One of the challenges of pediatric rheumatology is the broad spectrum of conditions ranging from the benign to the potentially life-limiting childhood malignancies that may present with relatively nonspecific musculoskeletal symptoms and signs. The importance of careful history taking, thorough physical examination, and appropriate use of investigations to arrive at the correct diagnosis, cannot be overemphasized. It is always appropriate in assessing a child with an arthritis or musculoskeletal pain to ask the question: Could this be a neoplastic mimic? Musculoskeletal manifestations of neoplasia in children can be considered under three overall groupings:
Primary malignant disease of bone marrow
Primary benign or malignant tumors of bone, cartilage, or adjacent tissues ( Table 50-1 )
Fibrous cortical defect
Aneurysmal bone cysts
Pigmented villondoular synovitis
Malignant diseases metastasizing to bone
In recent decades there have been significant improvements in the overall survival, disease-free survival, and treatment-associated morbidity in most of the childhood malignancies. These improvements have resulted from sequential multi-institutional clinical trials, the progressive refinement of prognostic factors allowing therapy stratification, and the rapidly changing fields of diagnostic tumor cytogenetics and molecular biology in addition to newer techniques in radiologic evaluation and reconstructive surgery.
Primary Malignant Disease of Bone Marrow
Acute lymphoblastic leukemia (ALL) accounts for 80% of leukemia in childhood and is the most common neoplastic mimic of juvenile idiopathic arthritis (JIA). Advances in diagnostic techniques and therapeutic strategies have resulted in a cure rate of approximately 85% in patients with B cell lineage ALL. B-precursor ALL is the most common immunophenotypic subgroup accounting for 75% of childhood ALL, the remainder being of T cell lineage. It is B-precursor ALL that can occasionally present real challenges in diagnosis because marrow replacement occurs slowly and musculoskeletal pain, which is often worse at night, may be present over a protracted period in association with relatively minor, nonspecific symptoms such as lethargy or fever. Pain is usually metaphyseal, but joint swelling can occur. Back pain is relatively common due to leukemic infiltration, which may be associated with diffuse osteopenia with vertebral compression fractures. Conversely, bone pain is unusual in recent onset JIA. Importantly, neither the total number of active joints, the distribution of the arthritis, nor the presence of a positive antinuclear antibody (ANA) can differentiate ALL from JIA. Plain radiographs may be normal or may show transverse metaphyseal lucencies ( Fig. 50-1 ). MRI shows diffuse marrow changes even when plain radiographs are normal.
Full blood examination may be entirely normal but frequently shows a mild normocytic anemia. The total white blood cell (WBC) count may be normal, elevated, or low and blasts may be absent. A multicenter case control study of children presenting to rheumatology clinics, but ultimately diagnosed with ALL, reported that 75% did not have blasts in the initial peripheral blood film. Other features suggestive of ALL include an elevated ESR, particularly if out of keeping with the degree of arthritis, unexplained neutropenia or thrombocytopenia, and elevated levels of lactic dehydrogenase (LDH) and uric acid. Bone marrow evaluation is warranted if there is sufficient uncertainty about the possibility of leukemia.
In order to afford each child the best chance of cure, it is essential that all appropriate diagnostic investigations be performed before instigation of any therapy. Treatment with corticosteroids or methotrexate for a presumptive diagnosis of JIA may result in amelioration of symptoms in a child with ALL and obscure vital prognostic information because a partial or even complete remission may be induced.
Therapy regimens are “risk adapted”; that is, designed to minimize exposure to drugs with potential long-term effects in the patient groups shown to have the best outcomes and to intensify therapy for patients with poorer prognostic factors. Age and WBC at disease presentation together with the presence or absence of extramedullary disease have prognostic significance and allow initial risk group assignment. “Standard risk” patients must be aged 1 to less than 10 years with a WBC less than 50 × 10 9 /µl and have no extramedullary disease. Those classified as “high risk” are aged 10 years or greater, have a WBC greater than 50 × 10 9 /µl, and/or central nervous system or testicular involvement at diagnosis. Further refinement of risk groups based on cytogenetic and molecular studies and on the speed of response to induction therapy determines the intensity of postinduction therapy.
Given the concerns of delay in correct diagnosis and the potential for inappropriate initiation of therapy, it is perhaps reassuring that the survival rate of children with ALL presenting initially to pediatric rheumatologists is reported to be higher in these children. This probably reflects the fact that the same predictive factors that may heighten a rheumatologists’ diagnostic concern (e.g., low WBC) also place the child in the better prognostic group for anticipated treatment response.
Tumors of Bone
Benign Tumors of Bone
Osteoid osteoma is a common benign bone tumor developing typically in the second decade, although occasionally reported in infants. There is a 3 : 1 male to female preponderance. Children present with insidious onset of pain, which is classically nocturnal. Other features may include gait disturbance, muscle wasting, or scoliosis. If intraarticular bone is involved there may be joint swelling and reduced range of movement mimicking arthritis.
Osteoid osteomas are small (<15 mm) and typically affect cortical bone, usually of the long bones and less commonly vertebrae or carpal/tarsal bones. Plain radiograph can be diagnostic if demonstrating an area of lysis and surrounding sclerosis. The sclerotic nidus within the area of lysis is more distinct on CT ( Fig. 50-2, A ). MRI may demonstrate an area of adjacent bone edema around the nidus ( Fig. 50-2, B ) and technetium radionuclide bone scan reveals a discrete area of increased activity. Osteoblastoma tend to occur in older children with a predilection for medullary bone. They are of larger size (>20mm), but are histologically the same as osteoid osteoma.
The nocturnal pain associated with an osteoid osteoma is reduced by aspirin and nonsteroidal antiinflammatories (NSAIDs). The fact that a thousand-fold increase in prostaglandin concentration has been reported in the nidus material is relevant to this response. A useful diagnostic hint is when parents have used simple analgesia for the nocturnal pain, such as acetaminophen, but note a greater reduction in the degree of pain when aspirin or a nonprescription NSAID, such as ibuprofen, has been used.
Treatment is very successful with CT guided radiofrequency ablation, but CT guided resection is also used to overcome the need for open resection. Surgical excision is generally required for the larger osteoblastoma lesions. Osteoid osteomas have not been reported to evolve into malignant lesions and typically will resolve spontaneously over some years. As such, long-term medical treatment with NSAIDs is an option, particularly for lesions in sites that may be difficult to access by interventional means, with the reported mean duration of medical therapy required being 1.5 to 2.5 years.
Malignant Tumors of Bone
Osteosarcoma (osteogenic sarcoma) is the most common malignant bone tumor in the pediatric age group. Median peak age at presentation is 16 years, with males more commonly affected (1.6 : 1). It is very rare in children under 5 years. High cell turnover, as occurs in the metaphyses during puberty, may be a factor in the development of osteosarcomas as presentation is earlier in girls and it appears to occur more commonly in children of taller stature.
A variety of rare genetic conditions with germline mutations in tumor suppressor genes (hereditary bilateral retinoblastoma, Li–Fraumeni syndrome) or in genes associated with maintenance of chromosome stability (Bloom and Rothmund–Thomson syndromes) are associated with an increased risk of developing osteosarcoma. Radiation exposure is the only proven environmental risk factor for the development of osteosarcoma, with a prolonged postexposure latency of 10 to 20 years.
The typical presenting symptom is pain, which may be nocturnal, followed by development of a tender swelling of hard consistency. Systemic symptoms such as fever, weight loss, and fatigue are not common. The metaphysis or metadiaphysis of the long bones are the most common sites: distal femur (40%), proximal tibia (20%), and proximal humerus (10%); the axial skeleton is involved in less than 10% of pediatric cases. Pathological fracture may occur. At diagnosis, classic osteosarcoma is localized to the primary site in 80% of patients, but 20% will already have metastases, typically to the lung or, less frequently, to distant bones. Occasionally, “skip lesions” occur within the same bone as the primary tumor. A lesion typically starts within the medullary cavity, invading through the cortex, elevating the periosteum, creating the classic radiologic appearance of the triangle of immature bone (Codman’s sign), and then into surrounding tissue forming a soft tissue mass. The radiologic appearances of lesions vary from osteosclerotic (45%), osteolytic (30%), or mixed (25%). Imaging with technetium bone scan, CT, and MRI will define the site of any metastases and delineate the extent of the primary lesion, enabling a carefully planned biopsy ( Fig. 50-3 ).
Preoperative chemotherapy to eradicate micrometastatic disease and to shrink the primary tumor facilitates subsequent resection utilizing limb-sparing techniques rather than amputation. Complete surgical resection remains essential for cure. Histological assessment of the degree of tumor necrosis in response to the initial chemotherapy is important in guiding the choice of agents used in postoperative chemotherapy. Osteosarcomas are poorly responsive to radiation therapy, which has a limited role in therapy.
Ten-year survival for patients with nonmetastatic disease at diagnosis is approximately 70% with current treatment approaches; however, 5-year survival is only 20% to 30% in the presence of metastatic disease.
Ewing sarcoma (EWS) is the second most common primary bone tumor in children and adolescents. The tumor may occur in very young children but more typically occurs in the second decade. It belongs to the spectrum of tumors known as the Ewing Sarcoma family of tumors (ESFT), which includes primary bone tumors (87%), primary extra osseous EWS (8%), and peripheral primitive neuroectodermal tumors (PPNETs) (5%). All are small round cell tumors with differences in their degree of differentiation and expression of neural markers reflecting their neural crest derivation. They share an identical translocation t(11;22) found in up to 95% of ESFT, which has an oncogenic fusion protein. Immunohistochemistry and the identification of translocations within tumor tissue are important aids in differentiating ESFT tumors from other small round cell tumors such as neuroblastoma, lymphoma, or rhabdomyosarcoma.
Ewing sarcoma is more common in males and has a nine times greater incidence in Caucasians than in the African population. That segments of the EWS gene are smaller in individuals of African heritage, with fewer polymorphisms, has been postulated as a possible explanation for such marked ethnic variation. Any bone may be affected, with only a slight predominance in the limbs (53%) over bones of the axial skeleton. Metastatic disease is present in about 25% of patients at the time of diagnosis, predominantly to lung (60%), bone (43%), and bone marrow (19%).
The most common presenting symptoms are intermittent pain and a palpable swelling with a median duration of 4 to 6 months between symptom onset and diagnosis. Pathological fracture may be the presenting feature in up to 10% of cases. Systemic features may include fever and weight loss, leading on occasion to misdiagnosis of osteomyelitis, particularly as biopsy specimens may be totally necrotic and mistaken for pus.
Plain radiographs show a destructive lesion of the diaphysis, or within flat bones of the axial skeleton, which may demonstrate the classic “onion-skin” appearance due to areas of tumor lysis accompanied by periosteal reaction, but may also demonstrate a spiculated pattern of new bone formation mimicking an osteogenic sarcoma. The cortex is generally breached and there is typically an associated large soft tissue component. Imaging by MRI, CT, technetium bone scan, and increasingly FDG-PET have become standard modalities for evaluation of the primary tumor and staging and assessment of metastatic disease ( Fig. 50-4 ).
Treatment involves aggressive preoperative chemotherapy to induce rapid resolution of soft tissue masses enabling resection of the primary bone lesion. Extensive residual tumor within bone or in the associated resected soft tissues requires postoperative radiotherapy in addition to chemotherapy.
Patients with localized disease at diagnosis who receive intensive therapy have a 5-year event-free survival of 73%. Cure rates for those with metastatic disease remain low at approximately 25%, with small pulmonary metastases faring better than for those with bony metastases. Cure rates after disease recurrence are poor.
Tumors of Cartilaginous Origin
Benign Cartilage Tumors
Cartilaginous tumors contain foci of chondroid matrix. As many of these entities are asymptomatic, an assessment of the true incidence is difficult but osteochondroma is most common followed by enchondroma, chondroblastoma, and chondromyxoid fibroma. Diagnosis is typically based on radiologic features, such the bone involved, the size, and whether solitary or multiple lesions are present.
Osteochondromas are cartilage capped bony projections usually of the metaphyseal region of long bones but also the ileum and scapula. There is an equal sex distribution. Approximately 15% of patients have multiple lesions, of which approximately 62% have a positive family history (e.g., multiple hereditary osteochondromatosis). Although usually asymptomatic, significant growth deformity, symptoms of local impingement, and pain may be presenting features, particularly in those with multiple lesions. Assessment using the Child Health Questionnaire has demonstrated differences in pain and self-esteem in affected individuals compared to normative pediatric data indicating that even these benign lesions can have a negative impact on children and adolescents.
The osteochondroma has three components: perichondrium, cartilage cap, and bony stalk (pedunculated or sessile). Of these, only the cartilage cap is neoplastic ( Fig. 50-5 ). In puberty the cartilage cap thins and undergoes calcification. Although rare, malignant transformation to a secondary peripheral chondrosarcoma can occur in 1% of solitary and 5% of multiple lesions for which the suggestive clinical features include a large cartilage cap (>1.5-2 cm), continued growth post-puberty, and the development of pain. These clinical features appear more predictive of malignant change than many histological features.
Mutations of the EXT1 and EXT2 genes have shown strong linkage with the development of multiple osteochondromas. It has been postulated that the development of osteochondromas following irradiation, including total body irradiation prior to bone marrow transplantation for the treatment of childhood leukemia, results from induction of EXT mutations.
Treatment by surgical excision is only warranted if the lesions are causing pain or if significant growth disturbances such as valgus deformities at the ankle or knee, develop. As malignant transformation is rare, prophylactic excision is not recommended.
Enchondromas are benign hyaline cartilage neoplasms of medullary bone generally affecting adolescents with an equal sex ratio. The hands and feet are affected in 50% of cases ( Fig. 50-6 ) but other sites including the femur and humerus may be affected. The majority are solitary but, if multiple, it is diagnosed as Ollier disease or, if in association with soft tissue hemangiomas, Marfucci syndrome. Calcification around the periphery of the lesions (bone encasement) is characteristic. Malignant transformation into a chondrosarcoma is reported in 15% to 30% of multiple lesions prompting need for appropriate surveillance.
These rare lesions have a male predilection (2 : 1) and typically involve the epiphysis of the long bones of prepubertal children, most commonly the humerus, followed by the femur and tibia. Pain is the typical presenting feature and up to one third may involve a secondary aneurysmal bone cyst. On radiograph, the classic appearance is of a well-circumscribed, ovoid lytic lesion with thin sclerotic margins ( Fig. 50-7 ). A variety of genetic rearrangements have been demonstrated but the relevance to tumor production is unknown. Treatment is by excision and, if relevant, management of the associated bone cyst.
These rare tumors have their peak incidence in adolescence with a male predominance. They can be found in any osseous site but the majority occur in the proximal tibia or iliac bone. On plain radiograph they appear as lytic lesions with sclerotic borders. Histology shows abundant myxoid and chondroid matrix. Although differentiation from chondrosarcoma may be necessary, the immunohistochemical appearances are distinct.
Malignant Cartilage Tumors
Primary chondrosarcoma is primarily a disease of adulthood, however secondary chondrosarcoma due to malignant transformation of benign osteochondromas can develop in multiple hereditary osteochondromatosis or in the syndromes associated with multiple enchondromas. The development of pain, often insidious in nature, is the most consistent feature of malignant transformation. There may be a soft tissue mass and pathological fracture may occur. Radiologic features suggesting chondrosarcoma are endosteal scalloping greater than two thirds of the cortical width on plain radiograph, peritumoral edema, and intense enhancement on T2-weighted MRI and positive uptake on technetium bone scan. Newer modalities such as PET-CT also demonstrate high degrees of sensitivity and specificity.
The preferred treatment is wide surgical excision followed by reconstruction of the affected bone. Most chondrosarcomas are resistant to both chemotherapy and radiotherapy.
Tumors of Fibrous Tissue
Benign Fibrous Tissue Tumors
Fibrous Cortical Defect (Non Ossifying Fibroma):
These benign fibrous lesions are the most common of all focal bone lesions affecting up to 40% of children between 4 and 8 years. They are generally asymptomatic and resolve spontaneously so that the diagnosis is usually an incidental finding on plain radiograph taken for other reasons. They typically occur near the epiphyseal growth plate at sites of tendon or ligament insertions, most commonly at the distal femur or proximal tibia. The characteristic radiographic appearance is of an eccentric, metaphyseal lucency with sclerotic margins ( Fig. 50-8 ). Biopsy is not usually required, and active management is required only for large lesions deemed to be at risk of fracture, in which case curettage and bone grafting may be necessary.
These uncommon lesions are classified into superficial and deep fibromatoses. They share similar histological appearances but widely divergent growth patterns, genetic changes, and clinical characteristics. The superficial fibromatoses occur predominantly in adults (e.g., Dupuytren contracture); however, superficial plantar fibromatosis does occur during adolescence, with ill-defined thickening in the plantar fascia. Infantile digital fibromas present as discrete nodular lesions over the dorsum of fingers and/or toes in children less than 3 years of age. They can be isolated or multiple and may produce local deformity. Interestingly, spontaneous resolution is not unusual so that decisions regarding timing of potential surgical intervention can be difficult.
The deep fibromatoses, also known as aggressive fibromatosis or desmoids tumors, are much rarer, arise from musculoaponeurotic tissues, demonstrate an infiltrative pattern along tissue planes, and may invade adjacent tissues such as bone, but do not have metastatic potential. They occur throughout life but exhibit a relative peak in early childhood and are strongly associated with Gardner syndrome and familial adenomatous polyposis. There is a female predominance.
Lesions typically present as a firm, slow growing and painless swelling attached to underlying soft tissue or bone, with the major sites of involvement being in the head and neck, upper limb, thigh, and trunk ( Fig. 50-9 ).