Lytic Bone Lesions

Etiology

The etiology of bone tumors varies greatly. They can be congenital, developmental, secondary to metabolic disorders and other primary bone tumors, or metastasis of primary elsewhere. For example, fibrous dysplasia arises from sporadic mutation of alpha-subunit Gs stimulatory protein leading to inappropriate overproduction of cyclic-adenosine monophosphate (c-AMP)[4]. This causes the replacement of normal bone formation with fibrous stroma and islands of immature woven bone.

Epidemiology

Benign tumors and tumor-like lesions constitute about 79.3% of cases of all musculoskeletal lesions and show a slight female predominance. However malignant tumors constitute only 20.7% of lesions and show a male predominance.[5] The most common benign bone lesions are osteochondroma, enchondroma, and simple bone cysts. Benign bone tumors are more prevalent than malignant bone tumors in the younger age group.[6] Malignant bone tumors, mainly metastasis and myeloma, are more common in the older age group, especially in those older than 40 years of age.

Pathophysiology

Imaging characteristics to narrow the differential diagnosis of lesions:

Periosteal reaction: Periosteal reaction or periostitis is a non-specific radiographic finding that occurs due to irritation caused by an underlying bone tumor, either benign or malignant. The periosteal reaction is classifiable into continuous versus interrupted, single versus multiple layers, and benign versus aggressive forms.

Benign periosteal reaction: Chronic low-grade irritation allows the periosteum to lay down thick, wavy, and uniform calluses, resulting in a solid periosteal reaction. Fracture healing, osteoid osteoma, and chronic osteomyelitis can all lead to a solid periosteal reaction.

Aggressive periosteal reaction: This results when there is not enough time for the periosteum to lay down and consolidate the bone formation. The cortex appears multilayered, lamellated, amorphous, or spiculated (sunburst); sometimes, there is Codman's periosteal reaction. A malignant lesion like osteosarcoma causes interrupted periosteal reaction and Codman's triangle. Ewing's sarcoma causes lamellated and interrupted periosteal reaction. The aggressive periosteal reaction can be present in benign lesions like infection, eosinophilic granuloma, ABC, osteoid osteoma, trauma, and hemophilia.

Zone of transition: A zone of transition can help differentiate benign versus malignant lesions. A narrow zone of transition results in a sharp well-circumscribed border and is a sign of poor biological activity. However, in patients more than 40 years of age, despite benign radiographic appearances metastasis and myeloma should be considered in differentials. A wide zone of transition results in an ill-defined or imperceptible border is a sign of high biological activity or aggressive growth and is a feature of malignant bone tumors. However, two benign bone lesions that may show similar aggressive features are infection and eosinophilic granuloma. The permeative or moth-eaten appearance of bone appears as multiple endosteal lucent lesions with a poor zone of transition; this is due to bone marrow involvement. They can present in multiple myeloma, lymphoma, infections and, eosinophilic granuloma.

Cortical destruction: Cortical destruction is a frequent finding in bone lesions. However, it is not very useful in differentiating benign versus malignant lesions. Complete cortical destruction may be present in high-grade malignant lesions like osteosarcoma and Ewing sarcoma and also in locally aggressive benign lesions. Ballooning is a particular type of cortical destruction that involves the destruction of the inner cortex and new bone formation outside the cortex at the same time. This is seen in giant cell tumors (locally aggressive expansile lesion with cortical destruction, a wide zone of transition, interrupted new bone formation peripherally) and in the case of chondromyxoid fibroma (well-defined, expansile lesion with regular destruction of the cortex and uninterrupted new bone formation). A group of small cell tumors involving marrow like Ewing, lymphoma, and small cell osteosarcoma can spread along entire Haversian canals without cortical destruction.

Matrix: Calcification or matrix mineralization are essential features to differentiate bone tumors. There are 2 types of matrix mineralization. The chondroid matrix is present in cartilaginous tumors like enchondroma, chondroblastoma, and chondrosarcoma and presents as a ring and arc, floccular, stippled, or popcorn-like. Osteoid tumors demonstrate the osteoid matrix. There is a trabecular ossification pattern in the case of an osteoid matrix and cloud-like bone formation in the case of osteosarcoma.

Location: Bone tumors are described according to their location in the skeleton (axial, appendicular, and flat bones), part of the bone (epiphysis, metaphysis, and diaphysis), and site of bone (centric, eccentric, or juxtacortical).

Age: Age is among the most vital criteria for possible differentials. Multiple myeloma and metastasis must always be considered differentials in those who are 40 and older.

History and Physical

Relevant clinical history and physical examination are the initial and most important steps in bone tumor evaluation. The patient may present with pain, mass, or incidental radiographic findings in radiographs taken for some other purpose. Benign bone lesions are mostly asymptomatic. They are often incidentally diagnosed on imaging. They may present with pain. Pain may be initially activity-related or due to periostitis. Periostitis is the reaction of bone adjacent to the lesion; they are present in most bone tumors. Benign lytic bone lesions showing no periostitis or pain need separate mention: fibrous dysplasia, enchondroma, non-ossifying fibroma, and solitary bone cyst. In the case of malignant bone tumors like primary or metastasis pain may be persistent, unrelated to activity due to the involvement of neurovascular structures. Soft tissue tumors often present as a mass except for nerve sheath tumors which present as pain.

Although some bone tumors show a sex predilection, like ABC and GCT, are more common in females, this rarely makes any difference in the diagnosis and management of tumors.[7] Family history can occasionally be helpful, as with multiple enchondromas (autosomal dominant) and bone dysplasia in neurofibromatosis (autosomal dominant).[8] Most benign and malignant bone tumors are known to occur in specific age groups, making age one of the most important information in guiding the differentials. Some bone lesions can be multiple like fibrous dysplasia, eosinophilic granuloma, enchondroma, metastasis, and myeloma, hyperparathyroidism, hemangiomas, and infection. Specific syndromes can cause bone lesions like fibrous dysplasia in McCune-Albright syndrome and Mazabraud syndrome. The physical examination should include a general examination which includes the overall health of the patient, any other abnormality or findings other than the region of interest like cafe-au-lait spots in the skin must be noted. Specific examination of the region interest which includes inspection, palpation, change with mobility, inspection of adjacent structures, and other relevant examinations.

Evaluation

Different imaging techniques are pivotal in diagnosing bone tumors. Radiograph comprises the initial and one of the most important diagnostic modalities. Often radiographic findings and the patient's age are sufficient to arrive at a diagnosis. The radiographic examination begins with locating the site of the lesion (epiphyseal, metaphyseal, or diaphyseal). An epiphyseal lesion in an unfused physis is likely chondroblastoma whereas that in a fused physis is likely a giant cell tumor.[9] The differential diagnosis of diaphyseal lesions includes fibrous dysplasia, osteoblastoma, histiocytosis, osteomyelitis, and others. In younger patients with vertebral body lesions, the most likely diagnosis is histiocytosis, whereas the lesions involving posterior elements of the spine may have ABC, Osteoblastoma, and Tuberculosis as differentials. However in patients older than 40 years, while dealing with posterior element lesions, metastasis must always be kept in mind. Similarly, the aggressiveness of the lesion and whether it is benign or malignant can be a radiographic determination. Less aggressive lesions often are well-marginated with a surrounding sclerotic rim. More aggressive lesions usually have an ill-defined margin with no clear sclerotic rim because the host bone response is slower than the growth of the tumor. Cortical expansion may be visible in aggressive benign lesions like ABC, but the cortical break is a feature in malignant lesions like osteosarcoma. Often, bone lesion replaces the normal trabecular pattern of a bone matrix with the chondroid or osteoid matrix. A typical cartilaginous matrix shows stippled calcification as in enchondroma or chondrosarcoma. Osteoid matrix with bone destruction is present in osteosarcoma, while disorganized osteoid formation in collagenous stroma gives the ground glass appearance seen in fibrous dysplasia. Periostitis or reactive new bone formation occurs when the tumor irritates the cortex. The periosteal reaction can be benign or aggressive like Codman's triangle or onion skinning in malignant tumors. A plain radiograph is less helpful in soft tissue tumors; however, it may give some useful information like phleboliths in hemangioma.

Computed tomography (CT) is less useful in the diagnosis of benign bone tumors as compared to that of malignant bone tumors[10]. However, CT helps assess calcification, ossification, and integrity of the cortex. This helps to localize nidus in osteoid osteoma, thin rim of reactive sclerosis in ABC and for malignant tumors, it helps assess cortical breach, soft tissue involvement, and extent of tumor involvement for surgical planning. Saggital and coronal reconstruction images help in delineating the extent of the tumor in three planes and assist in surgical planning. CT of the lungs helps in ruling out lung metastasis in case of malignancy. MRI helps in better soft tissue imaging, differentiating certain benign bone cysts like unicameral and aneurysmal bone cysts. In malignant bone tumors, they assist in evaluating the extent of marrow involvement and skip lesions, for surgical planning. Technetium bone scans are used to determine active bone lesions and to rule out bone metastasis. However, a bone scan may be positive in specific active benign lesions, and it may be falsely negative in multiple myeloma[11]. However, most of the time a normal bone scan is reassuring. Positron emission tomography (PET) records the whole-body distribution of positron-emitting radioisotopes. In musculoskeletal tumors, PET is useful in staging, biopsy planning, response to chemotherapy, detecting recurrence, and follow-up imaging. Ultrasonography is useful for differentiating solid from cystic bone lesions and better imaging of soft tissue lesions.

Blood and urine tests may be helpful in selected clinical situations. The complete blood count may help predict wound healing following surgery and rule out any infection or leukemia. Erythrocyte sedimentation rate (ESR) may show as elevated in infection, metastatic carcinoma, and leukemia. Elevated prostate-specific antigen (PSA) is often present in prostate cancer metastasis. Hypercalcemia is a presenting feature in certain malignancies and hyperparathyroidism. Biopsy should be the last step after the complete evaluation of musculoskeletal tumors for the site of the lesion, the behavior of the tumor, and the extent of resectability. Type of biopsy, placement of biopsy incision, and histopathological workup of biopsy tissue require planning. MRI and bone scans can be adversely affected by biopsy and postoperative changes in the tissue; hence they are generally obtained preoperatively. 

Important imaging features of certain different lytic bone lesions bear mentioning:

Fibrous dysplasia: This condition is a common benign lesion with no age predilection. Classically, it presents as a well-defined lytic lesion, ground glass matrix, and no periosteal reaction. Common sites are ribs (monostotic disease), pelvis, and extremities.[12] Clinically four types of fibrous dysplasia (FD) are known: monostotic, polyostotic, craniofacial, and cherubism (maxilla and mandible in children). This is a disorder of bone characterized by the replacement of bone with structurally disorganized fibrous tissue. FD lesions may be quiescent, nonaggressive, or aggressive types.

Eosinophilic granuloma: This is a form of histiocytosis X; it can be lytic or blastic, with or without sclerotic margin, and with or without periostitis. There are no clear radiological features for this entity. However, based on previous experiences, EG is rare in those older than 30; it can be monostotic or polyostotic and is also known to show sequestrum.

Enchondroma: This is the most common benign lesion of phalanges. The calcified chondroid matrix is invariable except when in phalanges. There is no periostitis. The most important differential is bone infarct. The syndrome associated with multiple enchondromas is Ollier disease, and if presenting with multiple hemangiomas, then Maffucci syndrome.

Giant cell tumors: They occur typically in the closed epiphysis, eccentric lesion, subarticular abutting the epiphysis with possible extension into metaphysics, and sharply defined nonsclerotic border; they are considered moderately aggressive tumors.

Nonossifying fibroma: This is one of the most common incidental bone tumors; this is benign, asymptomatic, and has a well-defined sclerotic margin. Juxtacortical in location, it typically occurs in the metaphysis of long bones and is most common in people younger than 30. When the lesion is smaller than 2 cm, it is called a fibrous cortical defect (FCD).

Aneurysmal bone cysts: They are an expansile lytic lesion, typically seen in those younger than 30. A magnetic resonance imaging (MRI) shows multiple fluid-fluid levels. They can be of 2 types: primary and secondary, with other underlying lesions like osteosarcoma and chondrosarcoma, and frequently present with pain.[13]

Osteoblastoma: This is a rare solitary benign tumor. This is one of the differentials of tumors involving the posterior element of the spine. Typically it is more than 2 cm, to differentiate from osteoid osteoma.

Solitary bone cyst: This is a well-defined lytic lesion, central in a location involving the proximal humerus and femur. This occurs in an age group of under 30 years. Most commonly presents with pain due to fracture through the cyst wall.

Chondroblastoma, chondromyxoid fibroma: These are cartilaginous tumors and typically arise in the epiphysis and show no calcified matrix.

Metastasis: This must be included in the differential in those age 40 and older, whether lytic or sclerotic, and well-defined or ill-defined. Bone metastasis has a predilection for hematopoietic bone marrow such as the spine, pelvis, rib, cranium, and proximal long bones.

Myeloma: This must be a consideration in the differential for individuals greater than 40 years. The most common location is an axial skeleton. Myelomas demonstrate multiple punched-out lesions on CT; this does not show any uptake on bone scans.

Infection: Bone infection, or osteomyelitis, is a great mimicker of the tumor. It can present anywhere in the bone.

Hyperparathyroidism or Brown tumor: Brown tumor can occur in any bone and present as multiple osteolytic lesions. Important differentials are metastasis, ABC, and GCT according to the site of the lesion.

Treatment / Management

Most bone lesions are diagnosed based on their clinical, radiological, and biopsy characteristics. Enneking and others have proposed a staging system for benign and malignant musculoskeletal tumors.[14] Staging helps in planning treatment, predicting tumor prognosis, and comparing different treatment options.

Benign tumor staging is as follows:

Stage 1: Latent (intracapsular, asymptomatic, and incidental) lesions. The radiograph shows a well-defined lesion with a thick sclerotic rim and no cortical destruction or expansion. These lesions do not necessitate treatment because they do not compromise the strength of the involved bone. For example, small asymptomatic non-ossifying fibroma are diagnosed incidentally. 

Stage 2: Active (intracapsular, actively growing, presents with symptomatic pain or pathological fracture) lesions. They have well-defined margins but may expand and thin the cortex. They usually have a thin rim of reactive margin. Treatment involves extended curettage. 

Stage 3: Aggressive (extracapsular) lesions. They are known to breach natural anatomical barriers and usually have broken through the cortex. Extended curettage, marginal resection, or wide resection if needed.

Musculoskeletal sarcomas are also staged according to histological grade, local extent, presence or absence of metastasis by Enneking as follows:

• Stage IA/B: low-grade lesions, intracompartmental/extracompartmental, no metastasis
• Stage IIA/B: high grade, intracompartmental/extracompartmental, no metastasis
• Stage IIIA/B: any tumor that has metastasis regardless of grade or size of the tumor

Alternatively, many orthopedic oncologists stage musculoskeletal tumors according to the American Joint Committee on Cancer System (AJCC), which is periodically updated.

Treatment of bone lesions must be undertaken by experienced surgeons who are well aware of the basic principles of management of different bone tumors. The choice of treatment depends on a variety of factors. Surgical intervention versus conservative treatment, single-drug therapy or a combination of curettage, bone grafting, and cyst injections, management of difficult areas like tumors involving the spine, and the effect of therapy on continued skeletal growth must be considered while deciding on treatment. As an example, ABC is managed by curettage and bone grafting or injection and embolization while infection needs appropriate antibiotic treatment and surgical debridement if necessary.[14] The primary goal of treatment in case of primary bone malignancy is to make patients disease-free. In the case of metastatic disease of bone, the primary purpose of treatment is pain management. Combination therapy with radiotherapy, chemotherapy, and surgery is a common choice

There are specific benign bone lesions that do not need any intervention; they are better left alone. These are benign lesions and normal variants. A good example of obviously benign lesions is a non-ossifying fibroma. This is a lytic lesion located in the cortex of the metaphysis of a long bone with a well-defined sclerotic border. Their involuting nature may show increased activity in a bone scan. When diagnosed by a radiologist, it does not need a biopsy. Another similar frankly benign lesion is a unicameral bone cyst of the calcaneus. They are asymptomatic and rarely undergo fracture as other limb lesions. Bone infarct also never causes a diagnostic dilemma to a reporting radiologist; it doesn't need a biopsy.[15]

Differential Diagnosis

Epiphyseal Lesions

• Chondroblastoma (10 to 25 years)
• Giant cell tumor (20 to 40 years)
• Chondrosarcoma (rare) 

Diaphyseal Lesions

• Ewing sarcoma (5 to 25 years)
• Lymphoma
• Fibrous dysplasia (5 to 30 years)
• Adamantinoma (in tibia)
• Histiocytosis (5 to 30 years)

Multiple Lesions

• Histiocytosis
• Enchondroma
• Osteochondroma
• Fibrous dysplasia
• Metastasis
• Multiple myelomas
• Infection
• Hyperparathyroidism
• Hemangioma

Complications

Complications related to benign bone tumors can be due to the tumor itself, like pain, pathological fracture, the formation of an aneurysmal bone cyst, or malignant transformation. Treatment-related complications include recurrence, mobility disorder, and other side effects. Malignant bone lesions are known to cause pain, pathological fracture, loss of function, and poor quality of life associated with treatment side effects and, in extreme cases, leading to death. Management of musculoskeletal lesions includes dealing with all these issues.