Chapter 21

Sclerosing Bone Lesions

Sclerosing bone lesions represent a unique group of dysplastic anomalies with a wide range of clinical presentations, radiographic characteristics, and genetic backgrounds.⁷ They can be separated into two major groups with hereditary and nonhereditary clinical presentations.³ A comprehensive description of all conditions included in the group is beyond the scope of this book. In this chapter, we describe some of these conditions that may occasionally simulate a neoplasm and may require microscopic examination to confirm the diagnosis or to rule out a neoplastic process.

In the radiologic literature, these conditions are grouped into two major categories: those associated with abnormal enchondral ossification and those primarily affecting the sites of membranous bone formation. It is generally accepted that the common feature of the conditions described in this chapter is that they all arise from defects in bone resorption or formation during the process of skeletal development, maturation, and remodeling.¹^,⁵^,⁸^,¹⁰ Sometimes several such conditions can coexist, resulting in the so-called overlapping dysplastic syndromes, which further supports the concept of their unified pathogenesis.⁵^,⁶^,⁹ An abbreviated list of sclerosing bone dysplasias classified on the basis of the so-called target-site approach originally proposed by Norman and Greenspan⁵^,¹⁰ (i.e., specific phase, site of skeletal development affected, or both) is provided in Table 21-1. A summary of clinical presentations, radiographic characteristics, and genetic alterations implicated in the development of hereditary bone dysplasia is provided in Table 21-2.⁷

TABLE 21-2

Summary of the Hereditary Sclerosing Bone Dysplasias

Dysplasia	Inheritance Pattern	Genetics	Type of Dysplasia	Age at Onset	Osseous Findings	Other Findings
Osteopetrosis	AR, AD	TCIRG1 (ATP6i), CLCN7, GL (OSTM1), RANKL, CA2, PLEKHM1	Endochondral (primary spongiosa)	Stillbirth or infancy to adulthood	Diffusely increased bone density; type 1: uniform sclerosis of the skull, spine, and long bones; type 2: endobone appearance	Anemia, cranial nerve deficits (rare with AD inheritance pattern)
Pyknodysostosis	AR	Cathepsin K	Endochondral (primary spongiosa)	Infancy or early childhood	Hyperostosis of long bones with preserved medullary cavities	Dwarfiism, acro-osteolysis, wormian bones
Osteopoikilosis	AD	LEMD3	Endochondral (secondary spongiosa)	Childhood or adulthood	Multiple enostoses	Dermatofibrosis lenticularis disseminate
Osteopathia striata	X linked	Unknown	Endochondral (secondary spongiosa)	Childhood or adulthood (incidental finding)	Dense striations in metadiaphyses of long bones	No other associated abnormalities
Progressive diaphyseal dysplasia	AD	LAP of TGFB1	Intramembranous ossification	Childhood	Bilateral/symmetric periosteal and endosteal cortical thickening involving long bones or calvaria	Gait disturbances, pain, weakness
Hereditary multiple diaphyseal sclerosis	AR	Unknown	Intramembranous ossification	After puberty	Unilateral/asymmetric cortical thickening involving long bones only	Milder neuromuscular symptoms than with progressive diaphyseal dysplasia
Hyperostosis corticalis generalisata	AR (Van Buchem disease, sclerosteosis), AD (Worth disease)	SOST (Wnt signaling pathway), LRP5 (Wnt signaling pathway)	Intramembranous ossification	Childhood	Endosteal cortical thickening involving the long bones, skull, and facial bones; mandible enlargement	Van Buchem disease: facial nerve palsy; sclerosteosis: facial nerve palsy, syndactyly, bone overgrowth; Worth disease: no cranial nerve palsy, torus palatinus

Osteoma and Bone Island

Several benign, slow-growing bony lesions are identified under the general heading of osteoma (Fig. 21-1). They can be divided into (1) calvarial and mandibular ivory exostoses; (2) osteomas of the paranasal sinuses, facial bones, and orbit (sino-orbital osteomas); (3) enostoses or bone islands; and (4) surface (juxtacortical) osteomas of long bones.

FIGURE 21-1 Clinicopathologic variants of osteoma. Lesions classified microscopically as osteomas can be separated into several distinct clinicopathologic variants; ivory exostosis, sinoorbital osteoma, bone island, and surface osteoma of long bones.

Some authors consider these lesions to be hamartomatous or dysplastic in nature, but there is a rationale for regarding those that affect the orbit, facial bones, and paranasal sinuses (sinoorbital osteoma) as benign bone-forming tumors.

Ivory Exostosis

Ivory exostoses represent a type of osteoma that affects bones formed by membranous ossification, chiefly affecting calvarial and mandibular surfaces ²^,⁴^,⁶^,¹⁰^–¹²^,²⁰^,²²^,²⁸ (Fig. 21-2). Multiple osteomas of this type are frequently associated with colonic polyposis and fibrous soft tissue tumors, including mesenteric fibromatosis and epidermal inclusion cysts in the familial disorder known as Gardner’s syndrome.¹³^,¹⁴^,¹⁷^,²⁴^,²⁹ Some patients also had distinct hyperplastic changes of the retinal pigmented epithelium.²²^,³²^,³³ The development of ocular lesions may precede the development of colonic and osseous manifestations. The polyps of the gastrointestinal tract are adenomatous and typically involve the colon but can also be present in the duodenum and stomach. The adenomatous polyps of the gastrointestinal tract have a high propensity for malignant transformation. In fact, colon cancer develops in all affected individuals unless prophylactic colectomy is performed.²³ The disorder is transmitted by an autosomal dominant pattern of inheritance. Similar to other major familial colonic polyposis syndromes, such as flat adenoma and Turcot’s syndrome (colorectal polyposis with brain tumor), Gardner’s syndrome is linked to a malfunctioning adenomatous polyposis coli (APC) gene mapped to chromosome 5q21.²⁶ Mutations involving different regions of APC are associated with the severity of the clinical syndrome and the extent of extracolonic manifestations. It has been shown that mutations involving the 38 end around codon 1444 of the APC gene are associated with particularly severe osseous manifestations.¹⁶ Patients with this type of APC alteration also have a higher incidence of soft tissue fibromatosis. The soft tissue fibrous lesions range from aggressive fibromatosis at one end of the spectrum to a lesion which is histologically similar to nuchal-type fibroma.¹⁵^,¹⁹^,²⁷ These fibromas of low cellularity have been designated as Gardner fibromas, and their significance as early indicators of the development of other manifestations of Gardner’s syndrome such as desmoid-type fibromatosis has been proposed.¹⁵^,³⁴ Unlike typical nuchal-type fibromas, which most often affect patients in the third through fifth decades of life, Gardner-associated fibromas arise in younger patients and the majority of them present in the first decade of life. The most common location is in the back and paraspinal region followed by the head and neck and extremities. Immunohistochemically, these lesions stain positively for CD34 and CD99. Many of these lesions show positive nuclear immune-reactivity for β-catenin.¹⁵^,¹⁹ Approximately 50% of patients with Gardner-associated fibromas eventually develop a desmoid-type fibromatosis at the same site. Overall, 10% to 15% of patients with Gardner’s syndrome develop aggressive desmoid-type fibromatosis. They typically develop intraabdominally spontaneously or more often after surgery. Similar to Gardner-associated fibromas, desmoid fibromatoses associated with this syndrome harbor the inactivating mutations of the APC gene. However, similar to sporadic fibromatoses, they are positive immunohistochemically for nuclear β-catenin.¹⁵^,¹⁹ In addition to osteomas, which are often multiple, dental malformation or more diffuse sclerotic changes in the craniofacial region may develop in patients with Gardner’s syndrome.²⁵ Osteomas in Gardner’s syndrome may increase in size over time; that is, progressively more severe malformation of the craniofacial bones may develop.³¹ Osseous lesions in Gardner’s syndrome do not behave as true neoplasms, and there is no evidence of their evolution into malignant lesions. Moreover, the presence of osteoblastoma-like areas, predominantly seen in sporadic sinoorbital osteomas, is not a feature of osseous lesions in Gardner’s syndrome.

Microscopically, ivory exostoses are button-like excrescences of mature lamellar bone limited to the cortical surfaces and usually continuous with the outer table of the skull or the mandibular cortex. The dense cortical lamellar bone making up these exostoses contains osteons with haversian canals. Rare cases of compact surface osteoma have been reported in other flat bones as well as on long bones.⁴⁴

Sinoorbital Osteoma

Osteomas involving paranasal sinuses, orbit, and facial bones tend to project into the sinus cavity from a broad attachment to the affected bone (Figs. 21-3 and 21-4).²¹^,³³^,³⁴^,³⁶^,³⁹^,⁴¹^,⁴²^,⁴⁵^,⁴⁶ Some osteomas involving this region, especially those that are multifocal, are associated with Gardner’s syndrome. Microscopically, they are indistinguishable from ivory exostosis. In contrast, the so-called sporadic sinoorbital osteomas (not associated with Gardner’s syndrome) are usually composed of dense, immature bone and may have osteoblastic rimming as well as signs of bone resorption (Fig. 21-5). These lesions may contain central or peripheral foci of spongy or cancellous appearance (Figs. 21-6 and 21-7). Sometimes the latter areas show active remodeling, with cellular fibrous tissue filling the interstices, osteoblastic activity, and osteoclastic resorption.³³ In ethmoid and frontal sinus osteomas, these lesions may occasionally contain radiolucent areas that are histologically indistinguishable from conventional osteoblastoma and even aggressive osteoblastoma (Fig. 21-8).³⁸^,⁴⁰^,⁴⁷ The latter cases sometimes resemble multifocal osteoblastomas arising within osteomas. The clinical behavior of these lesions is similar to that seen in osteoblastomas and aggressive osteoblastoma groups; that is, they exhibit a local destructive growth pattern and recurrences. For this reason, we prefer to regard the sporadic osteomas that arise in the orbit, paranasal sinuses, and facial bones, especially those that contain osteoblastoma-like foci or features of active bone production and remodeling, as benign bone-forming neoplasms rather than as hamartomas or dysplasias. Osteomas in this region typically do not exceed 2 cm in diameter. Occasionally, they attain a larger size (giant osteoma) that compresses adjacent structures and cause a disfiguring deformity.²⁸^,³⁵^,³⁷^,⁴³