An 18-year-old girl with quadriplegic cerebral palsy underwent posterior spinal fusion from T2 to the pelvis 3 weeks ago. She now has a low-grade fever and mild midline erythema in a 1-cm area from which there is slight clear yellowish drainage. What

Wound culture with incision and debridement, IV antibiotics, and retention of instrumentation

What is the recommended treatment of a skeletally immature 12-year-old boy who has an anterior cruciate ligament-deficient knee?

Reduced activity, rehabilitation exercises, and functional bracing until the patient is near skeletal maturity

Figures 1a through 1c are the radiographs of a 40-year-old woman who sustained a minor injury to her left ring finger. Prior to this injury, she was asymptomatic, but she now notes pain and swelling. What is the best course of treatment?

Splint immobilization with curettage and possible grafting after the fracture has healed

What do the T2-weighted, fat-saturated MRI scans shown in Figures 76a through 76d reveal? Review Topic

ACL tear and medial meniscus tear

A 43-year-old man who works as a plumber has a painful stiff elbow in his dominant arm. He notes that while he recalls no single event of injury, he thinks the many years of pulling wrenches and soldering pipes have resulted in his problem. He report

Osteophyte resection and capsular release

Orthopedic Pathology Review MCQs | Basic Science

Question 1

A 15-year-old boy presents with knee pain and a mass in the distal femur. A biopsy reveals malignant mesenchymal cells producing osteoid. The patient's family history is significant for a sister who developed breast cancer at age 28 and a mother who died of an adrenocortical carcinoma. Which of the following gene mutations is most likely associated with this patient's underlying syndrome?

Explanation

The patient's presentation and family history are classic for Li-Fraumeni syndrome, an autosomal dominant disorder caused by a germline mutation in the TP53 tumor suppressor gene. Patients are at high risk for osteosarcoma, breast cancer, leukemia, brain tumors, and adrenocortical carcinoma. EXT1 is associated with multiple hereditary exostoses. RB1 is associated with hereditary retinoblastoma (also high risk for osteosarcoma, but different family history). GNAS is associated with fibrous dysplasia/McCune-Albright syndrome. RECQL4 is associated with Rothmund-Thomson syndrome.

Question 2

A 12-year-old boy presents with a painful, swollen thigh. Radiographs demonstrate a diaphyseal permeative lytic lesion with a periosteal 'onion skin' reaction. Biopsy reveals uniform small round blue cells expressing CD99. Which of the following is the most common cytogenetic abnormality associated with this tumor?

Explanation

Ewing sarcoma is characterized by the t(11;22)(q24;q12) translocation, which fuses the EWSR1 gene on chromosome 22 with the FLI1 gene on chromosome 11. t(X;18) is seen in synovial sarcoma. t(12;16) is seen in myxoid liposarcoma. t(2;13) is seen in alveolar rhabdomyosarcoma. t(9;22)(q22;q12) is seen in extraskeletal myxoid chondrosarcoma (EWSR1-NR4A3) or a variant of Ewing sarcoma (EWSR1-ERG, t(21;22)).

Question 3

A 32-year-old woman presents with knee pain. Radiographs reveal an eccentric, lytic epiphyseal lesion in the proximal tibia. Biopsy shows multinucleated giant cells in a background of mononuclear stromal cells. Denosumab therapy is considered for this patient. What is the mechanism of action of this drug?

Explanation

Denosumab is a monoclonal antibody that binds to RANKL. In Giant Cell Tumor of bone, the neoplastic cells are the mononuclear stromal cells, which express high levels of RANKL. This RANKL binds to the RANK receptor on the non-neoplastic osteoclast-like giant cells, promoting their differentiation and leading to osteolysis. Denosumab interrupts this pathway by binding to RANKL, preventing osteoclast formation and bone destruction.

Question 4

A 55-year-old man presents with a large, painful mass in his pelvis. Biopsy shows a cartilaginous tumor with hypercellularity, pleomorphism, and binucleated cells. Foci of the tumor show abrupt transition to a high-grade, non-cartilaginous spindle cell sarcoma. What is the most likely diagnosis?

Explanation

Dedifferentiated chondrosarcoma is characterized by a low-grade cartilaginous tumor (usually enchondroma or low-grade chondrosarcoma) that undergoes an abrupt histologic transition to a high-grade, non-cartilaginous sarcoma (such as osteosarcoma, fibrosarcoma, or undifferentiated pleomorphic sarcoma). It has a very poor prognosis. Mesenchymal chondrosarcoma features a biphasic pattern of small round blue cells and islands of well-differentiated cartilage.

Question 5

A 14-year-old girl sustains a minor fall and complains of persistent arm pain. Radiographs show an expansile, multiloculated, radiolucent lesion in the metaphysis of the humerus. MRI demonstrates multiple fluid-fluid levels. Genetic analysis of the biopsy tissue is most likely to reveal a rearrangement involving which of the following genes?

Explanation

Primary Aneurysmal Bone Cysts (ABCs) are now recognized as true neoplasms driven by translocations involving the USP6 gene on chromosome 17p13. The most common translocation is t(16;17)(q22;p13), fusing CDH11 to USP6. GNAS is mutated in fibrous dysplasia. IDH1/2 are mutated in enchondromas and chondrosarcomas. EXT1/EXT2 are mutated in osteochondromas. BRAF mutations are seen in Langerhans cell histiocytosis and non-ossifying fibromas.

Question 6

A 25-year-old man presents with a long history of anterior tibial bowing and pain. Radiographs show a multiloculated, 'soap bubble' radiolucent lesion in the anterior diaphyseal cortex of the tibia. Biopsy reveals a biphasic tumor with both epithelial and osteofibrous components. Immunohistochemistry will be strongly positive for which of the following?

Explanation

The clinical scenario describes an adamantinoma, a rare low-grade malignant bone tumor that almost exclusively occurs in the anterior diaphyseal cortex of the tibia. It has a biphasic histologic pattern containing both epithelial cells and a fibrous stroma. The epithelial cells will stain positive for epithelial markers such as cytokeratins (e.g., AE1/AE3). Osteofibrous dysplasia can resemble adamantinoma clinically and radiographically but generally lacks the prominent epithelial islands (though it can have scattered cytokeratin-positive cells).

Question 7

A 9-year-old girl presents with a limp and a discrepancy in leg length. Radiographs demonstrate a 'ground-glass' appearance in the proximal femur with a 'shepherd's crook' deformity. She is also noted to have large, irregular hyperpigmented macules on her trunk. Which endocrine abnormality is most commonly associated with this patient's condition?

Explanation

The patient has McCune-Albright syndrome, which is characterized by the triad of polyostotic fibrous dysplasia, café-au-lait spots (with irregular 'coast of Maine' borders), and endocrine hyperfunction. The most common endocrinopathy is precocious puberty, although hyperthyroidism, growth hormone excess, and Cushing syndrome can also occur. The syndrome is caused by a post-zygotic activating mutation in the GNAS gene, leading to mosaicism.

Question 8

A 40-year-old woman is incidentally found to have a well-circumscribed, lobulated, cartilaginous lesion in the proximal humerus with punctate calcifications. There is no endosteal scalloping or cortical breakthrough. Molecular testing of such lesions frequently demonstrates mutations in which of the following enzymes?

Explanation

Somatic mutations in the isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) genes are found in the majority of solitary enchondromas and central chondrosarcomas. These mutations lead to the production of an oncometabolite, 2-hydroxyglutarate (2-HG), which alters DNA methylation and promotes tumorigenesis. Multiple enchondromatosis (Ollier disease and Maffucci syndrome) is also associated with IDH1/2 mutations.

Question 9

A 60-year-old man presents with chronic low back pain and new-onset bowel incontinence. MRI shows a large, destructive midline mass involving the sacrum. Biopsy reveals lobules of physaliferous cells with a myxoid stroma. Which of the following immunohistochemical markers is most specific for this diagnosis?

Explanation

Chordoma is a rare, locally aggressive tumor arising from remnants of the embryonic notochord, most commonly occurring in the sacrococcygeal region or spheno-occipital (clivus) region. Histologically, it is characterized by large, vacuolated cells known as physaliferous cells. While chordomas stain positive for cytokeratin, EMA, and S-100, the nuclear transcription factor brachyury is highly specific for notochordal differentiation and is the hallmark diagnostic marker for chordoma.

Question 10

A 28-year-old woman presents with a slow-growing, painful mass near her knee joint. MRI shows a heterogeneous soft tissue mass adjacent to, but not within, the knee joint capsule, with calcifications. Core biopsy shows a biphasic tumor with spindle cells and glandular-like epithelial elements. Cytogenetic evaluation is most likely to show which translocation?

Explanation

Synovial sarcoma is characterized by the t(X;18)(p11;q11) translocation, which results in the fusion of the SS18 (formerly SYT) gene on chromosome 18 with one of the SSX genes (SSX1, SSX2, or SSX4) on the X chromosome. Despite its name, it rarely arises within a joint cavity, typically presenting in periarticular soft tissues. It can be biphasic (spindle and epithelial cells) or monophasic (spindle cells only).

Question 11

A 19-year-old male presents with severe nocturnal pain in his right thigh that is dramatically relieved by ibuprofen. Radiographs show a small radiolucent nidus surrounded by dense reactive sclerosis in the femoral diaphysis. The profound pain relief provided by NSAIDs is primarily due to the high local production of which of the following?

Explanation

Osteoid osteoma is a benign bone-forming tumor characterized by a central nidus (<1.5 cm) surrounded by reactive sclerosis. The tumor cells produce exceptionally high levels of prostaglandins, particularly PGE2, largely due to strong expression of cyclooxygenase-2 (COX-2). This high PGE2 concentration mediates the intense, nocturnal pain, which explains the characteristic dramatic response to NSAIDs (which inhibit COX enzymes).

Question 12

A 35-year-old man undergoes arthroscopy for chronic knee swelling and locking. The synovium is diffusely hypertrophic and reddish-brown. Histology shows mononuclear cells, multinucleated giant cells, and prominent hemosiderin deposition. The pathogenesis of this condition is primarily driven by an overexpression of which of the following?

Explanation

Pigmented Villonodular Synovitis (PVNS), now classified as Tenosynovial Giant Cell Tumor (TGCT), is a neoplastic process driven by a specific genetic alteration in a minority of the cells. The neoplastic mononuclear cells have a translocation involving the Colony Stimulating Factor 1 (CSF1) gene, leading to its overexpression. The excess CSF1 acts in a paracrine manner to recruit a massive influx of non-neoplastic macrophages and multinucleated giant cells, which make up the bulk of the tumor. Drugs blocking the CSF1 receptor (e.g., pexidartinib) are effective treatments for extensive disease.

Question 13

A 10-year-old boy presents with a pathologic fracture through a central, lytic, expansile lesion in the proximal humerus metaphyseal-diaphyseal junction. A 'fallen leaf' sign is noted on the radiograph. If the lesion had been aspirated prior to fracture, the fluid obtained would typically show high levels of which of the following compared to serum?

Explanation

Unicameral bone cysts (UBCs), or simple bone cysts, are fluid-filled cavities primarily found in the long bones of children. The cystic fluid has been shown to contain high concentrations of prostaglandins (especially PGE2), interleukins, and other bone-resorbing factors compared to serum. This has historically been a rationale for treating them with intralesional corticosteroid injections, which inhibit prostaglandin synthesis.

Question 14

A 6-year-old boy presents with skull pain and a soft tissue mass over his parietal bone. Radiographs show a 'punched-out' lytic lesion with no sclerotic rim. Biopsy reveals sheets of mononuclear cells with grooved, 'coffee-bean' nuclei admixed with eosinophils. These cells will characteristically test positive for S-100, CD1a, and which other immunohistochemical marker?

Explanation

Langerhans Cell Histiocytosis (LCH) features a proliferation of abnormal Langerhans cells. Histologically, these cells have pale, grooved nuclei (coffee-bean shape) and are often accompanied by an eosinophilic infiltrate. The classic immunophenotype for LCH cells includes positivity for S-100, CD1a, and Langerin (CD207). Electron microscopy historically showed Birbeck granules (tennis racket-shaped organelles), the formation of which is mediated by Langerin. Activating mutations in BRAF (most commonly V600E) are found in >50% of LCH cases.

Question 15

A 65-year-old man presents with diffuse back pain, fatigue, and recent weight loss. Laboratory studies show anemia and hypercalcemia. Radiographs demonstrate multiple 'punched-out' lytic lesions in the skull and vertebrae. Bone marrow biopsy is likely to show a proliferation of neoplastic cells that express which of the following surface markers?

Explanation

The clinical picture is classic for multiple myeloma, a plasma cell dyscrasia characterized by CRAB symptoms (hyperCalcemia, Renal involvement, Anemia, Bone lytic lesions). Neoplastic plasma cells typically lose early B-cell markers like CD20 and strongly express plasma cell markers such as CD138 (syndecan-1) and CD38.

Question 16

A 30-year-old man presents with a slowly enlarging, painful mass bound to the Achilles tendon. Biopsy reveals nests of pale, spindled to epithelioid cells. The cells are strongly positive for S-100, HMB-45, and Melan-A. Molecular testing reveals a t(12;22)(q13;q12) translocation. What is the most appropriate diagnosis?

Explanation

Clear cell sarcoma of soft parts is often called 'melanoma of soft parts' because it shares immunophenotypic features with melanoma, strongly expressing neural crest/melanocytic markers (S-100, HMB-45, Melan-A). However, unlike conventional melanoma, clear cell sarcoma is defined by the specific translocation t(12;22)(q13;q12), which fuses the EWSR1 gene to the ATF1 gene. It typically arises in deep soft tissues, often associated with tendons or aponeuroses of the lower extremities.

Question 17

A 28-year-old woman presents with a slow-growing, painless mass on the posterior aspect of her distal femur. Radiographs reveal a heavily ossified, lobulated mass attached to the posterior cortex by a broad base, with a 'string sign' visible between the tumor and the underlying bone. Histology shows low-grade spindle cells between well-formed trabeculae of woven bone. This tumor is characterized by the amplification of which gene?

Explanation

Parosteal osteosarcoma is a low-grade, surface-based osteosarcoma that most commonly occurs on the posterior aspect of the distal femur. Radiographically, it is heavily ossified and may show a radiolucent cleft (string sign) separating it from the underlying cortex. Cytogenetically, parosteal osteosarcomas are characterized by supernumerary ring chromosomes containing amplifications of the 12q13-15 region, which includes the MDM2 and CDK4 genes. MDM2 inhibits p53. (This same amplification is seen in well-differentiated/dedifferentiated liposarcomas).

Question 18

A 12-year-old boy has a radiograph of his knee following a minor twisting injury, which incidentally reveals an eccentric, radiolucent, multi-loculated lesion with a sclerotic margin in the distal femoral metaphysis. Biopsy would typically reveal spindle cells in a storiform pattern admixed with multinucleated giant cells and clusters of lipid-laden macrophages. Which of the following pathways is often mutated in these lesions?

Explanation

Non-ossifying fibroma (NOF) is a common benign fibrohistiocytic bone lesion of childhood, typically presenting as an incidental eccentric, sclerotic-rimmed radiolucency. Histologically, they consist of spindle cells in a storiform pattern, giant cells, and foam cells. Recent molecular studies have shown that NOFs frequently harbor activating somatic mutations in the MAPK/ERK pathway, most notably in the KRAS, FGFR1, or BRAF genes. Jaffe-Campanacci syndrome involves multiple NOFs, café-au-lait spots, and is linked to the MAPK pathway (often neurofibromatosis-related).

Question 19

A 16-year-old boy presents with right knee pain. Radiographs reveal a well-defined, 2 cm lytic lesion within the epiphysis of the proximal tibia with a thin sclerotic rim. Biopsy demonstrates mononuclear cells with 'chicken-wire' calcifications. Immunohistochemistry of this tumor frequently shows positivity for which of the following?

Explanation

Chondroblastoma is a rare benign cartilaginous bone tumor that characteristically arises in the epiphysis or apophysis of long bones in skeletally immature patients. Histology shows sheets of uniform, round to polygonal mononuclear cells (chondroblasts), multinucleated giant cells, and a classic pericellular 'chicken-wire' pattern of calcification. Because they are of cartilaginous origin, chondroblasts are typically S-100 positive. They are also characterized by H3F3B (histone H3.3) gene mutations.

Question 20

A 60-year-old man presents with a massive, deep intramuscular mass in his proximal thigh. Biopsy reveals a well-differentiated liposarcoma. He undergoes marginal excision, but the tumor recurs rapidly 18 months later. Re-biopsy of the recurrence shows areas of high-grade, non-lipogenic sarcoma consistent with dedifferentiation. Molecular analysis of both the primary and recurrent tumor will show amplification of:

Explanation

Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are characterized cytogenetically by amplification of the 12q13-15 region, which leads to overexpression of the MDM2 and CDK4 genes. MDM2 is an E3 ubiquitin ligase that degrades the p53 tumor suppressor. A t(12;16) translocation (FUS-DDIT3) is the hallmark of myxoid liposarcoma, a completely different subtype of liposarcoma with distinct clinical and histologic features.

Question 21

A 55-year-old man presents with progressive pelvic pain. Radiographs reveal a large, expansile radiolucent lesion in the ilium with internal 'rings and arcs' calcifications. Biopsy demonstrates hypercellular hyaline cartilage with nuclear atypia and myxoid changes. Which of the following gene mutations is most frequently implicated in the pathogenesis of this tumor?

Explanation

This patient has a conventional chondrosarcoma. Mutations in IDH1 and IDH2 are found in up to 50% of conventional central chondrosarcomas and enchondromas.

Question 22

A 25-year-old man presents with a slow-growing, painful mass near his ankle joint. MRI shows a soft tissue mass adjacent to, but not communicating with, the joint space. Biopsy reveals a biphasic pattern consisting of epithelial elements forming gland-like structures and a spindle cell stroma. Which of the following chromosomal translocations is characteristic of this lesion?

Explanation

Synovial sarcoma is characterized by the t(X;18)(p11;q11) translocation, which results in the SYT-SSX fusion gene. Despite its name, it rarely arises from within the joint space.

Question 23

A 10-year-old girl is evaluated for a limp and a leg-length discrepancy. Radiographs show a 'shepherd's crook' deformity of the proximal femur with 'ground-glass' opacities. Physical exam reveals large, irregular café-au-lait macules. What is the underlying molecular mechanism of her condition?

Explanation

McCune-Albright syndrome consists of polyostotic fibrous dysplasia, café-au-lait spots, and endocrinopathies. It is caused by an activating missense mutation in the GNAS gene, leading to excessive cAMP production.

Question 24

A 16-year-old girl complains of localized pain in her proximal humerus. Radiographs show an eccentric, expansile, lytic metaphyseal lesion with cortical thinning. MRI reveals multiple fluid-fluid levels. Biopsy shows blood-filled cystic spaces lacking an endothelial lining. Which of the following genetic alterations is diagnostic for the primary form of this lesion?

Explanation

Primary aneurysmal bone cysts (ABCs) are neoplastic and driven by translocations involving the USP6 gene on chromosome 17. Secondary ABCs lack this mutation.

Question 25

A 45-year-old man has a large, painless mass deep in his posterior thigh. Histologic examination reveals uniform, small, round to oval cells, scattered lipoblasts, and a prominent arborizing capillary network described as 'chicken wire' vasculature in a myxoid background. Which translocation is diagnostic?

Explanation

Myxoid liposarcoma is characterized by the t(12;16) translocation creating the FUS-DDIT3 fusion protein. The 'chicken wire' capillary network is a classic histological hallmark.

Question 26

A 14-year-old boy presents with knee pain. Radiographs show a well-defined lytic lesion in the epiphysis of the proximal tibia with a sclerotic rim. Biopsy reveals mononuclear cells with longitudinal nuclear grooves and 'chicken wire' calcifications. Which of the following gene mutations is highly specific for this tumor?

Explanation

Chondroblastoma typically occurs in the epiphysis of skeletally immature patients and is characterized by mutations in the H3F3B gene. Giant cell tumors, in contrast, typically harbor H3F3A mutations.

Question 27

A 25-year-old man presents with anterior tibial pain. Radiographs show a multilocular, eccentric, diaphyseal lytic lesion with cortical thickening. Histology reveals nests of epithelial-appearing cells in a fibrous stroma. Which immunohistochemical marker will best differentiate this lesion from osteofibrous dysplasia?

Explanation

Adamantinoma exhibits a biphasic histology with epithelial cells that stain positive for cytokeratin. While osteofibrous dysplasia can have scattered keratin-positive cells, broad cytokeratin positivity is diagnostic of adamantinoma.

Question 28

A 30-year-old woman presents with a slow-growing nodule attached to her Achilles tendon. The tumor consists of nests of uniform spindle cells with clear cytoplasm separated by dense fibrous septa. Immunohistochemistry is positive for HMB-45 and S-100. What is the associated cytogenetic abnormality?

Explanation

Clear cell sarcoma (malignant melanoma of soft parts) presents in tendons/aponeuroses and shares melanocytic markers (S-100, HMB-45) with melanoma. It is distinguished by the t(12;22) translocation.

Question 29

A 35-year-old woman reports recurrent knee swelling without trauma. Joint aspiration yields brownish fluid. MRI reveals a thickened synovium with hypointense nodules on T2-weighted imaging showing 'blooming' artifact. The pathogenesis of this condition is driven by a translocation leading to the overexpression of which factor?

Explanation

Tenosynovial giant cell tumor (formerly PVNS) is driven by a t(1;2) translocation causing overexpression of colony-stimulating factor 1 (CSF1). This recruits non-neoplastic inflammatory cells that form the bulk of the tumor.

Question 30

A 6-year-old boy presents with back pain and a solitary 'punched-out' lytic lesion in his skull. Spine radiographs show a complete collapse of the T8 vertebral body (vertebra plana). Biopsy reveals cells with reniform nuclei and eosinophilic cytoplasm, intermixed with eosinophils. Which marker is diagnostic?

Explanation

Langerhans cell histiocytosis (LCH) presents with solitary or multiple lytic bone lesions and vertebra plana in children. The neoplastic Langerhans cells are characteristically positive for CD1a, S100, and Langerin (CD207).

Question 31

A 60-year-old man presents with insidious onset of sacral pain and recent bowel/bladder incontinence. Imaging reveals a destructive midline sacral mass. Biopsy shows large cells with copious bubbly cytoplasm in a myxoid stroma. Which immunohistochemical marker is highly specific for the presumed diagnosis?

Explanation

Chordoma arises from notochordal remnants and classically presents in the sacrum or clivus with physaliferous ('bubbly') cells. Brachyury is a highly specific nuclear transcription factor marker for notochordal differentiation.

Question 32

A 14-year-old boy is evaluated for short stature and multiple hard, painless bumps around his knees and wrists. Radiographs confirm multiple pedunculated bone projections pointing away from the joints. The genetic mutations responsible for this syndrome directly impair the synthesis of which of the following?

Explanation

Multiple hereditary exostoses (MHE) is caused by mutations in EXT1 or EXT2. These genes encode glycosyltransferases essential for the polymerization of heparan sulfate chains.

Question 33

A 20-year-old man presents with an aching back pain that is poorly relieved by NSAIDs. Imaging reveals a 3.5 cm lytic lesion with a sclerotic rim in the posterior elements of L3. Histology shows irregular osteoid trabeculae lined by plump osteoblasts in a highly vascular stroma. What is the most likely diagnosis?

Explanation

Osteoblastoma is histologically identical to osteoid osteoma but is distinguished by a size greater than 2 cm, progressive pain less responsive to NSAIDs, and a higher propensity for progressive growth.

Question 34

A 70-year-old man presents with anterior bowing of the tibia and progressive hearing loss. Labs show an elevated alkaline phosphatase with normal calcium and phosphorus. Biopsy of the tibia shows a mosaic pattern of lamellar bone. The primary cellular defect in this disease is located in which cell type?

Explanation

Paget disease of bone is initiated by hyperactive, highly multinucleated osteoclasts, often linked to SQSTM1 mutations. The abnormal osteoblastic bone formation (mosaic pattern) is a secondary reactive process.

Question 35

A 15-year-old boy presents with a rapidly growing mass deep in his forearm. Histology demonstrates malignant small round blue cells arranged in nests separated by fibrous septa, forming cleft-like spaces. Molecular testing confirms the presence of which of the following genetic fusions?

Explanation

Alveolar rhabdomyosarcoma frequently involves the extremities in adolescents and is characterized by the t(2;13) translocation, resulting in the PAX3-FOXO1 fusion gene. It is highly aggressive.

Question 36

A 30-year-old postpartum woman presents with a firm mass in her abdominal wall. Excisional biopsy reveals a poorly circumscribed proliferation of bland spindle cells surrounded by dense collagen, lacking significant pleomorphism or atypical mitoses. Which of the following signaling pathways is characteristically altered in this lesion?

Explanation

Desmoid fibromatosis features mutations in either the APC or CTNNB1 genes, leading to dysregulation of the Wnt/beta-catenin signaling pathway. Nuclear beta-catenin staining is a useful diagnostic marker.

Question 37

A 25-year-old woman is evaluated for multiple bony deformities and soft tissue nodules. Imaging shows numerous enchondromas and multiple phleboliths in the soft tissues, indicative of hemangiomas. Which of the following mutations is most strongly associated with her underlying syndrome?

Explanation

Maffucci syndrome involves multiple enchondromas and soft tissue spindle cell hemangiomas. Like Ollier disease, it is strongly associated with somatic mosaic mutations in IDH1 or IDH2.

Question 38

A 65-year-old woman with a history of breast cancer treated with local radiation 15 years ago presents with severe shoulder pain. Radiographs show a destructive, permeative lytic lesion in the proximal humerus with an aggressive periosteal reaction. Biopsy confirms a secondary bone sarcoma. What is the most common histologic subtype in this setting?

Explanation

Radiation-induced secondary osteosarcomas are almost exclusively high-grade conventional osteosarcomas (often osteoblastic or fibroblastic). They carry a very poor prognosis compared to primary osteosarcomas.

Question 39

A 25-year-old man presents with jaw pain. Imaging reveals a well-defined lytic lesion in the mandible. Histology shows abundant interlacing collagen fibers and bland spindle cells, identical to a soft-tissue desmoid tumor. It is locally aggressive. What is the diagnosis?

Explanation

Desmoplastic fibroma is a rare primary bone tumor considered the intraosseous counterpart to soft tissue desmoid fibromatosis. It features bland spindle cells and abundant collagen, and has a high local recurrence rate.

Question 40

A 30-year-old woman presents with a painless, hard mass behind her knee. Radiographs reveal a heavily ossified, lobulated mass attached to the posterior cortex of the distal femur by a broad base, with a visible radiolucent cleft (string sign). Which molecular hallmark is diagnostic of this condition?

Explanation

Parosteal osteosarcoma is a low-grade surface osteosarcoma characterized by amplification of the MDM2 and CDK4 genes on chromosome 12q13-15. The 'string sign' represents a cleavage plane between the tumor and the underlying cortex.

Question 41

A 14-year-old boy presents with knee pain. Radiographs show an eccentric epiphyseal lytic lesion in the proximal tibia with a sclerotic margin. Biopsy shows polyhedral mononuclear cells with grooved nuclei and scattered multinucleated giant cells with fine chicken-wire calcifications. Which of the following mutations is most characteristic of this lesion?

Explanation

The clinical and histological description is classic for a chondroblastoma. These tumors are driven by a specific H3F3B (K36M) mutation, which reliably differentiates them from giant cell tumors of bone that harbor H3F3A (G34W) mutations.

Question 42

A 35-year-old woman presents with a slow-growing mass on the posterior aspect of her distal femur. Radiographs reveal a heavily ossified, broad-based mass attached to the cortex with a radiolucent cleft between the mass and bone. Histology shows well-differentiated bone trabeculae and a low-grade fibroblastic stroma. Which of the following genetic alterations is most specific for this diagnosis?

Explanation

This is a parosteal osteosarcoma, a low-grade surface malignancy. It is cytogenetically characterized by supernumerary ring chromosomes leading to the amplification of MDM2 and CDK4 genes on chromosome 12.

Question 43

A 25-year-old man presents with a painful swelling in his right foot. MRI shows a soft tissue mass with high signal on T2. Biopsy reveals spindle cells and epithelial cells forming glandular structures. The tumor is positive for cytokeratin, EMA, and TLE1. Which of the following translocations is diagnostic?

Explanation

The diagnosis is a biphasic synovial sarcoma, which frequently arises in the extremities of young adults. It is driven by the t(X;18)(p11;q11) translocation, resulting in the SYT-SSX fusion gene.

Question 44

A 10-year-old girl is evaluated for precocious puberty, irregular cafe-au-lait spots, and multiple lytic bone lesions exhibiting a ground-glass appearance. Biopsy of a bone lesion shows curvilinear woven bone lacking osteoblastic rimming. The pathogenesis of this syndrome involves a mutation in a gene encoding which of the following?

Explanation

McCune-Albright syndrome consists of polyostotic fibrous dysplasia, cafe-au-lait spots, and endocrinopathies. It is caused by a post-zygotic activating mutation in the GNAS gene, which encodes the stimulatory alpha subunit of G-proteins.

Question 45

A 40-year-old man presents with a locally aggressive soft tissue mass in the deep tissues of his thigh. Biopsy shows a biphasic population of osteoclast-like giant cells and mononuclear cells, with abundant hemosiderin deposition. Cytogenetic analysis identifies a t(1;2)(p13;q37) translocation. The targeted therapy for severe, unresectable cases typically inhibits which of the following?

Explanation

Tenosynovial giant cell tumor (pigmented villonodular synovitis) features a t(1;2) translocation causing CSF1 overexpression. Pexidartinib, a targeted CSF1R inhibitor, is approved for advanced, symptomatic cases.

Question 46

A 28-year-old man presents with an expansile, multiloculated radiolucent lesion in the metaphysis of his proximal tibia. MRI demonstrates multiple fluid-fluid levels. Biopsy reveals blood-filled spaces separated by fibrous septa containing reactive woven bone and osteoclast-like giant cells. A gene rearrangement involving which of the following loci is pathognomonic for this primary lesion?

Explanation

Primary aneurysmal bone cysts (ABCs) are neoplastic processes characterized by USP6 gene rearrangements on chromosome 17p13. This helps distinguish primary ABCs from secondary ABCs arising in other tumors.

Question 47

A 65-year-old man presents with severe back pain and a destructive sacral mass. Biopsy reveals cords of large, vacuolated physaliferous cells in a myxoid stroma. The tumor cells are strongly positive for cytokeratin and S-100. Expression of which of the following immunohistochemical markers is most specific for confirming this diagnosis?

Explanation

Chordomas arise from notochord remnants and typically occur in the sacrum or clivus. Brachyury is a nuclear transcription factor critical for notochord development and serves as the most sensitive and specific marker for chordoma.

Question 48

An 8-year-old girl presents with a limp and shortening of the left leg. Radiographs reveal multiple expansive, purely lytic lesions with a "ground-glass" appearance in her left femur and tibia. Physical exam notes large, irregular café-au-lait macules with "coast of Maine" borders, and she has signs of precocious puberty. Which of the following gene mutations is responsible for this condition?

Explanation

McCune-Albright syndrome is characterized by polyostotic fibrous dysplasia, café-au-lait macules, and endocrinopathies like precocious puberty. It is caused by an early postzygotic, activating mutation in the GNAS gene, leading to increased intracellular cAMP.

Question 49

A 25-year-old male presents with a slowly enlarging mass on the plantar aspect of his foot. A biopsy reveals a biphasic tumor consisting of both spindle cells and epithelial cells forming gland-like structures. Which of the following chromosomal translocations is considered the pathognomonic driver for this tumor?

Explanation

Synovial sarcoma classically presents as a slow-growing mass in the extremities of young adults and can exhibit a biphasic or monophasic histologic pattern. It is uniquely driven by the t(X;18) translocation, resulting in the SYT-SSX fusion protein.

Question 50

A 14-year-old boy complains of worsening left knee pain over 3 months. Radiographs demonstrate a 2 cm eccentric, well-circumscribed, lytic epiphyseal lesion with thin sclerotic margins in the proximal tibia. Histology shows mononuclear cells with grooved (coffee bean) nuclei and areas of fine, pericellular "chicken-wire" calcification. What is the most likely diagnosis?

Explanation

Chondroblastoma is a rare, benign cartilage-producing tumor that typically arises in the epiphyses of skeletally immature patients. The histological hallmarks are chondroblasts with grooved nuclei and "chicken-wire" calcifications.

Question 51

A 16-year-old girl presents with a rapidly expanding, painful lesion in her distal femur. MRI reveals multiple fluid-fluid levels within an expansile cavity. Biopsy demonstrates blood-filled cavernous spaces lacking an endothelial lining, surrounded by septa containing fibroblasts and multinucleated giant cells. Primary lesions of this type are uniquely associated with a rearrangement of which gene?

Explanation

Primary aneurysmal bone cysts (ABCs) are genuine neoplasms driven by rearrangements of the USP6 gene (most commonly t(16;17)). Identifying this mutation helps distinguish primary ABCs from secondary ABC-like changes in other tumors.

Question 52

A 55-year-old male presents with chronic lower back pain and new-onset bowel and bladder incontinence. Imaging reveals a large, destructive, midline sacral mass. Core needle biopsy shows a lobulated architecture with large cells containing highly vacuolated cytoplasm in a myxoid stroma. Which immunohistochemical marker is highly sensitive and specific for the suspected diagnosis?

Explanation

The patient has a chordoma, a malignant bone tumor arising from notochordal remnants, characterized by physaliferous (bubbly) cells. Brachyury is a crucial transcription factor for notochord development and serves as a highly specific diagnostic marker for chordoma.

Question 53

A 60-year-old male with a history of hematuria presents with severe arm pain.

Radiographs show a large, destructive lytic lesion in the humeral diaphysis. A diagnosis of metastatic renal cell carcinoma is confirmed, and prophylactic internal fixation is planned. What is the most critical step prior to proceeding with surgical stabilization?

Explanation

Renal cell carcinoma and thyroid carcinoma metastases are notoriously hypervascular. Preoperative angiographic embolization is essential to minimize the risk of massive, life-threatening intraoperative hemorrhage during stabilization.

Question 54

A 65-year-old female presents with generalized bone pain, fatigue, and weight loss. Radiographs demonstrate multiple "punched-out" lytic skull lesions. Laboratory workup reveals hypercalcemia and an elevated creatinine level. The profound bone destruction in this condition is primarily mediated by which cytokine profile in the bone marrow microenvironment?

Explanation

In multiple myeloma, malignant plasma cells upregulate RANKL and downregulate osteoprotegerin (OPG) production by marrow stromal cells. This extreme imbalance leads to unrestrained osteoclast activation and characteristic lytic lesions without reactive bone formation.

Question 55

A 30-year-old male presents with a painful anterior shin.

Radiographs reveal a multicentric, eccentric "soap bubble" lytic lesion in the anterior tibial diaphysis. Biopsy demonstrates a biphasic tumor with nests of cytokeratin-positive epithelial cells intermixed within a bland fibrous stroma. What is the recommended definitive management?

Explanation

Adamantinoma is a low-grade malignant bone tumor that almost exclusively occurs in the anterior tibial diaphysis. Intralesional treatments have unacceptably high local recurrence rates, making wide surgical resection the standard of care.

Question 56

A 22-year-old male with a known history of multiple palpable bone bumps since childhood notes recent rapid growth and pain originating from a protuberance on his distal femur. MRI reveals an exophytic mass with marrow continuity and a peripheral cartilage cap measuring 2.5 cm in thickness. Which of the following gene mutations is characteristic of his underlying syndrome?

Explanation

Hereditary multiple exostoses (HME) is an autosomal dominant disorder caused by mutations in the EXT1 or EXT2 genes, resulting in defective heparan sulfate synthesis. A cartilage cap thicker than 2 cm in an adult strongly suggests malignant transformation of an osteochondroma into a secondary chondrosarcoma.

Question 57

A 35-year-old female presents with chronic, insidious swelling of her left knee and recurrent hemarthrosis despite no history of trauma. MRI displays extensive synovial thickening with a low signal intensity on T1 and T2, accompanied by severe blooming artifact on gradient-echo sequences. The pathogenesis of this condition involves a translocation resulting in the overexpression of which factor?

Explanation

Pigmented villonodular synovitis (tenosynovial giant cell tumor) features a neoplastic clone of cells harboring a t(1;2) translocation. This causes overexpression of colony-stimulating factor 1 (CSF-1), which recruits a massive non-neoplastic inflammatory infiltrate of macrophages.

Question 58

A 45-year-old male undergoes wide excision of a deep thigh mass. Histology demonstrates proliferating lipoblasts in a copious myxoid stroma with an intricate, arborizing "chicken-wire" capillary network. What specific cytogenetic abnormality defines this soft tissue sarcoma?

Explanation

Myxoid liposarcoma is characterized by the t(12;16) chromosomal translocation, fusing the FUS and DDIT3 genes. It is known for its distinct "chicken-wire" vascularity and an unusual propensity to metastasize to distant soft tissues and the spine rather than exclusively the lungs.

Question 59

A 70-year-old male presents with progressive hearing loss, increasing hat size, and anterolateral bowing of his tibiae. Serum alkaline phosphatase is markedly elevated, while calcium and phosphorus are normal. Familial forms of this highly active bone remodeling disorder are most strongly associated with mutations in which of the following genes?

Explanation

Paget disease of bone is driven by primary osteoclast overactivity. Mutations in the SQSTM1 gene (encoding the p62 protein) are the most common genetic cause of familial Paget disease, leading to increased osteoclastogenesis via the RANK/NF-kB pathway.

Question 60

A 24-year-old male presents with dull, aching pain in his mid-back that awakens him at night. The pain is only partially relieved by NSAIDs. CT scan shows a 2.8 cm radiolucent, expansile lesion in the posterior elements of L3 with surrounding sclerosis. How does this lesion biologically differ most significantly from an osteoid osteoma?

Explanation

Osteoblastoma is histologically identical to osteoid osteoma but is clinically distinguished by a size greater than 2 cm and a capacity for progressive local growth and bone destruction. Both lesions produce prostaglandins, though osteoblastoma pain tends to be less exquisitely responsive to NSAIDs.

Question 61

A 24-year-old male presents with a slow-growing mass in the plantar aspect of his foot. Biopsy reveals a biphasic tumor with both epithelial and spindle cell components. Cytogenetic analysis reveals a t(X;18) translocation. Which of the following fusion genes is diagnostic of this patient's condition?

Explanation

Synovial sarcoma is characterized by the t(X;18) translocation, resulting in the SYT-SSX fusion gene. It commonly presents in young adults in the extremities, notably the foot, ankle, and knee.

Question 62

A 16-year-old boy presents with chronic knee pain. Radiographs show a well-circumscribed, eccentric, lytic lesion in the epiphysis of the proximal tibia. Biopsy demonstrates mononuclear cells, osteoclast-like giant cells, and a characteristic "chicken-wire" pattern of calcification. What is the most likely diagnosis?

Explanation

Chondroblastoma is a benign, locally aggressive bone tumor that classically occurs in the epiphysis or apophysis of skeletally immature patients. Histologically, it is defined by chondroblasts, giant cells, and pericellular "chicken-wire" calcification.

Question 63

A 9-year-old girl is evaluated for a limp and a leg length discrepancy. Physical examination reveals large, irregularly bordered cafe-au-lait spots. Radiographs of the femur demonstrate a "ground-glass" appearance and a "shepherd's crook" deformity. An activating mutation in which of the following genes is responsible for this condition?

Explanation

This presentation is classic for McCune-Albright syndrome, which features polyostotic fibrous dysplasia, cafe-au-lait macules, and endocrinopathies. It is caused by an activating post-zygotic somatic mutation in the GNAS gene.

Question 64

A 65-year-old man presents with worsening back pain and fatigue. Radiographs show multiple punched-out lytic lesions in his skull and pelvis. Laboratory studies reveal hypercalcemia and anemia. A bone marrow biopsy would most likely show a proliferation of cells strongly positive for which of the following surface markers?

Explanation

Multiple myeloma is a plasma cell dyscrasia characterized by CRAB symptoms (hyperCalcemia, Renal involvement, Anemia, Bone lesions). Neoplastic plasma cells classically express the surface marker CD138 (syndecan-1).

Question 65

A 55-year-old man presents with bowel and bladder dysfunction alongside intractable sacral pain. Imaging reveals a destructive sacral midline mass.

Biopsy identifies large cells with vacuolated cytoplasm (physaliferous cells). Which immunohistochemical marker is highly sensitive and specific for confirming this diagnosis?

Explanation

Chordomas are locally aggressive malignant tumors arising from notochordal remnants, most commonly in the sacrum or clivus. They are histologically characterized by physaliferous cells and show strong nuclear expression of the transcription factor brachyury.

Question 66

A 14-year-old girl presents with pain and swelling over her distal femur. Radiographs show an eccentric, expansile, lytic metaphyseal lesion. MRI demonstrates multiple fluid-fluid levels. Genetic analysis of this lesion would most likely show a rearrangement involving which of the following genes?

Explanation

Primary aneurysmal bone cysts (ABCs) are now known to be true neoplasms driven by translocations involving the USP6 gene on chromosome 17. Secondary ABCs arise in the context of other tumors and lack this specific genetic rearrangement.

Question 67

A 68-year-old man presents with a progressively enlarging, painful pelvic mass. Radiographs show a destructive lesion with intralesional "rings and arcs" calcifications.

Which of the following mutations is most frequently associated with this primary bone malignancy?

Explanation

Conventional chondrosarcomas frequently harbor point mutations in the isocitrate dehydrogenase genes (IDH1 or IDH2). These tumors typically present in adults over 50 with characteristic cartilage matrix calcifications.

Question 68

A 25-year-old male presents with a long-standing anterior bowing deformity of his tibia and new-onset pain. Radiographs reveal a multi-loculated, "bubbly" diaphyseal osteolytic lesion. Biopsy shows nests of epithelial cells in a fibrous stroma. This tumor is most likely to be strongly positive for which marker?

Explanation

Adamantinoma is a rare, low-grade malignant bone tumor that almost exclusively occurs in the anterior diaphyseal tibia. It has a biphasic histologic pattern of epithelial and osteofibrous components, making it strongly positive for cytokeratin.

Question 69

A 12-year-old boy presents with multiple painless, bony protuberances around his knees and ankles pointing away from the joint. His father has similar lesions. The genetic mutation responsible for this condition directly causes a defect in which of the following cellular processes?

Explanation

Multiple Hereditary Exostoses (MHE) is caused by autosomal dominant mutations in the EXT1 or EXT2 genes. These genes encode glycosyltransferases essential for the synthesis of heparan sulfate, which is crucial for normal physeal regulation.

Question 70

A 7-year-old boy complains of severe neck pain. Radiographs reveal flattening of the C3 vertebral body (vertebra plana).

Biopsy reveals cells with grooved nuclei resembling coffee beans, mixed with eosinophils. Electron microscopy of the neoplastic cells would most likely demonstrate:

Explanation

Langerhans Cell Histiocytosis (LCH) frequently presents as an eosinophilic granuloma causing vertebra plana in children. The characteristic neoplastic Langerhans cells contain "tennis-racket" shaped Birbeck granules on electron microscopy and express CD1a and S100.

Question 71

A 30-year-old woman presents with a deep, firm mass in her right ankle. Biopsy shows nests of pale spindle cells separated by fibrous septa. Immunohistochemistry is strongly positive for S100 and HMB-45. What is the characteristic chromosomal translocation for this tumor?

Explanation

Clear cell sarcoma, historically known as melanoma of soft parts, typically presents in the foot and ankle of young adults and expresses melanocytic markers. It is driven by the t(12;22) translocation, creating the EWS-ATF1 fusion protein.

Question 72

An 80-year-old man presents with increasing hat size and dull, aching pain in his right femur. Laboratory studies show markedly elevated serum alkaline phosphatase with normal calcium and phosphorus levels. Which of the following gene mutations is most strongly implicated in the familial form of this disease?

Explanation

Paget disease of bone is characterized by accelerated bone remodeling, resulting in a mosaic pattern of lamellar bone. A significant proportion of familial cases are associated with mutations in the SQSTM1 gene (encoding p62), which hyperactivates osteoclasts.

Orthopedic Ob Basic Review | Dr Hutaif Basic Science Re -...

Orthopedic Pathology Review | Dr Hutaif Basic Science R -...

Key Takeaway

Orthopedic Pathology Review | Dr Hutaif Basic Science R -...

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