Malignant conditions of bone can arise from numerous sources, and the exact etiology is not always known. Early identification of malignancy equates to earlier appropriate treatment and improved long-term patient outcomes.1 Several conditions have been associated with a higher risk of malignant transformation. These conditions include benign osseous lesions with delayed malignant transformation, genetic predispositions to malignant degeneration, and extrinsic influences. This review discusses a multitude of diagnoses and factors that fall into these three categories.
Malignant transformation often results from abnormalities in either tumor suppressor genes or proto-oncogenes. Tumor suppressor genes are normal genes that regulate cellular processes, such as cell division, DNA repair, and apoptosis. When these genes are mutated, the normal regulation of these processes is lost and cells are able to proliferate and survive in an uncontrolled manner. Examples include TP53 and RB.2,3 Inherited disorders, such as Li-Fraumeni and Retinoblastoma, associated with tumor suppressor genes often affect one of the two copies of the gene. The patient subsequently develops a mutation in the second copy of the gene, causing malignant transformation.4 Proto-oncogenes are normal genes that promote cellular growth and proliferation, which can become constitutively active due to gene mutation, examples being RET and BCL-2.5,6 Activation of proto-oncogenes results in unchecked growth and proliferation of cells, which can lead to papillary thyroid carcinoma,7 osteosarcoma,8 and lymphoma.9 Often tumor suppressor gene mutations are inherited, while proto-oncogene mutations are acquired.10Table 1 presents all conditions included in this review and their associated protein mutations.
Table 1 -
Premalignant Conditions, Associated Mutated Protein, and Protein Function
||Associated Mutated Protein (Gene)
||Exostosin-1,2,3 (EXT1, EXT2, EXT3)
||Heparan sulfate biosynthesis
||Isocitrate dehydrogenase-1&2 (IDH1&2)
||Tricarboxylic acid cycle
|Paget disease of bone
||Autophagosome cargo protein
||Signal transduction protein
||No associated gene mutation
||H3.3 histone B (H3F3B)
||Nucleosome structure and genetic integrity
|Giant cell tumor of bone
||H3.3 histone A (H3F3A)
||Nucleosome structure and genetic integrity
||Proto-oncogene, target gene promotor and enhancer
||Tumor suppressor gene, cell-cycle checkpoint regulation
||Tumor protein p53 (TP53)
||Tumor suppressor gene, cell-cycle checkpoint regulation
||RecQ helicase (RECQL4)
||Telomerase maintenance protein
||RecQ helicase (BLM)
||Telomerase maintenance protein
||RecQ helicase (WRN)
||Telomerase maintenance protein
||No associated gene mutation
||Cyclin dependent kinase inhibitor 2A&B (CDKN2A&B)
||Tumor suppressor gene, cell-cycle checkpoint regulation
Benign Osseous Conditions With Delayed Malignant Transformation
Solitary osteochondromas are the most common benign lesions of bone accounting for approximately 30% of all benign bone lesions (Table 2).11 These are often referred to as exostoses and can arise in any bone of the body, but most often develop in areas of notable growth, such as the distal femur, proximal tibia, and proximal humerus. The true incidence of osteochondromas is likely underrepresented because they often present as incidental findings on imaging studies.12 These exostoses are characterized as pedunculated or sessile boney masses in direct continuity of the medullary canal with an overlying cartilage cap13 (Figure 1, A–C). Histologically, these “mushroom” shaped lesions show a cartilaginous cap composed of mature hyaline cartilage with normal underlying bone that includes trabecular bone and marrow contents (Figure 1D). Malignant transformation can occur within the cartilage cap with degeneration to chondrosarcoma and occurs in approximately 1% of benign cases.14,15 The exception to this low rate of malignant transformation in osteochondromas is found in patients with multiple hereditary exostoses (MHE). These patients have a notably increased whole-body risk of osteochondroma degeneration to chondrosarcoma with references rates as high as 35%.16,17 More recent MHE studies, however, suggest much lower rates of malignant transformation at around 2% to 5%.13,18–21
Table 2 -
Summary of Key Points
||Benign Osseous Conditions
||Osteochondromas and enchondromas are benign cartilaginous lesions of bone with low rates of malignant degeneration which is increased in conditions characterized by multiple lesions
||Paget disease of bone and fibrous dysplasia are disorders of disorganized or dysplastic bone formation and can develop osteosarcoma secondarily
||Synovial chondromatosis is a metaplastic process with low rates of chondrosarcomagenesis
||Chondroblastoma and giant cell tumor of bone are benign bone tumors associated with lung metastases and rarely develop malignant transformation posttreatment of an initial lesion
MHE is an autosomal dominant genetic predisposition to the development of multiple diffuse osteochondromas.22,23 Mutations in the EXT1, EXT2, and EXT3 genes have been attributed to this condition.24 All three EXT gene proteins function in heparin sulfate proteoglycan biosynthesis with loss of function mutations resulting in dysregulated growth.25 While occurring almost equally between male and female patients, the more severe phenotype predominates in male patients.18 Common symptomatology among these patients includes localized nerve compression, limb-length discrepancies, and genu valgum.26
Malignant transformation of an osteochondroma is associated with several symptoms. Previously dormant lesions that insidiously continue growing, particularly after skeletal maturity, can be suggestive of malignant transformation.27 This is especially true if the lesion becomes painful without a clear etiology.27 In addition, osteochondromas with a cartilage cap greater than 2 cm by radiographic imaging are associated with the development of chondrosarcoma.28 This cartilage cap may be measured using MRI or CT scan images with higher interobserver reliability for measurements obtained on CT imaging.28
When this malignant transformation does occur, it is most often to low-grade chondrosarcoma that can often be treated effectively with wide excision alone and with a good prognosis at >90% survival.17,27,29 Patients with chondrosarcoma arising from osteochondromas in the axial skeleton, particularly in the pelvis, may have worse outcomes due to delays in identification and subsequent treatment.27,30
Characterized as benign intramedullary hyaline cartilaginous tumors, enchondromas are one of the most common primary bone tumors in the body31 (Figure 2, A and B). They account for 3% of all bone tumors and 13% of all benign bone tumors.32 The exact incidence is unknown because these are typically asymptomatic and found incidentally.33 As these lesions are benign, treatment is most often with observation alone when found. Tumors that do present, often present secondarily to a pathologic fracture, because they can create a relative area of weakness in the bone.
Malignant transformation is of notable concern in patients who have enchondromatosis.31,34 Two main subtypes of enchondromatosis include Ollier disease and Maffucci syndrome. Both disorders are nonhereditary, and the malignant transformation occurs most often during the fourth decade of life.35 Isolated enchondromas, Ollier disease, and Maffucci syndrome are all associated with mutations in IDH1 and IDH2 genes, encoding proteins involved in the tricarboxylic acid cycle with downstream effects on histone modification and DNA hypermethylation.36,37 Rates of malignant transformation are 10% to 40% for Ollier disease and up to 15% to 50% for Maffucci syndrome.35,38,39 Other malignancies can occur as well in these patients including astrocytoma, gliomas, and mesenchymal ovarian tumors.39,40
Although uncommon, the most common secondary malignancy to occur in the setting of an enchondroma is dedifferentiation into chondrosarcoma. Differentiating a benign enchondroma from low-grade chondrosarcoma can be difficult, both on radiographic evaluation and biopsy analysis.38,41 Signs and symptoms of malignant transformation include the development of a mass in the region of a previously known enchondroma or, very importantly, new-onset pain. Radiographic findings include periosteal reaction, endosteal scalloping, soft-tissue invasion, and poorly demarcated lesions.42 Microscopically, they show lobules of hyaline cartilage that are often encased by bone or fibrous perichondrium (Figure 2C). Treatment for low-grade chondrosarcomas of the extremities and symptomatic enchondromas is the same and usually entails marginal curettage excision, bone grafting, and/or polymethylmethacrylate augmentation.38 Low-grade pelvic chondrosarcomas and all higher-grade chondrosarcomas should be treated with wide resection.43 Prognosis is best when enchondromas occur in the short bones of the body.35
Paget Disease of Bone
Paget disease of bone, also referred to as osteitis deformans, is a metabolic disorder characterized by osteoclast-mediated disorganized bone remodeling,44 typically found in patients aged older than 55 years.45,46 It most often affects people of European descent with a predilection for the axial skeleton. Although the exact mechanism is not understood, it is thought to be secondary to multiple environmental factors, including nutrition, infection, and activity level of the patients.47 Radiographically, it is characterized by osteolytic extension from epiphysis toward metaphysis with a widening of the affected bone with coarsened trabeculae and cortical thickening48 (Figure 3A–D). The histology varies based on the temporal phase of this lesion: osteolytic phase, mixed osteoclastic/osteoblastic phase, or osteosclerotic phase. The earlier presentation shows woven bone and a mosaic pattern (or jigsaw puzzle) appearance of lamellar bone along cement lines, (Figure 3E), while the later stages show thick bone trabeculae with myelofibrosis.
A genetic predisposition for Paget disease of bone has been established as displayed through a mutation in the ubiquitin-associated domain of the SQSTM1 gene; this resulting mutation displays autosomal dominance with variable penetrance.49 Paget osteosarcoma, often referred to as Paget sarcoma, is a devastating complication of Paget disease of bone with poor outcomes.50–54 Although osteosarcoma is the most common subtype of Paget-associated tumor, chondrosarcoma and fibrosarcoma are also documented.55 This malignant transformation thankfully occurs in only approximately 1% to 3% of cases.56,57 The rate of transformation is higher in severe polyostotic Paget patients at 5% to 10%.48 Symptoms of transformation include acute-onset pain or sudden increase in a previously stable chronic pain. Additional signs can include swelling or the development of a soft-tissue mass. Radiographically, malignancy is characterized by invasive growth within the medullary canal, cortical destruction, and soft-tissue expansion.57 The femur, humerus, and skull are most often affected by the sarcomatous transformation.
Diagnosis and treatment, when a malignant transformation is suspected, should be confirmed with a biopsy and followed with early aggressive treatment. Overall prognosis with Paget sarcoma is poor with 80% to 90% of patients dying within 3 years.48,58,59 These poor survival rates may be secondary to the frank malignant disease on presentation or simply due to its occurrence in older, more medically comorbid patients who cannot tolerate the aggressive chemotherapeutic and surgical treatment options. Treatment can include surgery, chemotherapy, and radiation therapy and is largely dependent on the sarcoma that develops.60 Fortunately, the rates of Paget sarcoma seem to be declining overall.58
As a relatively common lesion, fibrous dysplasia (FD) has been well described in the literature. Occurring as both mono-ostotic and polyostotic, FD is a disorder where fibro-osseous bone forms in lieu of native bone marrow with cancellous bone. The etiology for FD is a GNAS gene mutation with downstream constitutive activation of cAMP production and activation of the parathyroid hormone receptor.61 Monostotic FD comprises 75% of cases,62 often presenting in the second to fourth decades of life secondary to pain or pathologic fracture. Polyostotic patients often present earlier and are more likely to have an associated limb deformity present. On radiographic examination, the affected bone has a classically coined ground glass appearance (Figure 4, A and B). Histologically, the lesion shows thin trabecular bone in a background of fibroblast-like spindle cells (Figure 4C). These irregular-shaped trabeculae typically lack conspicuous osteoblastic rimming. These osseous locations most commonly affected in descending order include the femur, tibia, pelvis, foot, and facial bones.63
There are two major associated genetic disorders with FD, which include McCune-Albright and Mazabraud syndrome. First described by Albright and colleagues, McCune-Albright is known to display a classic triad of polyostotic FD, café-au-lait spots, and precocious puberty, although only roughly half of patients will phenotypically display the triad.64 Mazabraud syndrome is polyostotic FD with intramuscular myxomas. Similar to Paget disease, FD most commonly undergoes malignant transformation to osteosarcoma, chondrosarcoma, and fibrosarcoma at a rate of approximately 1%.65 However, malignant transformation is more common with polyostotic involvement with rates of around 4% in both McCune-Albright and Mazabraud patients.61,66 The most common locations for malignant transformation are, unsurprisingly, the proximal femur, humerus, and pelvis. Historically, one of the contributing factors to malignancy has been the treatment of FD with radiation therapy,67 and thankfully, more conservative approach to FD has become the standard of care.
Radiographically, malignant transformation should be suspected when poorly marginated, mineralized, and osteolytic lesions are identified.68 Treatment can include surgery, chemotherapy, and radiation therapy. Transformation often occurs during the fifth decade of life.66,68
The formation of cartilaginous and osteochondral bodies by synovium is the hallmark of synovial chondromatosis. This rare, benign condition can occur in any joint of the body. It often presents nonspecifically and can have a delayed diagnosis of up to 5 years after the onset of symptoms.69,70 There is a predilection for weight-bearing joints, with the most common locations being the knee followed by the hip, shoulder, elbow, and ankle.44 Overall, it is believed to be a metaplastic process of hyaline cartilaginous with loose body production (Figure 5A–D) that microscopically forms nodules of mature hyaline cartilage with variable cellularity and nuclear atypia (Figure 5E). Typical symptoms include pain, swelling, catching, popping, or crepitus within the affected joint.
Although malignant transformation of synovial chondromatosis is rare, there have been multiple case reports and series.70–74 These small sample-sized studies postulate the rate of chondrosarcomatous transformation of up to 6.3%; however, the authors caution that this may be a high estimate because many cases of synovial chondromatosis are asymptomatic.70 Typically, low-grade or intermediate-grade chondrosarcoma arises from a range of 2 to 39 years after initial diagnosis, with an average of 20 years.70 Clinically differentiating primary synovial chondromatosis from secondary chondrosarcoma can be very difficult,75 so clinical suspicion should be raised based on lesion recurrence alone. As is typical of chondrosarcoma treatment, radiation and chemotherapy have limited roles in these patients and surgical intervention is the mainstay of treatment.76 Surgical treatment is often wide resection or, if necessary for adequate control, amputation38
Occurring most specifically within the epiphysis of long bones, chondroblastoma is a rare benign primary bone tumor with a frequently aggressive nature.77,78 It is most often diagnosed in the second or third decade of life due to pain and often has associated joint symptoms due to its periarticular location. Radiographically, these are seen as well-circumscribed, lytic lesions in the epiphysis. Histologically, there is the proliferation of round chondroblasts in a background of a pink chondroid matrix, interspersed giant cells, and mature cartilage.77 Pericellular lace-like calcification is often seen in degenerative chondroblasts. Mutations in the H3F3B gene are found in up to 70% of patients with chondroblastoma79 and can help differentiate it from other giant-cell containing tumors. Treatment options include radiofrequency ablation in small lesions or local surgical excision with curettage.80 Chondroblastoma exhibits a relatively low recurrence rate of approximately 5% to 8%.81,82
Although chondroblastoma has metastatic potential itself, with 2% metastasizing to the lung,83 more aggressive chondroblastoma may represent its own category of malignant chondroblastoma. However, there is some dispute in malignant chondroblastoma being a separate entity but rather an initial misdiagnosis.77 Other malignancies have been found in the setting of chondroblastoma as well, including osteosarcoma and malignant fibrous histiocytoma.82,83 Nearly all malignant chondroblastomas occur in patients who have had a previous resection that later develops recurrence of their lesions.77,82,83 Prognosis of malignant chondroblastoma is difficult to assess because it is rare and not fully understood; however, metastatic lesions in the setting of benign chondroblastoma portend a poor prognostic implication.82,84
Giant Cell Tumor of Bone
As a benign tumor, giant cell tumor of bone (GCTB) is known to display locally aggressive features with an underrecognized metastatic potential, most often to the lungs.85,86 These tumors most often affect the epiphyseal and metaphyseal regions of long bones and are characterized by their classic histologic mononuclear stromal cells with frequent multinucleated giant cells. Bone destruction is mediated through overexpression of RANK ligand, which stimulates precursor monocytes to become the aforementioned osteoclastic giant cells.87,88 Mutations in H3F3A are present in most GCTB cases, which affects the histone H3.3.89,90 The size and overall localized tumor burden of GCTB considerably vary as does the proposed treatment modalities. Systemic adjuvant medical treatment with diphosphonate therapy has been shown to promote apoptosis of the stromal component in GCTB and stabilize inoperable disease.91,92 Bisphosphonates may also help prevent local recurrence.93 Surgery with extended intralesional curettage, with or without local adjuvant options, is considered the primary treatment modality and the benchmark.94 Denosumab, an antibody against receptor activator of nuclear factor-κb-ligand, is a recent treatment option, which has been shown to prevent disease progression in up to 96% of patients in one clinical trial at 13 months.95 The overall benefit of denosumab is being called into question, with recent studies showing possible association with malignant transformation96,97 and local recurrence in patients undergoing curettage.98
Although benign in nature, GCTB does have an ability to metastasize to the lungs, commonly in the setting of recurrent disease or primary axial skeletal location.99–101 Lung metastases are often indolent but can be aggressive and fatal.102 The metastatic rate in benign tumors is approximately 1% to 9%, although this may not change the long-term outcomes or mortality in these patients.103,104 Importantly, the pulmonary metastases are histologically identical to the primary bone lesion.105,106 Treatment is usually satisfactory with resection of the pulmonary metastasis.85,104
Malignant transformation of GCTB is broken into primary or secondary. Primary malignant GCTB is defined by an area of highly pleomorphic cells within an otherwise benign GCTB, whereas secondary GCTB occurs in an area of previously treated GCTB.107 Most malignant GCTBs are secondary to radiation therapy, accounting for up to 75% of all cases.107 Comparing malignant versus benign primary GCTB can be very difficult, with only one study finding that benign GCTB was more likely to have well-defined margins and the presence of a thin rim of bone.108 Other factors evaluated in the study found that there were no other differences between malignant and benign. Genetic mutations involving TP53 and H-RAS have been identified in secondary malignant GCTB which occur in nonpreviously irradiated patients.109 Mortality is influenced by previous radiation therapy, with postirradiation malignancy increasing 5-year mortality from 13% in nonirradiated patients to 72% or greater in postirradiated patients.107,108
Osteoblastoma is a lytic fibro-osseous tumor of bone that produces an osteoid matrix. They were first described as a lesion related to osteoid osteoma, however, with greater growth potential.110 Osteoblastoma is differentiated from osteoid osteoma by its larger size (>1.5 cm) and lack of nocturnal night pain relieved by nonsteroidal anti-inflammatory drugs.111 However, both entities share similar histology, consisting of trabecular woven bone that is rimmed by plump osteoblasts in a vascularized stroma. As benign neoplasms of bone, osteoblastomas are maybe found incidentally and however are more classically symptomatic.112 There is a predilection for the axial spine location with male patients between ages 10 and 25 years being the most common patient cohort.113–115 Although benign, these can be locally aggressive with variable clinical course.112 These can be differentiated from osteoid osteomas usually by their size, location, and their aggressive nature.114 However, both osteoid osteomas and osteoblastomas often carry a c-FOS mutation and have other similarities in microscopic morphology.116 Treatment is typically with curettage and bone grafting or resection, and prognosis is excellent. There is a 15% to 25% recurrence rate after treatment, typically with curettage and grafting.117
Malignant transformation of osteoblastoma to osteosarcoma has been described, most commonly into osteosarcoma after postsurgical resection recurrence.118–121 These case reports however have been called into question as possible initial misdiagnosis due to the similarities in histologic examination.113 This counter-argument to true malignant degeneration has been supported by genomic examination.121
The tumor suppressor gene retinoblastoma (RB1) serves as a cell-cycle checkpoint regulator (Table 3). Lack of the allele, RB1, displays Mendelian inheritance patterns in an autosomal dominant fashion. Due to the mutation with subsequent loss of this tumor suppressor gene, various neoplasms can result including osteosarcoma, melanoma, breast, and supratentorial primitive neuroectodermal tumors.122,123 Although RB1 mutation results in classic retinoblastoma of the eye,122 osteosarcoma remains the second most common malignancy in this patient cohort.124 Screening for retinoblastomas is done in neonates with red reflex testing before discharge from the neonatal nursery.125
Table 3 -
Summary of Key Points
||Retinoblastoma is secondary to loss of tumor suppressor gene RB1 with classically ocular retinoblastoma formation and often osteosarcoma formation
||Li-Fraumeni syndrome is characterized by loss of p53 tumor suppressor gene and lifetime cancer risk greater of 70% to 90%
||Rothmund-Thompson, Bloom, and Werner syndromes have mutations in genes associated with DNA replication and are at risk for several forms of cancer
Secondary malignancies in patients with retinoblastoma, including osteosarcoma, are common, particularly in the setting of radiation therapy which historically was part of the treatment algorithm.3,126 Rates of development are around 13.1% to 38.5% at 30 years or longer after irradiation.127,128 However, current rates of secondary malignancy are likely decreasing today because radiation therapy is becoming less frequently used in these patients from 30.5% to 2.6% of cases.128 Screening for sarcoma development in patients with heritable retinoblastoma has not been shown to have benefit.129
Another predisposition syndrome, Li-Fraumeni, has a high association with numerous malignancies. Like RB1 dysfunction, TP53 serves as a cell-cycle checkpoint regulator and inherited loss of function mutations displays Mendelian inheritance characteristics in an autosomal dominant fashion.124 Heterozygous germline variation in the TP53 allele results in a lifetime cancer risk of ≥90% for women and ≥70% for men.130 The five most common malignancies in these patients are adrenocortical carcinomas, breast cancer, central nervous system tumors, osteosarcomas, and soft-tissue sarcomas.131
These patients tend to develop malignancies early in life with 41% occurring before age 18 years,133 with osteosarcoma occurring in approximately 12% of individuals.132 Families with Li-Fraumeni syndrome do demonstrate anticipation as well, likely secondary to telomerase shortening.133 Overall, 3% of osteosarcoma cases are found in Li-Fraumeni patients.134 Cancer-screening guidelines for these patients have been described by multiple organizations.135–140 Screening includes whole-body MRI, laboratory studies, and endoscopy. The Toronto protocol for screening has been shown to have improved overall survival compared with no surveillance.138
Because of a mutation of RECQL4, a telomerase maintenance protein, Rothmund-Thompson is an autosomal recessive disorder characterized by rash, sparse hair, small size, skeletal and dental abnormalities, and juvenile cataracts.141,142 These patients also have an increased risk of cancers, usually osteosarcoma which occurs in 30% to 60% of patients.133,134,143 The average age of patients who develop their first malignancy is 15 years, although those who develop osteosarcoma typically do so at an earlier age around 11 years.143,144
Congenital telangiectatic erythema, or Bloom syndrome, is an autosomal recessive disorder. Genomic instability results from mutations in the BLM gene, a RecQ helicase, and patients are predisposed to all types of cancers.133,145,146 There is a higher rate of Bloom syndrome in the Ashkenazi Jewish population, accounting for approximately 25% of all cases.147 Besides malignancy, these patients often have small stature with proportional bodies, sunlight sensitivities, insulin resistance, and immune abnormalities.148
The mean age of death in patients with Bloom syndrome is 26 years, and typically due to complications of malignancy.145,146 The most common malignancies in this syndrome are leukemia and lymphoma accounting for 44% of cases with osteosarcoma occurring in approximately 2% of cases.145
Patients with Werner syndrome present with premature aging, bilateral cataracts, short stature, osteoporosis, and hypogonadism.149 It is more commonly seen in the Japanese population and is usually caused by mutations in the WRN gene, which encodes a RecQ Helicase.133 This genetic mutation predisposes these patients to malignancy, often including thyroid neoplasms (16.7% of cases), but also soft-tissue sarcomas (10.1%) and osteosarcomas (7.7%).150 When osteosarcoma does develop, it is often in unusual locations such as the foot, ankle, or patella.133
Chronic nonhealing wounds are a well-known risk factor for the development of malignancy, referred to as Marjolin ulcers (Table 4).151 They have an incidence of approximately 1.6% to 23% in the setting of chronic osteomyelitis .152 Osteomyelitis is the etiology in only 2.6% of Marjolin ulcers however with burns accounting for the vast majority at 76.5%.153 The latency period from ulcer development to malignancy is on average 29 to 43 years.153–155 The most common location is the lower extremity.153,155
Table 4 -
Summary of Key Points
||Chronic osteomyelitis with an associated nonhealing wound can result in a Marjolin ulcer or carcinoma formation at the site of the nonhealing wound
||Postradiation sarcoma is rare but can result in osteosarcoma or soft-tissue sarcomas after doses of 45–60 Gy
||Extrinsic conditions typically result in secondary malignant transformation 15 + years after radiation or the development of osteomyelitis
||Chronic osteomyelitis with an associated nonhealing wound can result in a Marjolin ulcer or carcinoma formation at the site of the nonhealing wound
Although squamous cell carcinoma is the most common type of malignancy to develop in this patient population, other malignancies have been identified such as fibrosarcoma, angiosarcoma, osteosarcoma, adenocarcinoma, basal cell carcinoma, and malignant fibrous histiocytoma.152 Malignant degeneration may have occurred whether the patient reports worsening pain, increased drainage, enlargement, or lymphadenopathy.152,154 Unfortunately, the prognosis in these patients is poor, predominately due to late diagnosis of the malignancy. Metastasis is found in 10% to 27% of patients on initial diagnosis.153,156 Treatment has often been with amputation proximal to the tumor,156–158 although wide excision with reconstruction may also be a viable option dependent on patient and tumor-specific characteristics.152
Ionizing radiation is a known risk factor for the development of malignancy. Presentation of postradiation sarcoma is on average 15 to 16 years after radiation exposure and most often develops as a bone sarcomas, specifically osteosarcoma.159–161 The most common soft-tissue sarcoma to develop is undifferentiated pleomorphic sarcoma.161,162 Rates of sarcoma formation after radiation are low at roughly 0.03% to 0.9%.162,163 Prior radiation doses of 45 to 60 Gy are often found in these patients, but sarcomas can still arise in lower doses such as 30 Gy.159,161 Other risk factors for development are younger age at the time of radiation treatment and concurrent chemotherapy with alkylating agents.164,165 Genetic mutations are similar between sporadic and postradiation sarcomas, such as RB1 involvement; however, postradiation sarcomas are more likely to have CDKN2A and CDKN2B.166 The survival rate in these patients is variable in the literature with an average 5-year overall survival of 33% to 68.2%.159–162 Patients presenting without metastatic disease at the time of diagnosis when treated with surgery and chemotherapy may have similar outcomes to primary sarcoma; however, those treated with surgery alone or present with the metastatic disease already present have worse outcomes.167
Multiple factors and conditions that affect bone can predispose patients to the later development of malignancy including benign neoplasms, genetic conditions, and extrinsic factors. Although malignant transformation is rare in many of these conditions, a high index of suspicion must be kept when evaluating and following these patients to provide aggressive appropriate treatment if malignancy develops. Often malignant transformation will present as new-onset pain or mass formation in these patients and should trigger further workup and evaluation for these patients.
1. Vasquez L, Silva J, Chavez S, et al.: Prognostic impact of diagnostic and treatment delays in children with osteosarcoma. Pediatr Blood Cancer 2020;67:e28180.
2. Levine AJ, Momand J, Finlay CA: The p53 tumour suppressor gene. Nature 1991;351:453-456.
3. Rodriguez-Galindo C, Orbach DB, VanderVeen D: Retinoblastoma. Pediatr Clin North Am 2015;62:201-223.
4. Knudson AG Jr: Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci U S A 1971;68:820-823.
5. Jhiang SM: The RET proto-oncogene in human cancers. Oncogene 2000;19:5590-5597.
6. Kroemer G: The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nat Med 1997;3:614-620.
7. Prescott JD, Zeiger MA: The RET oncogene in papillary thyroid carcinoma. Cancer 2015;121:2137-2146.
8. Kovac M, Woolley C, Ribi S, et al.: Germline RET variants underlie a subset of paediatric osteosarcoma. J Med Genet 2021;58:20-24.
9. Coultas L, Strasser A: The role of the Bcl-2 protein family in cancer. Semin Cancer Biol 2003;13:115-123.
10. Weinberg RA: Oncogenes and tumor suppressor genes. CA Cancer J Clin 1994;44:160-170.
11. Bozzola M, Gertosio C, Gnoli M, et al.: Hereditary multiple exostoses and solitary osteochondroma associated with growth hormone deficiency: To treat or not to treat? Ital J Pediatr 2015;41:53.
12. Siegal GP, Bloem JL, Cates JMM: Soft Tissue and Bone Tumours. Lyon, France, International Agency for Research on Cancer, 2020.
13. Tong K, Liu H, Wang X, et al.: Osteochondroma: Review of 431 patients from one medical institution in South China. J Bone Oncol 2017;8:23-29.
14. Wicklund CL, Pauli RM, Johnston D, Hecht JT: Natural history study of hereditary multiple exostoses. Am J Med Genet 1995;55:43-46.
15. Lamovec J, Špiler M, Jevtić V: Osteosarcoma arising in a solitary osteochondroma of the fibula. Arch Pathol Lab Med 1999;123:832-834.
16. Florez B, Monckeberg J, Castillo G, Beguiristain J: Solitary osteochondroma long-term follow-up. J Pediatr Orthop 2008;17:91-94.
17. Ahmed AR, Tan TS, Unni KK, Collins MS, Wenger DE, Sim FH: Secondary chondrosarcoma in osteochondroma: Report of 107 patients. Clin Orthop Relat Res 2003:193-206.
18. Pedrini E, Jennes I, Tremosini M, et al.: Genotype-phenotype correlation study in 529 patients with multiple hereditary exostoses: Identification of “protective” and “risk” factors. J Bone Joint Surg Am 2011;93:2294-2302.
19. Fei L, Ngoh C, Porter DE: Chondrosarcoma transformation in hereditary multiple exostoses: A systematic review and clinical and cost-effectiveness of a proposed screening model. J Bone Oncol 2018;13:114-122.
20. Jurik AG, Jørgensen PH, Mortensen MM: Whole-body MRI in assessing malignant transformation in multiple hereditary exostoses and enchondromatosis: Audit results and literature review. Skeletal Radiol 2020;49:115-124.
21. Legeai-Mallet L, Munnich A, Maroteaux P, Le Merrer M, Munnich A: Incomplete penetrance and expressivity skewing in hereditary multiple exostoses. Clin Genet 1997;52:12-16.
22. Jurik AG: Multiple hereditary exostoses and enchondromatosis. Best Pract Res Clin Rheumatol 2020;34:101505.
23. Beltrami G, Ristori G, Scoccianti G, Tamburini A, Capanna R: Hereditary multiple exostoses: A review of clinical appearance and metabolic pattern. Clin Cases Miner Bone Metab 2016;13:110-118.
24. Stieber JR, Dormans JP: Manifestations of hereditary multiple exostoses. J Am Acad Orthop Surg 2005;13:110-120.
25. Jennes I, Pedrini E, Zuntini M, et al.: Multiple osteochondromas: Mutation update and description of the multiple osteochondromas mutation database (MOdb). Hum Mutat 2009;30:1620-1627.
26. Wells M, Birchard Z: A 40-year-old male presenting with hereditary multiple exostosis: Management and considerations. Case Rep Orthop 2019;2019:4793043-4793044.
27. Lin PP, Moussallem CD, Deavers MT: Secondary chondrosarcoma. J Am Acad Orthop Surg 2010;18:608-615.
28. Bernard SA, Murphey MD, Flemming DJ, Kransdorf MJ: Improved differentiation of benign osteochondromas from secondary chondrosarcomas with standardized measurement of cartilage cap at CT and MR imaging. Radiology 2010;255:857-865.
29. Altay M, Bayrakci K, Yildiz Y, Erekul S, Saglik Y: Secondary chondrosarcoma in cartilage bone tumors: Report of 32 patients. J Orthop Sci 2007;12:415-423.
30. Bus MPA, Campanacci DA, Albergo JI, et al.: Conventional primary central chondrosarcoma of the pelvis: Prognostic factors and outcome of surgical treatment in 162 patients. J Bone Joint Surg Am 2018;100:316-325.
31. Herget GW, Strohm P, Rottenburger C, et al.: Insights into Enchondroma, Enchondromatosis and the risk of secondary Chondrosarcoma. Review of the literature with an emphasis on the clinical behaviour, radiology, malignant transformation and the follow up. Neoplasma 2014;61:365-378.
32. Mulligan ME: How to diagnose enchondroma, bone infarct, and chondrosarcoma. Curr Probl Diagn Radiol 2019;48:262-273.
33. Adler C-P: Bone Diseases: Macroscopic, Histological, and Radiological Diagnosis of Structural Changes in the Skeleton, Freiburg, Germany, Springer, 2000, Vol. 588.
34. Sassoon AA, Fitz-Gibbon PD, Harmsen WS, Moran SL: Enchondromas of the hand: Factors affecting recurrence, healing, motion, and malignant transformation. J Hand Surg Am 2012;37:1229-1234.
35. Verdegaal SHM, Bovée JVMG, Pansuriya TC, et al.: Incidence, predictive factors, and prognosis of chondrosarcoma in patients with Ollier disease and Maffucci syndrome: An International Multicenter Study of 161 patients. Oncologist 2011;16:1771-1779.
36. Amary MF, Damato S, Halai D, et al.: Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat Genet 2011;43:1262-1265.
37. Pansuriya TC, Van Eijk R, D'Adamo P, et al.: Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 2011;43:1256-1261.
38. Wells ME, Eckhoff MD, Kafchinski LA, Polfer EM, Potter BK: Conventional cartilaginous tumors: Evaluation and treatment. JBJS Rev 2021;9.
39. El Abiad JM, Robbins SM, Cohen B, et al.: Natural history of Ollier disease and Maffucci syndrome: Patient survey and review of clinical literature. Am J Med Genet 2020;182:1093-1103.
40. Amary MF, Bacsi K, Maggiani F, et al.: IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 2011;224:334-343.
41. Weinschenk RC, Wang WL, Lewis VO: Chondrosarcoma. J Am Acad Orthop Surg 2021;29:553-562.
42. Lubahn JD, Bachoura A: Enchondroma of the hand: Evaluation and management. J Am Acad Orthop Surg 2016;24:625-633.
43. Bus MPA, Campanacci DA, Albergo JI, et al.: Conventional primary central chondrosarcoma of the pelvis: Prognostic factors and outcome of surgical treatment in 162 patients. J Bone Joint Surg Am 2018;100:316-325.
44. Biermann JS, Siegel GW, American Academy of Orthopaedic Surgeons: Orthopaedic knowledge update Musculoskeletal tumors. Rosemont, IL, American Academy of Orthopaedic Surgeons, pp 528.
45. Van Staa TP, Selby P, Leufkens HGM, Lyles K, Sprafka JM, Cooper C: Incidence and natural history of Paget's disease of bone in England and Wales. J Bone Miner Res 2002;17:465-471.
46. Ralston SH: Clinical practice. Paget's disease of bone. N Engl J Med 2013;368:644, 650.
47. Layfield R: The molecular pathogenesis of Paget disease of bone. Expert Rev Mol Med 2007;9:1-13.
48. Smith SE, Murphey MD, Motamedi K, Mulligan ME, Resnik CS, Gannon FH: From the archives of the AFIP: Radiologic spectrum of paget disease of bone and its complications with pathologic correlation. Radiographics 2002;22:1191-1216.
49. Harvey L, Gray T, Beneton MNC, Douglas DL, Kanis JA, Russell RGG: Ultrastructural features of the osteoclasts from Paget's disease of bone in relation to a viral aetiology. J Clin Pathol 1982;35:771-779.
50. Schajowicz F, Santini Araujo E, Berenstein M: Sarcoma complicating Paget's disease of bone. A clinicopathological study of 62 cases. J Bone Joint Surg Br 1983;65:299-307.
51. Shaylor PJ, Peake D, Grimer RJ, Carter SR, Tillman RM, Spooner D: Paget's osteosarcoma - No cure in sight. Sarcoma 1999;3:191-192.
52. Frassica FJ, Sim FH, Frassica DA, Wold LE: Survival and management considerations in postirradiation osteosarcoma and Paget's osteosarcoma. Clin Orthop Relat Res 1991:120-127.
53. Dray MS, Miller MV: Paget's osteosarcoma and post-radiation osteosarcoma: Secondary osteosarcoma at Middlemore Hospital, New Zealand. Pathology 2008;40:604-610.
54. Calabrò T, Mavrogenis AF, Ruggieri P: Osteoblastic osteosarcoma in monostotic Paget's disease. Musculoskelet Surg 2011;95:37-40.
55. López C, Thomas DV, Davies AM: Neoplastic transformation and tumour-like lesions in Paget's disease of bone: A pictorial review. Eur Radiol 2003;13(Suppl 4):L151-L163.
56. Colina M, La Corte R, De Leonardis F, Trotta F: Paget's disease of bone: A review. Rheumatol Int 2008;28:1069-1075.
57. Seitz S, Priemel M, Zustin J, et al.: Paget's disease of bone: Histologic analysis of 754 patients. J Bone Miner Res 2009;24:62-69.
58. Mangham DC, Davie MW, Grimer RJ: Sarcoma arising in Paget's disease of bone: Declining incidence and increasing age at presentation. Bone 2009;44:431-436.
59. Mirabello L, Troisi RJ, Savage SA: Osteosarcoma incidence and survival rates from 1973 to 2004: Data from the surveillance, epidemiology, and end results program. Cancer 2009;115:1531-1543.
60. Mankin HJ, Hornicek FJ: Paget's sarcoma: A historical and outcome review. Clin Orthop Relat Res 2005;438:97-102.
61. Leet AI, Collins MT: Current approach to fibrous dysplasia of bone and McCune–Albright syndrome. J Child Orthop 2007;1:3-17.
62. Riddle ND, Bui MM: Fibrous dysplasia. Arch Pathol Lab Med 2013;137:134-138.
63. Most MJ, Sim FH, Inwards CY: Osteofibrous dysplasia and adamantinoma. J Am Acad Orthop Surg 2010;18:358-366.
64. Parekh SG, Donthineni-Rao R, Ricchetti E, Lackman RD: Fibrous dysplasia. J Am Acad Orthop Surg 2004;12:305-313.
65. Boyce AM, Florenzano P, de Castro LF, Collins MT: Fibrous Dysplasia/McCune-Albright Syndrome. Leiden, the Netherlands, Leiden University, 2019.
66. Ruggieri P, Sim FH, Bond JR, Unni KK: Malignancies in fibrous dysplasia. Cancer 1994;73:1411-1424.
67. Stanton RP, Ippolito E, Springfield D, Lindaman L, Wientroub S, Leet A: The surgical management of fibrous dysplasia of bone. Orphanet J Rare Dis 2012;7(suppl 1):1-9.
68. Qu N, Yao W, Cui X, Zhang H: Malignant transformation in monostotic fibrous dysplasia: Clinical features, imaging features, outcomes in 10 patients, and review. Medicine (Baltimore) 2015;94:e369.
69. Neumann JA, Garrigues GE, Brigman BE, Eward WC: Synovial chondromatosis. JBJS Rev 2016;4:e2.
70. Evans S, Boffano M, Chaudhry S, Jeys L, Grimer R: Synovial chondrosarcoma arising in synovial chondromatosis. Sarcoma 2014;2014:647939.
71. Kenan S, Abdelwahab IF, Klein MJ, Lewis MM: Case report 817: Synovial chondrosarcoma secondary to synovial chondromatosis. Skeletal Radiol 1993;22:623-626.
72. Sachinis NP, Sinopidis C, Baliaka A, Givissis P: Odyssey of an elbow synovial chondromatosis. Orthopedics 2015;38:e62-e67.
73. Davis RI, HAmilton A, Biggart JD, HAmilton A: Primary synovial chondromatosis: A clinicopathologic review and assessment of malignant potential. Hum Pathol 1998;29:683-688.
74. Bhadra AK, Pollock R, Tirabosco RP, et al.: Primary tumours of the synovium: A report of four cases of malignant tumour. J Bone Joint Surg Br 2007;89:1504-1508.
75. Murphey MD, Vidal JA, Fanburg-Smith JC, Gajewski DA: From the archives of the AFIP: Imaging of synovial chondromatosis with radiologic-pathologic correlation. Radiographics 2007;27:1465-1488.
76. Gelderblom H, Hogendoorn PCW, Dijkstra SD, et al.: The clinical approach towards chondrosarcoma. Oncologist 2008;13:320-329.
77. Chen W, DiFrancesco LM: Chondroblastoma: An update. Arch Pathol Lab Med 2017;141:867-871.
78. Ramappa AJ, Lee FY, Tang P, Carlson JR, Gebhardt MC, Mankin HJ: Chondroblastoma of bone. J Bone Joint Surg Am 2000;82:1140-1145.
79. Cleven AHG, Höcker S, Briaire-De Bruijn I, Szuhai K, Cleton-Jansen AM, Bovée JVMG: Mutation analysis of H3F3A and H3F3B as a diagnostic tool for giant cell tumor of bone and chondroblastoma. Am J Surg Pathol 2015;39:1576-1583.
80. Rybak LD, Rosenthal DI, Wittig JC: Chondroblastoma: Radiofrequency ablation--alternative to surgical resection in selected cases. Radiology 2009;251:599-604.
81. Xu H, Nugent D, Monforte HL, et al.: Chondroblastoma of bone in the extremities: A multicenter retrospective study. J Bone Joint Surg Am 2015;97:925-931.
82. Lin PP, Thenappan A, Deavers MT, Lewis VO, Yasko AW: Treatment and prognosis of chondroblastoma. Clin Orthop Relat Res 2005;438:103-109.
83. Narhari MD, Haseeb A, Lee S, Singh V: Spontaneous conventional osteosarcoma transformation of a chondroblastoma: A case report and literature review. Indian J Orthop 2018;52:87-90.
84. Laitinen MK, Stevenson JD, Evans S, et al.: Chondroblastoma in pelvis and extremities- A single centre study of 177 cases. J Bone Oncol 2019;17:100248.
85. Raskin KA, Schwab JH, Mankin HJ, Springfield DS, Hornicek FJ: Giant cell tumor of bone. J Am Acad Orthop Surg 2013;21:118-126.
86. Sobti A, Agrawal P, Agarwala S, Agarwal M: Giant cell tumor of bone - An overview. Arch Bone Joint Surg 2016;4:2-9.
87. Kim Y, Nizami S, Goto H, Lee FY: Modern interpretation of giant cell tumor of bone: Predominantly osteoclastogenic stromal tumor. Clin Orthop Surg 2012;4:107-116.
88. Wu PF, Tang JY, Li KH: RANK pathway in giant cell tumor of bone: Pathogenesis and therapeutic aspects. Tumour Biol 2015;36:495-501.
89. Yamamoto H, Ishihara S, Toda Y, Oda Y: Histone H3.3 mutation in giant cell tumor of bone: An update in pathology. Med Mol Morphol 2020;53:1-6.
90. Behjati S, Tarpey PS, Presneau N, et al.: Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat Genet 2013;45:1479-1482.
91. Chang SS, Suratwala SJ, Jung KM, et al.: Bisphosphonates may reduce recurrence in giant cell tumor by inducing apoptosis. Clin Orthop Relat Res 2004;426:103-109.
92. Balke M, Campanacci L, Gebert C, et al.: Bisphosphonate treatment of aggressive primary, recurrent and metastatic giant cell tumour of bone. BMC Cancer 2010;10:462.
93. Tse LF, Wong KC, Kumta SM, Huang L, Chow TC, Griffith JF: Bisphosphonates reduce local recurrence in extremity giant cell tumor of bone: A case–control study. Bone 2008;42:68-73.
95. Chawla S, Henshaw R, Seeger L, et al.: Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: Interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol 2013;14:901-908.
96. Park A, Cipriano CA, Hill K, Kyriakos M, McDonald DJ: Malignant transformation of a giant cell tumor of bone treated with denosumab: A case report. JBJS Case Connect 2016;6:e78.
97. Hasenfratz M, Mellert K, Marienfeld R, et al.: Profiling of three H3F3A-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation. Sci Rep 2021;11:5709.
98. Asano N, Saito M, Kobayashi E, et al.: Preoperative denosumab therapy against giant cell tumor of bone is associated with an increased risk of local recurrence after curettage surgery. Ann Surg Oncol 2022;29:3992-4000, doi:
99. Niu X, Zhang Q, Hao L, et al.: Giant cell tumor of the extremity: Retrospective analysis of 621 Chinese patients from one institution. J Bone Joint Surg Am 2012;94:461-467.
100. Kremen TJ, Bernthal NM, Eckardt MA, Eckardt JJ: Giant cell tumor of bone: Are we stratifying results appropriately?. Clin Orthop Relat Res 2012;470:677-683.
101. Chan CM, Adler Z, Reith JD, Gibbs CP: Risk factors for pulmonary metastases from giant cell tumor of bone. J Bone Joint Surg Am 2015;97:420-428.
102. Balke M, Schremper L, Gebert C, et al.: Giant cell tumor of bone: Treatment and outcome of 214 cases. J Cancer Res Clin Oncol 2008;134:969-978.
103. Rosario M, Kim HS, Yun JY, Han I: Surveillance for lung metastasis from giant cell tumor of bone. J Surg Oncol 2017;116:907-913.
104. Viswanathan S, Jambhekar NA: Metastatic giant cell tumor of bone: Are there associated factors and best treatment modalities? Clin Orthop Relat Res 2010;468:827-833.
105. Kay RM, Eckardt JJ, Seeger LL, Mirra JM, Hak DJ: Pulmonary metastasis of benign giant cell tumor of bone. Six histologically confirmed cases, including one of spontaneous regression. Clin Orthop Relat Res 1994:219-230.
106. Tubbs WS, Brown LR, Beabout JW, Rock MG, Unni KK: Benign giant-cell tumor of bone with pulmonary metastases: Clinical findings and radiologic appearance of metastases in 13 cases. AJR Am J Roentgenol 1992;158:331-334.
107. Palmerini E, Picci P, Reichardt P, Downey G: Malignancy in giant cell tumor of bone: A review of the literature. Technol Cancer Res Treat 2019;18:1533033819840000.
108. Domovitov SV, Healey JH: Primary malignant giant-cell tumor of bone has high survival rate. Ann Surg Oncol 2010;17:694-701.
109. Oda Y, SAkAmoto A, SaiTo T, et al.: Secondary malignant giant-cell tumour of bone: Molecular abnormalities of p53 and H-ras gene correlated with malignant transformation. Histopathology 2001;39:629-637.
110. Lichtenstein L, Sawyer WR: Benign Osteoblastoma. Further observations and report of twenty additional cases. J Bone Joint Surg Am 1964;46:755-765.
111. Gitelis S, Schajowicz F: Osteoid osteoma and osteoblastoma. Orthop Clin North Am 1989;20:313-325.
112. Yalcinkaya U, Doganavsargil B, Sezak M, et al.: Clinical and morphological characteristics of osteoid osteoma and osteoblastoma: A retrospective single-center analysis of 204 patients. Ann Diagn Pathol 2014;18:319-325.
113. Limaiem F, Byerly DW, Singh R, Osteoblastoma. StatPearls, 2021. https://www.ncbi.nlm.nih.gov/books/NBK536954/
114. Atesok KI, Alman BA, Schemitsch EH, Peyser A, Mankin H: Osteoid osteoma and osteoblastoma. J Am Acad Orthop Surg 2011;19:678-689.
115. Arkader A, Dormans JP: Osteoblastoma in the skeletally immature. J Pediatr Orthop 2008;28:555-560.
116. Amary F, Flanagan AM, O'Donnell P: Benign bone-forming tumors. Surg Pathol Clin 2021;14:549-565.
117. Berry M, Mankin H, Gebhardt M, Rosenberg A, Hornicek F: Osteoblastoma: A 30-year study of 99 cases. J Surg Oncol 2008;98:179-183.
118. Lucas DR, Unni KK, McLeod RA, O'Connor MI, Sim FH: Osteoblastoma: Clinicopathologic study of 306 cases. Hum Pathol 1994;25:117-134.
119. Mayer L: Malignant degeneration of so-called benign osteoblastoma. Bull Hosp Joint Dis 1967;28:4-13.
120. Görgün O, Salduz A, Kebudi R, Özger H, Bilgiç B: Malignant transformation of aggressive osteoblastoma to osteosarcoma. Eklem Hastalik Cerrahisi 2016;27:108-112.
121. Geller DS, Levine NL, Hoang BH, et al.: Genomic analysis does not support malignant transformation of osteoblastoma to osteosarcoma. JCO Precis Oncol 2019;3:1-7.
122. Dimaras H, Kimani K, Dimba EAO, et al.: Retinoblastoma. Lancet 2012;379:1436-1446.
123. Kleinerman RA, Tucker MA, Tarone RE, et al.: Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: An extended follow-up. J Clin Oncol 2005;23:2272-2279.
124. Ito M, Barys L, O'Reilly T, et al.: Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis. Clin Cancer Res 2011;17:416-426.
125. Retinoblastoma. Am Acad Pediatr, 2020. https://aapos.org/glossary/retinoblastoma
126. Wong FL, Boice JD, Abramson DH, et al.: Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 1997;278:1262-1267.
127. Kleinerman RA, Tucker MA, Abramson DH, Seddon JM, Tarone RE, Fraumeni JF: Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma. J Natl Cancer Inst 2007;99:24-31.
128. Shinohara ET, DeWees T, Perkins SM: Subsequent malignancies and their effect on survival in patients with retinoblastoma. Pediatr Blood Cancer 2014;61:116-119.
129. Tonorezos ES, Friedman DN, Barnea D, et al.: Recommendations for long-term follow-up of adults with heritable retinoblastoma. Ophthalmology 2020;127:1549-1557.
130. Schneider K, Zelley K, Nichols KE, Garber J, Li-Fraumeni Syndrome. GeneReviews(®), 2019. http://europepmc.org/books/NBK1311
131. Bougeard G, Renaux-Petel M, Flaman JM, et al.: Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol 2015;33:2345-2352.
132. Mirabello L, Yeager M, Mai PL, et al.: Germline TP53 variants and susceptibility to osteosarcoma. J Natl Cancer Inst 2015;107:101.
133. Hameed M, Mandelker D: Tumor syndromes predisposing to osteosarcoma. Adv Anat Pathol 2018;25:217-222.
134. Ottaviani G, Jaffe N: The epidemiology of osteosarcoma. Cancer Treat Res 2009;152:3-13.
135. Ballinger ML, Mitchell G, Thomas DM: Surveillance recommendations for patients with germline TP53 mutations. Curr Opin Oncol 2015;27:332-337.
136. McBride KA, Ballinger ML, Killick E, et al.: Li-Fraumeni syndrome: Cancer risk assessment and clinical management. Nat Rev Clin Oncol 2014;11:260-271.
137. Daly MB, Pilarski R, Axilbund JE, et al.: NCCN clinical practical guidelines in oncology genetic/familial high-risk assessment: Breast and ovarian. Natl Compr Cancer Netw 2017. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#genetics_screening
138. Villani A, Shore A, Wasserman JD, et al.: Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol 2016;17:1295-1305.
139. Villani A, Tabori U, Schiffman J, et al.: Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: A prospective observational study. Lancet Oncol 2011;12:559-567.
140. Kratz CP, Achatz MI, Brugieres L, et al.: Cancer screening recommendations for individuals with Li-Fraumeni syndrome. Clin Cancer Res 2017;23:e38-e45.
141. Wang LL, Plon SE, Rothmund-Thomson Syndrome. GeneReviews®. 2020. https://www.ncbi.nlm.nih.gov/books/NBK1237/
142. Ghosh AK, Rossi ML, Singh DK, et al.: RECQL4, the protein mutated in Rothmund-Thomson syndrome, functions in telomere maintenance. J Biol Chem 2012;287:196-209.
143. Wang LL, Gannavarapu A, Kozinetz CA, et al.: Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J Natl Cancer Inst 2003;95:669-674.
144. Simon T, Kohlhase J, Wilhelm C, Kochanek M, De Carolis B, Berthold F: Multiple malignant diseases in a patient with Rothmund–Thomson syndrome with RECQL4 mutations: Case report and literature review. Am J Med Genet 2010;152A:1575-1579.
145. German J: Bloom's syndrome. XX. The first 100 cancers. Cancer Genet Cytogenet 1997;93:100-106.
146. Hafsi W, Badri T, Rice AS. Bloom Syndrome. StatPearls. 2021. https://www.ncbi.nlm.nih.gov/books/NBK448138/
147. Li L, Eng C, Desnick RJ, German J, Ellis NA: Carrier frequency of the Bloom syndrome blmAsh mutation in the Ashkenazi Jewish population. Mol Genet Metab 1998;64:286-290.
148. Flanagan M, Cunniff C. Bloom Syndrome. NCBI Bookshelf. 2019. http://europepmc.org/books/NBK1398
149. Oshima J, Sidorova JM, Monnat RJ: Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev 2017;33:105-114.
150. Lauper JM, Krause A, Vaughan TL, Monnat RJ: Spectrum and risk of neoplasia in werner syndrome: A systematic review. PLoS One 2013;8:e59709.
151. Multhoff G, Molls M, Radons J: Chronic inflammation in cancer development. Front Immunol 2011;2:98.
152. Panteli M, Puttaswamaiah R, Lowenberg DW, Giannoudis PV: Malignant transformation in chronic osteomyelitis: Recognition and principles of management. J Am Acad Orthop Surg 2014;22:586-594.
153. Kerr-Valentic MA, Samimi K, Rohlen BH, Agarwal JP, Rockwell WB: Marjolin's ulcer: Modern analysis of an ancient problem. Plast Reconstr Surg 2009;123:184-191.
154. Bauer T, David T, Rimareix F, Lortat-Jacob A, LortAt-JAcob A: Marjolin's ulcer in chronic osteomyelitis: Seven cases and a review of the literature [in French]. Rev Chir Orthop Reparatrice Appar Mot 2007;93:63-71.
155. Onah II, Olaitan PB, Ogbonnaya IS, Onuigbo WIB: Marjolin's ulcer (correction of ulcer) at a Nigerian hospital (1993-2003). J Plast Reconstr Aesthet Surg2006;59:565-566.
156. Altay M, Arikan M, Yildiz Y, Saglik Y: Squamous cell carcinoma arising in chronic osteomyelitis in foot and ankle. Foot Ankle Int 2004;25:805-809.
157. Alami M, Mahfoud M, El Bardouni A, Berrada MS, El Yaacoubi M: Squamous cell carcinoma arising from chronic osteomyelitis. Acta Orthop Traumatol Turc 2011;45:144-148.
158. Pandey M, Kumar P, Khanna AK: Marjolin's ulcer associated with chronic osteomyelitis. J Wound Care 2009;18:504-506.
159. Inoue YZ, Frassica FJ, Sim FH, Unni KK, Petersen IA, McLeod RA: Clinicopathologic features and treatment of postirradiation sarcoma of bone and soft tissue. J Surg Oncol 2000;75:42-50.
160. Mavrogenis AF, Pala E, Guerra G, Ruggieri P: Post-radiation sarcomas. Clinical outcome of 52 Patients. J Surg Oncol 2012;105:570-576.
161. Joo MW, Kang YK, Ogura K, et al.: Post-radiation sarcoma: A study by the Eastern Asian Musculoskeletal Oncology Group. PLoS One 2018;13:e0204927.
162. Bjerkehagen B, Smeland S, Walberg L, et al.: Radiation-induced sarcoma: 25-year experience from the Norwegian radium hospital. Acta Oncologica 2008;47:1475-1482.
163. Kim KS, Chang JH, Choi N, et al.: Radiation-induced sarcoma: A 15-year experience in a single large tertiary referral center. Cancer Res Treat 2016;48:650-657.
164. Virtanen A, Pukkala E, Auvinen A: Incidence of bone and soft tissue sarcoma after radiotherapy: A cohort study of 295, 712 Finnish cancer patients. Int J Cancer 2006;118:1017-1021.
165. Menu-Branthomme A, Rubino C, Shamsaldin A, et al.: Radiation dose, chemotherapy and risk of soft tissue sarcoma after solid tumours during childhood. Int J Cancer 2004;110:87-93.
166. Lesluyes T, Baud J, Pérot G, et al.: Genomic and transcriptomic comparison of post-radiation versus sporadic sarcomas. Mod Pathol 2019;32:1786-1794.
167. Shaheen M, Deheshi BM, Riad S, et al.: Prognosis of radiation-induced bone sarcoma is similar to primary osteosarcoma. Clin Orthop Relat Res 2006;450:76-81.