteoma in Different Anatomic Sites


The microscopic appearance of nidus tissue in osteoid osteoma is identical regardless of the anatomic location. There is no correlation between the pain pattern and the degree of associated bone sclerosis. In different anatomic sites and age groups, osteoid osteomas may induce quite distinct secondary changes in the adjacent bone and soft tissue that lead to various diagnostic and therapeutic dilemmas. Therefore it is important from both the pathologic and the clinical points of view to discuss osteoid osteoma separately in three major anatomic locations: long tubular bones, small bones of the hands and feet, and the vertebral column. In addition, there are separate descriptions of subperiosteal and juxtaarticular lesions because of their distinct clinicoradiologic and pathologic features.



Osteoid Osteoma of Long Tubular Bones


Osteoid osteomas that occur in long tubular bones are most often found within the proximal or distal portions of the bone shafts (Fig. 4-16). Approximately 50% of cases are diagnosed in the lower extremities; the femoral neck is the single most frequent anatomic site. The tibia is the second most frequently involved long tubular bone; fibular lesions are very rare. In the upper extremities, the humerus is the most frequently involved bone, and a majority of cases occur around the elbow joint.108 Involvement of the distal ulna and radius is very rare. Radiographically, the intracortical lesions of long bones are usually associated with distinct fusiform cortical thickening that is sometimes accompanied by periosteal reaction. Occasionally, the periosteal reaction can be very exuberant, with multiple layers of new bone formation. The exuberant periosteal reaction can mimic that seen in stress fracture or that associated with Ewing’s sarcoma (Figs. 4-5 and 4-16). The intramedullary lesions usually produce less surrounding sclerosis. The absence of distinct sclerosis around the intramedullary nidus is probably related to its distant location from labile periosteum. A rare complication of osteoid osteoma of long tubular bones is localized overgrowth of bone, angular deformity, or both95 (Fig. 4-17). These complications typically happen in very young patients whose symptoms begin before age 5 years. Long-standing hyperemia induced by prostaglandins is probably a factor in accelerated growth of bone in osteoid osteoma. The resulting bone deformity and discrepancy in limb length may disappear after excision of the nidus. In some patients, however, the deformity and length discrepancy never completely resolve. This is particularly true in cases of many years’ duration.95





Osteoid Osteoma of Small Bones of Hands and Feet


In our mainly consultation series of osteoid osteomas, slightly more than 20% of osteoid osteomas occur in the small bones of the hands and feet, with tumors occurring twice as frequently in the hands as in the feet. In the hands, the phalanges are the most frequently involved sites.23,88 In small bones, the nidus is usually surrounded by a distinct zone of sclerosis. The bone contour can be expanded, and the entire bone can be markedly enlarged. Osteoid osteomas of small peripheral bones are almost always associated with a distinct swelling of soft tissue and synovitis of the adjacent joints. Therefore in this location, long delays in arriving at the correct diagnosis may occur because the tumor may frequently mimic an inflammatory process.26 Thus it is not unusual for patients with osteoid osteoma of the hands and feet to be treated initially for chronic osteomyelitis or other inflammatory conditions (Fig. 4-18).


May 31, 2017 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Benign Osteoblastic Tumors
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