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

Question 1

An 11-year-old boy presents with a painful mass in the diaphysis of his femur. Radiographs show an aggressive, permeative lytic lesion with an 'onion-skin' periosteal reaction. Biopsy reveals small round blue cells. Which of the following immunohistochemical markers and translocations are most characteristic of this lesion?

Explanation

Ewing sarcoma is classically characterized by the t(11;22)(q24;q12) translocation, which leads to the EWS-FLI1 fusion protein. Immunohistochemically, it strongly expresses CD99 (MIC2), a cell surface glycoprotein.

Question 2

A 28-year-old woman presents with knee pain. Radiographs demonstrate an eccentrically located lytic lesion in the distal femoral epiphysis that extends to the subchondral bone. Histology reveals mononuclear cells and multinucleated giant cells. Which of the following best describes the true neoplastic cells in this lesion?

Explanation

In Giant Cell Tumor (GCT) of bone, the true neoplastic cells are the mononuclear spindle/stromal cells, which express RANKL. The multinucleated giant cells are reactive, non-neoplastic osteoclast-like cells that express RANK and are recruited by the neoplastic stromal cells.

Question 3

A 25-year-old man presents with a slow-growing, deep-seated mass in his popliteal fossa. Imaging reveals a soft tissue mass with punctate calcifications. Biopsy demonstrates a biphasic spindle cell neoplasm with epithelial components. What is the pathognomonic chromosomal translocation associated with this tumor?

Explanation

Synovial sarcoma is uniquely characterized by the t(X;18)(p11;q11) translocation, which fuses the SYT gene on chromosome 18 with an SSX gene (SSX1, 2, or 4) on the X chromosome. It frequently exhibits calcification on plain radiographs.

Question 4

A 14-year-old girl is evaluated for a 'shepherd's crook' deformity of her proximal femur. Radiographs show a ground-glass intramedullary lesion. She also has multiple café-au-lait spots with irregular borders and a history of precocious puberty. What is the underlying genetic mechanism of her disease?

Explanation

The patient has McCune-Albright syndrome, characterized by polyostotic fibrous dysplasia, 'coast of Maine' café-au-lait spots, and endocrinopathies. This is caused by an activating post-zygotic somatic mutation in the GNAS (GNAS1) gene, leading to overproduction of intracellular cAMP.

Question 5

A 22-year-old man presents with an anterior tibial bowing deformity and a multi-loculated, lytic 'soap-bubble' lesion in the anterior cortex of the tibial diaphysis. Biopsy shows islands of epithelial cells surrounded by fibrous stroma. Immunohistochemistry is positive for cytokeratin. What is the most appropriate definitive management?

Explanation

The presentation (anterior tibial diaphysis) and biphasic histology with cytokeratin-positive epithelial cells are diagnostic of adamantinoma, a low-grade malignant bone tumor. Because it is relatively radio- and chemo-resistant and possesses metastatic potential, wide surgical resection with negative margins is the standard of care.

Question 6

An 18-year-old male complains of severe, progressively worsening nocturnal thigh pain that is completely relieved by ibuprofen. Radiographs reveal a cortical thickening with a 7mm radiolucent nidus. Which of the following is true regarding the pathophysiology of his pain?

Explanation

Osteoid osteomas produce high levels of prostaglandins (specifically PGE2 and prostacyclin) due to significantly increased COX-2 expression in the nidus. This chemical mediator causes the intense, unremitting nocturnal pain that is characteristically responsive to NSAIDs.

Question 7

A 65-year-old man presents with back pain, fatigue, and hypercalcemia. Radiographs demonstrate multiple 'punched-out' lytic lesions in his skull and pelvis. A technetium-99m bone scan is reportedly 'cold' in the areas of these lesions. What is the primary reason for the lack of uptake on the bone scan?

Explanation

Multiple myeloma lesions are purely lytic. Technetium-99m bone scans rely on osteoblastic activity (bone formation) to take up the tracer. Myeloma cells produce factors such as DKK1 which inhibit osteoblasts, leading to a lack of reactive bone formation and a consequently 'cold' bone scan.

Question 8

A 32-year-old woman presents with a firm mass in her foot, firmly attached to the plantar fascia. Biopsy shows nests of uniform cells with clear cytoplasm separated by fibrous septa. The cells are strongly positive for S-100 and HMB-45. Which of the following translocations is diagnostic for this tumor?

Explanation

Clear cell sarcoma of soft parts (malignant melanoma of soft parts) typically presents in the distal extremities (foot/ankle) in young adults. It is positive for melanocytic markers (S-100, HMB-45) and is characterized by the t(12;22)(q13;q12) translocation resulting in the EWSR1-ATF1 fusion.

Question 9

A 25-year-old male presents with multiple asymmetric cartilaginous tumors in his hands and long bones. He also has multiple soft tissue hemangiomas on his trunk and extremities. What is his most likely underlying diagnosis, and what gene mutation is most commonly associated with it?

Explanation

Maffucci syndrome is distinguished from Ollier disease by the presence of soft-tissue hemangiomas in addition to multiple enchondromas. Both conditions are heavily associated with somatic mosaic mutations in the IDH1 or IDH2 genes.

Question 10

A 72-year-old man with increasing hat size, hearing loss, and bowing of his tibias presents for evaluation. Radiographs show thickened cortices and a 'cotton wool' appearance of the skull. A bone biopsy in the sclerotic phase would most likely reveal which of the following histological features?

Explanation

Paget's disease (osteitis deformans) has three phases: lytic, mixed, and sclerotic. In the late (sclerotic) phase, histology classically shows a haphazard, 'mosaic' pattern of lamellar bone with prominent, irregular cement lines due to chaotic, repeated cycles of bone resorption and formation.

Question 11

A 6-year-old boy presents with back pain and is found to have a severe compression fracture (vertebra plana) of T8 on radiographs. Biopsy of the lesion shows histiocytes with grooved, 'coffee-bean' nuclei, mixed with eosinophils. Electron microscopy reveals Birbeck granules. Which marker is most reliably positive on immunohistochemistry?

Explanation

Langerhans cell histiocytosis (LCH) classically presents as vertebra plana in the pediatric spine. The neoplastic Langerhans cells exhibit grooved nuclei, contain Birbeck granules (tennis racket shape on EM), and stain positively for CD1a, S-100, and Langerin (CD207).

Question 12

An 18-year-old female sustains a pathologic fracture of her proximal humerus. Radiographs show an expansile, eccentrically placed, radiolucent lesion with 'fluid-fluid' levels on MRI. Biopsy shows blood-filled spaces lacking an endothelial lining and scattered giant cells. Which genetic alteration is primarily responsible for the primary form of this lesion?

Explanation

Primary Aneurysmal Bone Cysts (ABCs) are genuine neoplasms characterized by translocations involving the USP6 gene on chromosome 17p13. They present as expansile lytic lesions with fluid-fluid levels on MRI and blood-filled cystic spaces without endothelial lining on histology.

Question 13

A 15-year-old boy presents with knee pain. Radiographs demonstrate a 2 cm lytic lesion strictly confined to the proximal tibial epiphysis with a thin sclerotic rim. Histological examination shows mononuclear cells with grooved nuclei and areas of 'chicken-wire' calcification. Which of the following is the most appropriate treatment?

Explanation

The classic presentation of a lytic epiphyseal lesion in a skeletally immature patient with 'chicken-wire' calcification on histology is a Chondroblastoma. The standard of care is aggressive intralesional curettage and bone grafting.

Question 14

A 35-year-old man presents with recurrent bloody effusions and chronic swelling in his knee. MRI reveals a large, lobulated intra-articular mass with low signal intensity on both T1 and T2 weighted images, with prominent blooming artifact on gradient-echo sequences. What is the characteristic genetic translocation and resulting molecular driver of this condition?

Explanation

Pigmented Villonodular Synovitis (PVNS), or Tenosynovial Giant Cell Tumor (TGCT), is driven by a t(1;2) translocation involving the CSF1 gene. The resultant overexpression of Colony Stimulating Factor 1 heavily recruits macrophages, leading to the bulky, hemosiderin-laden mass that causes blooming on MRI.

Question 15

A 45-year-old male undergoes wide resection of a massive, painless, deep-seated soft tissue mass in his thigh. Pathology reveals a uniform proliferation of round cells, signet-ring lipoblasts, and a prominent plexiform ('chicken-wire') capillary network in a myxoid stroma. Which genetic abnormality is highly specific for this sarcoma?

Explanation

Myxoid liposarcoma classically features a myxoid background, lipoblasts, and a branching plexiform ('chicken-wire') capillary network. The pathognomonic mutation is the t(12;16)(q13;p11) translocation resulting in the FUS-DDIT3 fusion.

Question 16

A 9-year-old boy falls and sustains a pathologic fracture of his proximal humerus. Radiographs reveal a centrally located, completely lytic lesion in the metaphysis that abuts the physis. A bone fragment is seen resting at the dependent portion of the cyst. Which of the following statements about the cyst fluid is most accurate?

Explanation

The presentation is classic for a Unicameral Bone Cyst (UBC), noted by the 'fallen fragment' sign. The clear/serous cyst fluid in UBCs typically contains high levels of prostaglandins, alkaline phosphatase, and inflammatory cytokines (like IL-1) that mediate osteoclast stimulation.

Question 17

A 55-year-old man presents with a pathologic fracture of his right femur. Radiographs reveal an aggressive, blastic (sclerotic) lesion in the proximal femur. Which of the following primary malignancies is the most likely source of this metastasis?

Explanation

Prostate cancer characteristically produces osteoblastic (sclerotic) bone metastases. Renal, thyroid, lung, and multiple myeloma typically produce osteolytic lesions.

Question 18

A 25-year-old woman presents with a slow-growing mass on the posterior aspect of her distal femur. Radiographs show a heavily ossified, broad-based mass originating from the cortical surface without medullary involvement. Histology reveals low-grade spindle cells with abundant osteoid formation. What is her expected 5-year survival with wide surgical resection alone?

Explanation

Parosteal osteosarcoma is a low-grade surface osteosarcoma typically arising posterior to the distal femur. Because of its low grade and indolent behavior, wide surgical resection alone is often curative, yielding a greater than 90% 5-year survival rate. Adjuvant chemotherapy is generally not required unless there is evidence of dedifferentiation.

Question 19

A 16-year-old boy presents with a rapidly enlarging mass in his forearm. Biopsy shows small round blue cells arranged in nests separated by fibrous septa, with a loss of central cellular cohesion mimicking pulmonary alveoli. Immunohistochemistry is strongly positive for MyoD1 and myogenin. Which translocation implies the worst prognosis for this specific tumor type?

Explanation

Alveolar rhabdomyosarcoma (ARMS) frequently exhibits the t(2;13) PAX3-FOXO1 or t(1;13) PAX7-FOXO1 translocation. The t(2;13) translocation occurs more frequently and is associated with a significantly worse prognosis, a higher rate of metastasis, and lower overall survival.

Question 20

A 30-year-old Ashkenazi Jewish man presents with severe, acute left thigh pain and fever, initially mimicking osteomyelitis. Radiographs of the femur show an 'Erlenmeyer flask' deformity of the distal femur with scattered lytic and sclerotic areas. He also has hepatosplenomegaly. Deficiency of which of the following enzymes is responsible for his skeletal manifestations?

Explanation

Gaucher disease is a lysosomal storage disorder caused by a deficiency of glucocerebrosidase (beta-glucosidase). The accumulation of glucocerebroside in macrophages inside the bone marrow leads to 'bone crises' mimicking osteomyelitis, avascular necrosis, and the classic 'Erlenmeyer flask' deformity of the distal femur.

Question 21

A 45-year-old male presents with chronic knee pain. Radiographs reveal a lytic lesion in the proximal tibial epiphysis with faint mineralization. Biopsy shows lobules of cells with abundant clear cytoplasm and distinct boundaries, interspersed with reactive woven bone formation. Which of the following is the most likely diagnosis?

Explanation

Clear cell chondrosarcoma is a rare, low-grade malignant cartilage tumor that typically arises in the epiphysis of long bones (proximal femur or tibia) in adults (3rd-5th decades). While it shares the epiphyseal location with chondroblastoma, the latter typically occurs in skeletally immature patients. Histologically, clear cell chondrosarcoma is characterized by large cells with clear cytoplasm and distinct cell membranes, often interspersed with woven bone, distinguishing it from conventional chondrosarcoma.

Question 22

A 28-year-old female undergoes resection of a deep-seated soft tissue mass near her knee joint. Histology demonstrates a biphasic pattern of spindle cells and epithelial-like glandular structures. Which of the following chromosomal translocations is characteristic of this tumor?

Explanation

The diagnosis is synovial sarcoma, which frequently presents in young adults near large joints (especially the knee) but rarely involves the synovium itself. Histologically, it can be monophasic (spindle cells) or biphasic (spindle and epithelial cells). It is characterized by the t(X;18)(p11;q11) translocation, which results in the SYT-SSX fusion gene.

Question 23

A 14-year-old girl is evaluated for a 'shepherd's crook' deformity of her proximal femur. Biopsy reveals irregular woven bone trabeculae lacking osteoblastic rimming set in a bland fibrous stroma. Which of the following gene mutations is most strongly associated with this condition?

Explanation

Fibrous dysplasia is characterized by a missense mutation in the GNAS gene, which encodes the alpha subunit of the stimulatory G protein (Gs). This leads to increased intracellular cAMP, affecting the differentiation of osteoblasts and resulting in the classic 'Chinese character' woven bone trabeculae without osteoblastic rimming in a fibrous stroma.

Question 24

A 24-year-old male presents with anterior lower leg pain. Radiographs show a multicentric, eccentric, lytic lesion in the anterior cortex of the tibial diaphysis. Histopathology reveals clusters of basaloid epithelial cells arranged in nests within a fibrous stroma. What is the most appropriate definitive management?

Explanation

The clinical, radiographic, and histologic descriptions are classic for adamantinoma. Adamantinoma is a low-grade, malignant bone tumor almost exclusively found in the anterior cortex of the tibial diaphysis. Because it is a sarcoma with metastatic potential and does not typically respond well to chemotherapy or radiation, wide surgical resection with limb reconstruction is the treatment of choice.

Question 25

A 30-year-old female presents with a destructive, expansile lytic lesion in the distal femoral epiphysis. Biopsy confirms a giant cell tumor of bone. Molecular testing of the neoplastic cells is most likely to reveal a mutation in which of the following genes?

Explanation

Giant cell tumor of bone (GCTB) is characterized by a high frequency (>90%) of mutations in the H3F3A gene, specifically a G34W mutation. The true neoplastic cells in GCTB are the mononuclear spindle cells, which secrete RANKL to recruit the reactive multinucleated osteoclast-like giant cells.

Question 26

A 25-year-old female presents with a painless posterior knee mass. Radiographs show a densely ossified mass attached to the posterior cortex of the distal femur by a broad base, with a distinct radiolucent cleft separating it from the underlying bone. Genetic analysis of this lesion will most likely demonstrate amplification of which of the following genes?

Explanation

The radiographic description represents a parosteal osteosarcoma, a low-grade surface osteosarcoma that classicly arises on the posterior distal femur. A distinct radiolucent cleft (string sign) often separates it from the cortex. Cytogenetically, parosteal osteosarcoma is characterized by ring chromosomes leading to the amplification of MDM2 and CDK4 on chromosome 12q13-15.

Question 27

A 20-year-old male presents with a painful lytic lesion in the proximal tibial metaphysis. Radiographs show an eccentric, radiolucent defect with a sclerotic margin. Histology demonstrates lobules of stellate and spindle cells in a myxoid stroma, with increased cellularity at the periphery of the lobules. Multinucleated giant cells are present. What is the most likely diagnosis?

Explanation

Chondromyxoid fibroma (CMF) is a rare benign bone tumor. Histologically, it is distinctively lobular with hypercellular peripheries and hypocellular, myxoid centers containing stellate or spindle cells. Multinucleated giant cells are frequently found at the lobular peripheries.

Question 28

A 45-year-old man undergoes resection of a large intramuscular mass in his thigh. Pathology reveals a multinodular tumor with a myxoid background, an arborizing 'chicken-wire' capillary network, and small uniform lipoblasts. What chromosomal translocation is diagnostic for this tumor?

Explanation

The histologic description (myxoid background, chicken-wire vasculature, lipoblasts) is classic for myxoid liposarcoma. This tumor is defined by the t(12;16)(q13;p11) translocation, which produces the FUS-DDIT3 fusion protein.

Question 29

A 7-year-old boy presents with back pain. Radiographs demonstrate a flattened vertebral body (vertebra plana) at T10. Biopsy reveals a proliferation of mononuclear cells with grooved nuclei mixed with eosinophils. Immunohistochemistry will most likely be positive for which of the following markers?

Explanation

The clinical presentation of vertebra plana in a child, combined with histology showing cells with grooved ('coffee bean') nuclei and a background of eosinophils, is highly characteristic of Langerhans Cell Histiocytosis (eosinophilic granuloma). The Langerhans cells characteristically express S100, CD1a, and Langerin (CD207).

Question 30

A 68-year-old male with a long history of increasing hat size and bowing of his femurs presents with new, severe mid-thigh pain and a rapidly enlarging mass. Radiographs show a destructive lytic lesion in the bowed femur. What is the most likely histologic finding in the pre-existing bone?

Explanation

The patient has secondary osteosarcoma arising in Paget disease of bone. Paget disease is characterized histologically by chaotic bone remodeling resulting in thickened trabeculae with haphazard, intersecting cement lines forming a 'mosaic' or 'jigsaw puzzle' pattern.

Question 31

An 11-year-old boy presents with fever, weight loss, and thigh pain. Radiographs show a permeative, diaphyseal femoral lesion with an 'onion-skin' periosteal reaction. Histology reveals sheets of small, round, blue cells. Which immunohistochemical marker is characteristically strongly positive in this condition?

Explanation

Ewing sarcoma is a small round blue cell tumor that typically arises in the diaphysis of long bones. It is strongly associated with the t(11;22) translocation and shows diffuse, strong membranous staining for CD99 (MIC2).

Question 32

A 25-year-old woman is diagnosed with a high-grade bone tumor of the pelvis. Biopsy demonstrates a highly cellular tumor exhibiting a biphasic pattern: sheets of undifferentiated small round blue cells interspersed with distinct, abrupt islands of well-differentiated hyaline cartilage. Hemangiopericytoma-like vascular patterns are also noted. What is the most likely diagnosis?

Explanation

Mesenchymal chondrosarcoma is a rare, highly aggressive tumor characterized by a distinctive biphasic histology consisting of highly cellular areas of primitive, small round blue cells and abrupt islands of well-differentiated, benign-appearing hyaline cartilage. A hemangiopericytoma-like vascular pattern is frequently present.

Question 33

A 16-year-old boy presents with worsening night pain in his tibia that is dramatically relieved by NSAIDs. Radiographs show a 1 cm radiolucent nidus surrounded by dense reactive sclerosis. If excised, histologic examination of the nidus is most likely to demonstrate which of the following?

Explanation

The clinical scenario is classic for an osteoid osteoma. Histologically, the nidus of an osteoid osteoma consists of interconnected, disorganized trabeculae of woven bone (osteoid) rimmed by plump, active osteoblasts, set within a highly vascular connective tissue stroma containing numerous nerve fibers (which mediate the intense pain via prostaglandins).

Question 34

A 72-year-old man undergoes a biopsy of a densely sclerotic lesion in his L4 vertebral body. Pathology reveals irregular bone trabeculae lined by uniform atypical cells with prominent nucleoli forming back-to-back glands. Immunohistochemistry is strongly positive for PSA. Which of the following factors is primarily responsible for the osteosclerotic (osteoblastic) appearance of these metastases?

Explanation

Prostate cancer characteristically causes osteoblastic (sclerotic) metastases. Prostate cancer cells secrete Endothelin-1 (ET-1), which strongly stimulates osteoblast proliferation and new bone formation. Conversely, PTHrP and RANKL are primary mediators of osteolytic bone metastases (e.g., from breast or lung cancer).

Question 35

A 14-year-old boy presents with a rapidly growing soft tissue mass in his forearm. Biopsy reveals small round blue cells arranged in clusters divided by fibrous septa, forming pseudoalveolar spaces. Cytogenetics identifies a t(2;13) chromosomal translocation. This translocation results in the fusion of which two genes?

Explanation

The diagnosis is alveolar rhabdomyosarcoma. The characteristic translocation is t(2;13)(q35;q14), which creates the PAX3-FOXO1 (formerly PAX3-FKHR) fusion gene, portending a worse prognosis compared to embryonal rhabdomyosarcoma.

Question 36

A 12-year-old girl presents with a painful, rapidly expanding mass in the posterior elements of her cervical spine. Radiographs reveal an expansile, multicystic lesion. Biopsy shows blood-filled spaces lacking endothelial lining, separated by fibrous septa containing osteoclast-like giant cells. Which of the following genetic alterations is diagnostic of the primary form of this lesion?

Explanation

The lesion is an aneurysmal bone cyst (ABC). While ABCs can be secondary to other tumors (e.g., GCT, chondroblastoma), primary ABCs are true neoplasms characterized by a balanced translocation resulting in USP6 gene rearrangement (most commonly t(16;17)).

Question 37

A 60-year-old male presents with bowel and bladder incontinence and chronic lower back pain. Imaging shows a large, destructive midline mass involving the sacrum. Biopsy reveals lobules of large cells with prominent intracytoplasmic vacuoles in a myxoid background. Which immunohistochemical marker is highly sensitive and specific for confirming this diagnosis?

Explanation

The clinical and histologic findings (physaliferous cells with large intracytoplasmic vacuoles) point to a chordoma, a primary bone tumor arising from notochordal remnants. Brachyury, a transcription factor crucial in notochord development, is a highly specific and sensitive immunohistochemical marker for chordoma.

Question 38

A 28-year-old female presents with a lytic lesion in her distal radius. Biopsy demonstrates uniform, spindle-shaped fibroblasts separated by abundant collagenous matrix, without cytologic atypia, pleomorphism, or mitosis. Immunohistochemistry reveals nuclear positivity for beta-catenin. What is the most likely diagnosis?

Explanation

Desmoplastic fibroma is the rare intraosseous equivalent of a soft-tissue desmoid tumor (aggressive fibromatosis). Like desmoid tumors, it features uniform fibroblasts in a dense collagenous background without overt malignant features, and it typically exhibits aberrant nuclear expression of beta-catenin due to mutations in the Wnt/beta-catenin pathway.

Question 39

A 24-year-old male presents with a painless, slow-growing nodule on the volar aspect of his index finger. Initial excision was read as a necrotizing granuloma, but the mass recurred locally. Re-evaluation of the histology shows nodules of plump epithelioid cells surrounding central areas of necrosis. Immunohistochemistry shows loss of SMARCB1 (INI1) expression. What is the diagnosis?

Explanation

Epithelioid sarcoma often presents in the distal extremities of young adults. Because it forms nodules with central necrosis, it is notoriously misdiagnosed as a benign necrotizing granulomatous process (e.g., rheumatoid nodule). A classic molecular hallmark is the loss of INI1 (SMARCB1) protein expression.

Question 40

A 15-year-old male with a history of multiple soft-tissue hemangiomas presents with a newly symptomatic, expansile cartilaginous lesion in his right humerus. He is diagnosed with Maffucci syndrome. The pathogenesis of his skeletal and vascular lesions is most strongly associated with somatic mosaic mutations in which of the following genes?

Explanation

Maffucci syndrome (enchondromatosis with soft tissue hemangiomas) and Ollier disease (enchondromatosis alone) are non-hereditary disorders caused by early postzygotic somatic mutations in the isocitrate dehydrogenase genes, IDH1 or IDH2. These mutations lead to the overproduction of the oncometabolite D-2-hydroxyglutarate.

Question 41

A 25-year-old male presents with chronic leg pain. Radiographs reveal a 'soap-bubble' multiloculated osteolytic lesion in the anterior tibial diaphysis. Biopsy reveals islands of epithelial cells surrounded by a bland fibrous stroma. Immunohistochemistry is strongly positive for cytokeratin. Which of the following is the most appropriate management for this condition?

Explanation

The clinical and histologic presentation is classic for Adamantinoma, a rare, low-grade malignant bone tumor that almost exclusively occurs in the anterior tibial diaphysis. Histologically, it features nests of epithelial cells in a fibrous stroma and is cytokeratin positive. It is insensitive to radiation and chemotherapy. The treatment of choice is wide surgical resection with negative margins, often requiring intercalary reconstruction.

Question 42

A 55-year-old male presents with constipation and lower back pain. Imaging shows a large, destructive midline sacral mass. Biopsy reveals lobules of cells with prominent vacuolated cytoplasm in a myxoid background. To differentiate this lesion from a chondrosarcoma, which of the following immunohistochemical markers is the most specific?

Explanation

The presentation describes a chordoma, classically located in the sacrococcygeal region or spheno-occipital area (clivus). The cells with vacuolated cytoplasm are 'physaliferous' cells. While chordomas are positive for S-100, cytokeratin, and EMA (which helps distinguish them from chondrosarcomas that are cytokeratin negative), Brachyury—a transcription factor essential for notochordal development—is the most sensitive and highly specific diagnostic nuclear marker for chordoma.

Question 43

A 15-year-old boy presents with knee pain. Radiographs reveal a well-circumscribed, eccentrically located radiolucent lesion in the proximal tibial epiphysis. Biopsy demonstrates mononuclear cells with longitudinal nuclear grooves and areas of fine, intercellular 'chicken-wire' calcifications. Which of the following gene mutations is most characteristically associated with this tumor?

Explanation

The patient has a chondroblastoma, typically occurring in the epiphysis or apophysis of long bones in skeletally immature patients. Histology shows chondroblasts with 'coffee bean' (grooved) nuclei and 'chicken-wire' calcifications. Over 90% of chondroblastomas harbor a somatic mutation in the histone H3.3 genes, most commonly H3F3A (or H3F3B), specifically the K36M substitution.

Question 44

A 45-year-old male presents with progressive hip pain. Radiographs show a distinct, heavily calcified radiolucent lesion in the proximal femoral epiphysis. Biopsy reveals large cells with distinct borders, central round nuclei, and abundant optically clear cytoplasm, mixed with areas of conventional chondrosarcoma and reactive woven bone. What is the most likely diagnosis?

Explanation

Clear cell chondrosarcoma is a rare, low-grade variant of chondrosarcoma that characteristically arises in the epiphysis of long bones (most commonly the proximal femur or humerus) in adults (typically 3rd to 5th decades). Radiographically, it can mimic a chondroblastoma, but chondroblastoma occurs almost exclusively in skeletally immature patients (teens). The histology described is diagnostic of clear cell chondrosarcoma.

Question 45

A 35-year-old woman with recurrent, extensive pigmented villonodular synovitis (PVNS) of the knee is deemed unsuitable for further surgical resection. Systemic medical therapy is planned. This therapy most likely targets which of the following pathways?

Explanation

PVNS (also known as tenosynovial giant cell tumor) is driven by a t(1;2)(p13;q37) translocation, resulting in the fusion of COL6A3 to CSF1. This causes overproduction of Colony-Stimulating Factor 1 (CSF1), which attracts a large non-neoplastic infiltrate of macrophages and multinucleated giant cells. Pexidartinib is a CSF1R inhibitor that has been FDA-approved for adults with symptomatic, locally advanced TGCT associated with severe morbidity or functional limitations that are not amenable to improvement with surgery.

Question 46

A 12-year-old boy presents with severe, aching pain in his mid-thigh that is significantly worse at night and dramatically relieved by ibuprofen. Radiographs show cortical thickening with a small radiolucent nidus. The symptomatic relief provided by NSAIDs is primarily due to the inhibition of which biochemical mediator produced by the tumor?

Explanation

The clinical scenario is classic for an osteoid osteoma. The intense pain, particularly at night, and its dramatic relief with NSAIDs are hallmark features. The osteoblasts within the nidus of an osteoid osteoma produce very high levels of cyclooxygenase-2 (COX-2) and its downstream product, Prostaglandin E2 (PGE2), which mediates the pain response and local vasodilation.

Question 47

Fibrous dysplasia is associated with a post-zygotic, somatic activating mutation in the GNAS gene. This genetic alteration directly results in the constitutive activation of which of the following intracellular signaling mechanisms?

Explanation

Fibrous dysplasia (and McCune-Albright syndrome when associated with endocrinopathies and café-au-lait spots) is caused by a mutation in the GNAS gene, which encodes the alpha subunit of the stimulatory G protein (Gs-alpha). The activating mutation results in loss of GTPase activity, leading to constitutive activation of adenylate cyclase and persistently elevated intracellular levels of cyclic AMP (cAMP). This alters the differentiation of skeletal progenitor cells.

Question 48

Denosumab is an effective systemic treatment for surgically unsalvageable or metastatic Giant Cell Tumor of Bone (GCTB). It works by binding to RANKL. In the pathophysiology of GCTB, which cellular population is the primary source of RANKL expression?

Explanation

In Giant Cell Tumor of Bone (GCTB), the true neoplastic cells are the mononuclear spindle-shaped stromal cells (which frequently harbor an H3F3A mutation). These neoplastic stromal cells express high levels of RANK Ligand (RANKL). This RANKL recruits and stimulates normal osteoclast precursors to differentiate into the numerous, large, multinucleated reactive osteoclast-like giant cells characteristic of the tumor, which cause massive bone resorption.

Question 49

A 10-year-old girl presents with a large, destructive, permeative diaphyseal lesion of the femur with an 'onion-skin' periosteal reaction. A biopsy is performed. The diagnosis of Ewing sarcoma is supported by a strong, diffuse membranous staining for CD99. To further distinguish this from other small blue cell tumors, which of the following immunohistochemical markers is currently considered the most highly sensitive and specific adjunct?

Explanation

Ewing sarcoma is a small round blue cell tumor. While CD99 (MIC2) is highly sensitive, it is not specific (it can be seen in lymphoblastic lymphoma, mesenchymal chondrosarcoma, etc.). The pathognomonic translocation t(11;22) fuses EWSR1 to FLI1. This fusion protein strongly upregulates the transcription factor NKX2.2. NKX2.2 immunohistochemistry is highly sensitive and significantly more specific for Ewing sarcoma than CD99.

Question 50

A 30-year-old male presents with a slowly enlarging, deep-seated soft tissue mass in the thigh near the knee joint. Biopsy reveals a biphasic tumor comprised of both epithelial components (glandular structures) and a spindle cell mesenchymal stroma. Which of the following cytogenetic abnormalities is diagnostic for this tumor?

Explanation

The clinical and histologic description (biphasic appearance) is characteristic of Synovial Sarcoma. Despite its name, it rarely arises intra-articularly. The diagnostic cytogenetic hallmark of synovial sarcoma is the t(X;18)(p11;q11) translocation, which results in the fusion of the SYT (SS18) gene on chromosome 18 with one of the SSX genes on the X chromosome.

Question 51

A 28-year-old female presents with a painless, hard mass on the posterior aspect of her distal thigh. Radiographs demonstrate a dense, lobulated, heavily ossified mass arising from the posterior cortex of the distal femur, with a thin radiolucent 'cleft' separating the bulk of the tumor from the underlying cortex. Biopsy reveals a low-grade fibroblastic stroma with parallel trabeculae of woven bone. Amplification of which gene is the molecular hallmark of this entity?

Explanation

The presentation is classic for Parosteal Osteosarcoma, a low-grade surface osteosarcoma typically found on the posterior aspect of the distal femur. The 'string sign' or radiolucent cleft is characteristic. The underlying molecular driver is the amplification of the 12q13-15 chromosomal region, which contains the MDM2 and CDK4 genes. MDM2 amplification inhibits p53 function. This differentiates it from high-grade surface osteosarcoma or reactive processes.

Question 52

A 70-year-old man with advanced prostate cancer develops multiple dense, osteoblastic metastatic lesions in his lumbar spine and pelvis. The characteristic osteosclerotic nature of these metastatic bone lesions is primarily driven by tumor cell secretion of which of the following factors?

Explanation

Prostate cancer metastases are classically osteoblastic (bone-forming). While many metastatic tumors (like breast and lung) secrete PTHrP leading to RANKL upregulation and osteolytic lesions, prostate cancer cells uniquely secrete Endothelin-1 (ET-1), which acts as a potent stimulator of osteoblast proliferation and new bone formation, leading to the characteristic dense, sclerotic metastases.

Question 53

Multiple myeloma bone disease is characterized by purely osteolytic lesions with virtually no reactive new bone formation, leading to a negative ('cold') bone scan in many cases. The profound suppression of osteoblast function in these lesions is primarily mediated by myeloma cell secretion of which molecule?

Explanation

In multiple myeloma, the purely osteolytic nature of the lesions is dual-fold: upregulation of osteoclasts (via RANKL and MIP-1 alpha) and profound suppression of osteoblasts. The osteoblast suppression is primarily mediated by the secretion of Dickkopf-1 (DKK-1) by myeloma cells. DKK-1 is a potent inhibitor of the Wnt/beta-catenin signaling pathway, which is essential for osteoblast differentiation and function.

Question 54

A 60-year-old man presents with an increasing hat size and bowing of his tibiae. Radiographs show thickened, disorganized trabeculae and cortical thickening ('cotton wool' appearance). A genetic evaluation is performed due to a strong family history. An activating mutation in which of the following genes is most commonly associated with the familial form of this disease?

Explanation

The patient has Paget's disease of bone. The familial form of Paget's disease (which accounts for 15-40% of cases) is predominantly caused by mutations in the SQSTM1 gene (sequestosome 1, also known as p62). This mutation leads to an increase in osteoclast activity and sensitivity to RANKL, initiating the disorganized phase of osteolysis followed by haphazard osteoblastic bone formation.

Question 55

A 22-year-old male is evaluated for multiple bony deformities and is diagnosed with Ollier disease, characterized by multiple enchondromas. He is counseled regarding the risk of malignant transformation. Somatic mosaic mutations in which of the following genes are the primary driver for both Ollier disease and Maffucci syndrome?

Explanation

Ollier disease (multiple enchondromatosis) and Maffucci syndrome (multiple enchondromatosis plus soft tissue hemangiomas) are driven by somatic mosaic mutations in the Isocitrate Dehydrogenase genes (IDH1 or IDH2). These mutations lead to the production of the oncometabolite D-2-hydroxyglutarate, which alters DNA methylation and chondrocyte differentiation. EXT1/EXT2 are associated with Multiple Hereditary Exostoses (osteochondromas).

Question 56

A 16-year-old boy presents with a rapidly expanding, painful distal femoral lytic lesion. MRI reveals multiple fluid-fluid levels, mimicking an Aneurysmal Bone Cyst (ABC). A biopsy is performed to rule out Telangiectatic Osteosarcoma. Which of the following histologic features definitively establishes the diagnosis of Telangiectatic Osteosarcoma over an ABC?

Explanation

Both Aneurysmal Bone Cysts (ABC) and Telangiectatic Osteosarcoma feature blood-filled cystic spaces with fluid-fluid levels on MRI and lack endothelial lining. The critical distinguishing factor is the solid septa: in an ABC, the septa contain benign fibroblasts, reactive giant cells, and woven bone, whereas in Telangiectatic Osteosarcoma, the septa contain highly pleomorphic, overtly malignant sarcomatous cells that produce malignant osteoid matrix.

Question 57

A 7-year-old boy presents with back pain. Radiographs reveal a completely flattened T8 vertebral body (vertebra plana). Needle biopsy demonstrates an infiltrate of eosinophils mixed with prominent histiocytes that have folded, 'coffee-bean' shaped nuclei. Which of the following immunohistochemical markers is the most highly specific for the primary pathologic cell in this condition?

Explanation

The clinical presentation (vertebra plana in a child) and histology (eosinophils and histiocytes with folded nuclei) are classic for Eosinophilic Granuloma (Langerhans Cell Histiocytosis). While the Langerhans cells are positive for S-100 and CD1a, CD207 (Langerin) is highly specific because it directly correlates with the presence of Birbeck granules, the ultrastructural hallmark (tennis-racket shaped organelles) of Langerhans cells.

Question 58

A 5-year-old boy presents with a painless anterior bowing of his right tibia. Radiographs reveal a multilocular, intracortical radiolucent lesion of the anterior diaphyseal tibia. A biopsy is obtained to differentiate this from fibrous dysplasia. Which of the following histologic findings is characteristic of Osteofibrous Dysplasia and absent in classical Fibrous Dysplasia?

Explanation

Osteofibrous dysplasia (OFD) exclusively occurs in the tibia and fibula, typically in young children (<10 years). Histologically, it resembles fibrous dysplasia; however, a key distinguishing feature is that the woven bone trabeculae in OFD are prominently rimmed by active osteoblasts (zonal architecture), whereas classical fibrous dysplasia lacks conspicuous osteoblastic rimming.

Question 59

A 22-year-old male presents with chronic knee pain. Imaging reveals an eccentric, well-demarcated lytic lesion with a sclerotic rim in the proximal tibial metaphysis. Biopsy exhibits a distinct lobular architecture with a myxoid and chondroid background. The periphery of the lobules is highly cellular with spindle-shaped cells, whereas the center is hypocellular with stellate cells. What is the most likely diagnosis?

Explanation

The description is classic for Chondromyxoid Fibroma (CMF), a rare benign tumor of cartilaginous origin. It classically presents as an eccentric, metaphyseal lytic lesion. The hallmark histologic feature is the distinctly lobular architecture with zonal hypercellularity at the periphery of the lobules and hypocellular, myxoid centers containing stellate or spindle cells.

Question 60

A 35-year-old woman presents with a locally aggressive, destructive radiolucent lesion in the mandibular ramus, extending into the soft tissues. Biopsy reveals a dense proliferation of uniform, elongated spindle cells producing abundant collagen without nuclear atypia, mitosis, or any osteoid or chondroid matrix formation. Molecular analysis demonstrates a mutation in the CTNNB1 gene. This lesion is the intraosseous counterpart to which of the following soft tissue tumors?

Explanation

The diagnosis is a Desmoplastic Fibroma of bone. It is a rare, locally aggressive but non-metastasizing primary bone tumor that is histologically and genetically identical to extra-abdominal desmoid tumors (aggressive fibromatoses) of soft tissue. Both are characterized by uniform fibroblasts producing abundant collagen bundles and frequently harbor mutations in the CTNNB1 gene (beta-catenin).

Question 61

A 14-year-old boy presents with aching pain in his proximal tibia that is significantly worse at night and rapidly relieved by ibuprofen. Radiographs demonstrate a radiolucent nidus less than 1.5 cm surrounded by reactive sclerosis. Which biochemical mediator is produced in exceptionally high quantities by the cells within this nidus?

Explanation

Osteoid osteomas secrete high levels of Prostaglandin E2 due to increased expression of COX-2 enzymes in the nidus. This accounts for the intense night pain that is characteristically relieved by NSAIDs.

Question 62

A 25-year-old female presents with a slow-growing, painless mass on the posterior aspect of her distal femur. Radiographs reveal a dense, heavily ossified mass attached to the cortex via a broad base with a 'string sign' indicating a radiolucent cleft. Genetic analysis of the tumor cells is most likely to reveal which of the following abnormalities?

Explanation

The clinical and radiographic presentation is classic for a parosteal osteosarcoma, a low-grade surface osteosarcoma. These tumors are genetically characterized by supernumerary ring chromosomes containing amplifications of the MDM2 and CDK4 genes.

Question 63

A 32-year-old female presents with multiple asymmetrical, expanding cartilaginous tumors in the phalanges of her hands, accompanied by soft tissue hemangiomas exhibiting phleboliths on radiographs. Which gene mutation is most likely responsible for her underlying syndrome?

Explanation

The patient has Maffucci syndrome, characterized by multiple enchondromatosis and soft tissue hemangiomas. Both Ollier disease and Maffucci syndrome are heavily associated with somatic mosaic mutations in the IDH1 or IDH2 genes.

Question 64

A 30-year-old man presents with a slow-growing, deep-seated soft tissue mass in his foot. Biopsy reveals nests of pale-staining spindle cells separated by fibrous septa. Immunohistochemistry is strongly positive for HMB-45, Melan-A, and S-100. Which chromosomal translocation defines this neoplasm?

Explanation

Clear cell sarcoma (melanoma of soft parts) typically arises in the deep soft tissues of the foot and ankle in young adults. It shares immunohistochemical markers with melanoma but is uniquely characterized by the t(12;22) EWS-ATF1 translocation.

Question 65

A 40-year-old male undergoes excision of a deep thigh mass. Histopathology shows a proliferation of uniform round cells, signet-ring lipoblasts, and a prominent branching capillary network resembling 'chicken wire' in a myxoid stroma. What is the characteristic genetic translocation associated with this sarcoma?

Explanation

Myxoid liposarcoma is characterized by a 'chicken-wire' vascular pattern, myxoid stroma, and lipoblasts. The pathognomonic genetic alteration is the t(12;16) translocation, which fuses the FUS gene with the DDIT3 (CHOP) gene.

Question 66

A 12-year-old boy presents with a 'shepherd's crook' deformity of his proximal femur. Radiographs demonstrate an expansive, intramedullary ground-glass lesion. What is the underlying cellular mechanism driving the pathogenesis of this osseous lesion?

Explanation

The patient has fibrous dysplasia, caused by a post-zygotic activating mutation in the GNAS gene. This results in constitutive activation of the Gs-alpha protein, elevating cAMP levels and preventing the differentiation of osteoprogenitor cells.

Question 67

A 6-year-old boy presents with localized back pain. Radiographs demonstrate a 'vertebra plana' in the thoracic spine. Biopsy of the lesion shows a proliferation of cells with distinct nuclear grooves, admixed with eosinophils. Electron microscopy identifies tennis-racket shaped organelles. Which immunohistochemical marker will definitively identify the lesional cells?

Explanation

The clinical picture and presence of Birbeck granules (tennis-racket organelles) are diagnostic of Langerhans Cell Histiocytosis (LCH). The pathological Langerhans cells strongly express both S-100 and CD1a, with CD1a being highly specific.

Question 68

A 28-year-old male presents with dull, aching anterior lower leg pain. Radiographs show a multicystic, eccentric, expansile lytic lesion in the anterior tibial diaphysis. Histopathology reveals islands and nests of epithelial cells surrounded by a bland fibrous stroma. Which immunohistochemical stain is most likely positive in the lesional cells?

Explanation

Adamantinoma is a rare, low-grade malignant bone tumor that almost exclusively occurs in the anterior tibial diaphysis. It is biphasic, and its epithelial component uniquely stains positive for cytokeratin, differentiating it from osteofibrous dysplasia.

Question 69

A 55-year-old male presents with chronic constipation and saddle anesthesia. Imaging reveals a large, destructive midline sacral mass. Biopsy shows large, vacuolated cells arranged in lobules and cords within a prominent myxoid stroma. Which immunohistochemical marker is highly specific for confirming this diagnosis?

Explanation

The mass is a chordoma, characterized histologically by physaliferous (vacuolated) cells in a myxoid stroma. Brachyury is a transcription factor crucial for notochordal development and is highly sensitive and specific for chordomas.

Question 70

A 35-year-old female undergoes MRI for recurrent, unexplained bloody knee effusions. The imaging reveals a nodular synovial mass demonstrating low signal intensity on both T1 and T2 sequences, with a 'blooming' artifact on gradient echo. What is the primary pathogenic mechanism driving the growth of this mass?

Explanation

Pigmented villonodular synovitis (PVNS), or tenosynovial giant cell tumor, appears dark on MRI due to hemosiderin. It is a neoplastic process driven by a t(1;2) translocation causing CSF1 overexpression, which recruits abundant macrophages and multinucleated giant cells.

Question 71

A 9-year-old boy presents with a proximal humerus fracture after a minor fall. Radiographs show a centrally located, completely lytic metaphyseal lesion with a 'fallen leaf' sign. Aspiration of the fluid from this lesion would most likely reveal pathologically high levels of which of the following?

Explanation

The 'fallen leaf' sign indicates a pathologic fracture through a unicameral bone cyst (UBC). The cyst fluid typically contains high levels of prostaglandins, oxygen free radicals, and interleukins, which stimulate osteoclastic bone resorption.

Question 72

A 68-year-old man presents with severe generalized back pain, normocytic anemia, and hypercalcemia. Radiographs show multiple punched-out lytic skull lesions. Which of the following imaging modalities is generally considered the LEAST sensitive for detecting the extent of skeletal involvement in this specific disease process?

Explanation

In multiple myeloma, the neoplastic plasma cells secrete factors (like DKK1) that inhibit osteoblast activity. Therefore, a Technetium-99m bone scan, which relies on osteoblastic radiotracer uptake, is frequently falsely negative and less sensitive than CT or MRI.

Question 73

A 14-year-old female presents with acute knee pain. MRI shows an eccentric, expansile metaphyseal lesion in the distal femur containing multiple fluid-fluid levels. Biopsy confirms an aneurysmal bone cyst (ABC). Which specific gene rearrangement is considered the primary neoplastic driver of this primary lesion?

Explanation

Primary Aneurysmal Bone Cysts (ABCs) are now recognized as true neoplasms rather than reactive processes, primarily driven by a t(16;17) translocation leading to the upregulation of the USP6 oncogene.

Question 74

A 45-year-old man presents with chronic knee catching and swelling. Radiographs demonstrate dozens of small, uniform, radiopaque loose bodies confined to the joint space. This condition is primarily characterized by which of the following pathophysiologic processes?

Explanation

Primary synovial chondromatosis involves the benign, self-limiting neoplastic metaplasia of the synovial membrane into cartilage, which detaches to form uniform loose bodies that may subsequently ossify.

Question 75

A 14-year-old girl presents with a rapidly enlarging, painful mass in her proximal tibia. Radiographs demonstrate an eccentric, expansile, purely lytic metaphyseal lesion with thinning of the surrounding cortex. MRI shows multiple fluid-fluid levels. Biopsy reveals blood-filled cystic spaces separated by fibrous septa containing giant cells, without significant atypia. Which of the following genetic alterations is the primary driver of this neoplasm?

Explanation

This patient has a primary aneurysmal bone cyst (ABC). Primary ABCs are driven by rearrangements of the USP6 gene on chromosome 17p13, most commonly t(16;17), which leads to upregulation of matrix metalloproteinases.

Question 76

A 65-year-old man presents with severe back pain and fatigue. Laboratory studies reveal hypercalcemia, anemia, and an elevated serum creatinine. Radiographs show multiple punched-out lytic lesions in his skull and spine. A technetium-99m bone scan is notable for a lack of uptake in the corresponding lytic areas. What is the primary mechanism of bone destruction in this condition?

Explanation

Multiple myeloma causes lytic bone lesions via myeloma cell secretion of factors (e.g., RANKL, IL-6, MIP-1 alpha) that overstimulate osteoclasts. Simultaneously, DKK1 is secreted to suppress osteoblast differentiation, resulting in a 'cold' bone scan.

Question 77

A 55-year-old man presents with chronic low back pain and recent-onset bowel and bladder incontinence. MRI demonstrates a destructive, lobulated midline mass arising from the sacrum. Biopsy reveals nests of large, vacuolated cells in a myxoid stroma. Which of the following immunohistochemical markers is most specific for diagnosing this lesion?

Explanation

The clinical presentation and presence of physaliferous (vacuolated) cells indicate a chordoma. Brachyury is a transcription factor critical for notochordal development and is a highly sensitive and specific nuclear marker for chordoma.

Question 78

A 16-year-old boy presents with right shoulder pain. Radiographs show a well-circumscribed lytic lesion in the proximal humeral epiphysis with central calcifications. Histologic examination demonstrates mononuclear cells, scattered osteoclast-like giant cells, and a 'chicken-wire' pattern of pericellular calcification. Which genetic mutation is classically associated with this tumor?

Explanation

The lesion is a chondroblastoma, typically occurring in the epiphysis of young patients and featuring 'chicken-wire' calcifications. It is uniquely driven by a point mutation in the H3F3B gene (or less commonly H3F3A), altering histone H3.3.

Question 79

A 30-year-old man presents with anterior bowing of his lower leg. Radiographs reveal an eccentric, multiloculated 'soap-bubble' lytic lesion in the anterior diaphysis of the tibia. Biopsy shows a biphasic tumor with both epithelial and osteofibrous components. Which of the following is true regarding this pathology?

Explanation

Adamantinoma is a low-grade malignant bone tumor that almost exclusively occurs in the anterior tibial diaphysis. It is a biphasic tumor, and its epithelial component classically stains positive for cytokeratin.

Question 80

A 45-year-old woman presents with a deep-seated thigh mass. MRI shows a well-defined, multi-lobulated soft tissue mass. Histology demonstrates an abundant myxoid stroma, a rich branching capillary network resembling 'chicken-wire', and small lipoblasts. What is the characteristic chromosomal translocation associated with this sarcoma?

Explanation

Myxoid liposarcoma is characterized by a prominent plexiform capillary network ('chicken-wire' vascularity) and myxoid background. It is driven by the t(12;16) translocation, which fuses the FUS gene with the DDIT3 (CHOP) gene.

Question 81

A 7-year-old boy presents with severe localized thoracic back pain. Radiographs reveal uniform flattening of the T7 vertebral body (vertebra plana) with preserved adjacent disc spaces. Biopsy shows a cellular infiltrate including eosinophils and mononuclear cells with grooved, 'coffee-bean' nuclei. Electron microscopy is most likely to reveal which of the following?

Explanation

This patient has Langerhans Cell Histiocytosis (eosinophilic granuloma), which classically presents with vertebra plana in children. The neoplastic Langerhans cells contain Birbeck granules, which resemble tennis rackets on electron microscopy.

Question 82

A 24-year-old woman notes a painless, slow-growing mass on the posterior aspect of her distal thigh. Radiographs demonstrate a heavily ossified, broad-based mass attached to the posterior cortex of the distal femur, with a radiolucent cleft separating a portion of the tumor from the underlying bone (string sign). What molecular abnormality is the hallmark of this lesion?

Explanation

Parosteal osteosarcoma is a low-grade surface osteosarcoma arising from the posterior distal femur, classically showing a 'string sign' on radiographs. It is characterized genetically by ring chromosomes leading to amplification of MDM2 and CDK4.

Question 83

A 15-year-old boy presents with thigh pain and a destructive metaphyseal lesion in his distal femur. MRI reveals fluid-fluid levels, mimicking an aneurysmal bone cyst. However, biopsy of the septal walls demonstrates highly pleomorphic spindle cells producing fine, lace-like osteoid. Which of the following best describes the clinical behavior of this lesion?

Explanation

The diagnosis is telangiectatic osteosarcoma, which can mimic an ABC on imaging due to blood-filled cystic spaces. However, the presence of malignant cells producing osteoid in the septa confirms a high-grade malignancy requiring systemic chemotherapy and wide resection.

Question 84

A 12-year-old girl is evaluated for multiple bony deformities and numerous soft tissue masses. Radiographs reveal multiple enchondromas in her hands and long bones. Physical exam confirms the presence of several bluish, compressible soft tissue nodules representing hemangiomas. Patients with this specific syndrome are at the highest risk for developing which of the following malignancies?

Explanation

This patient has Maffucci syndrome, distinguished from Ollier disease by the presence of soft tissue hemangiomas. Patients with Maffucci syndrome have a nearly 100% lifetime risk of malignant transformation, most commonly to chondrosarcoma.

Question 85

A 26-year-old man presents with a firm, painless nodule on the volar aspect of his wrist. Initial biopsy was read as a necrotizing granuloma, but the mass recurred and enlarged, and he now has palpable axillary lymphadenopathy. Repeat deep biopsy shows sheets of eosinophilic epithelial-appearing cells transitioning into spindle cells. Which immunohistochemical finding is diagnostic of this aggressive sarcoma?

Explanation

Epithelioid sarcoma typically affects the distal extremities of young adults, often mimics a benign granulomatous process, and has a high rate of lymphatic spread. Diagnosis is confirmed by the loss of INI-1 (SMARCB1) nuclear expression.

Question 86

A 48-year-old man presents with hip pain. Radiographs reveal a lytic lesion in the proximal femoral epiphysis with distinct sclerotic margins. Biopsy shows sheets of large cells with abundant clear cytoplasm and distinct cell membranes, interspersed with areas of hyaline cartilage. What is the most appropriate management for this lesion?

Explanation

Clear cell chondrosarcoma typically presents in the epiphysis of long bones in adults (unlike chondroblastoma in teens). It is a low-grade malignant bone tumor that does not respond to chemotherapy or radiation; wide surgical resection is required.

Question 87

A 16-year-old girl is diagnosed with a high-grade soft tissue mass in her distal leg. Molecular testing demonstrates a t(2;13)(q35;q14) translocation resulting in a PAX3-FOXO1 fusion transcript. Based on these findings, which histological pattern is most likely to be seen on biopsy?

Explanation

The PAX3-FOXO1 fusion is diagnostic for alveolar rhabdomyosarcoma. Histologically, it presents as a small round blue cell tumor with cells arranged in aggregates separated by fibrous septa, resembling pulmonary alveoli.

Question 88

A 32-year-old woman presents with recurrent hemorrhagic effusions of her left knee. MRI reveals a nodular synovial mass with significant blooming artifact on gradient-echo sequences. The pathogenesis of this disease is primarily driven by a t(1;2) translocation causing the overexpression of which of the following?

Explanation

Pigmented Villonodular Synovitis (PVNS), or Tenosynovial Giant Cell Tumor, is driven by a t(1;2) translocation that causes overexpression of CSF1. This attracts a dense infiltrate of non-neoplastic macrophages and giant cells, which form the bulk of the tumor.

Question 89

A 19-year-old man presents with localized nighttime pain in his proximal femur that is dramatically relieved by ibuprofen. CT imaging reveals a 1-cm radiolucent nidus surrounded by dense reactive sclerosis. The nidus of this lesion is characterized by high levels of which of the following enzymes?

Explanation

Osteoid osteomas secrete high levels of prostaglandins (especially PGE2) secondary to robust COX-2 expression within the nidus osteoblasts. This pathogenesis explains the classic nocturnal pain that is highly responsive to NSAIDs.

Question 90

A 35-year-old man with a known history of Neurofibromatosis type 1 (NF-1) presents with rapid enlargement and new-onset severe resting pain in a long-standing, palpable thigh mass. A biopsy confirms a high-grade spindle cell sarcoma. Which genetic event is most strongly associated with the malignant transformation of his pre-existing lesion?

Explanation

Patients with NF-1 have plexiform neurofibromas that can undergo malignant transformation to Malignant Peripheral Nerve Sheath Tumors (MPNSTs). This transformation is typically driven by secondary genetic hits, most notably the loss of CDKN2A or p53.

Question 91

A 14-year-old boy completes neoadjuvant chemotherapy and undergoes a wide resection of a conventional osteosarcoma in his distal femur. Pathological analysis of the resected specimen is performed. According to the Rosen grading system, what histological finding in the resected specimen is the most powerful predictor of long-term survival?

Explanation

The most important prognostic factor for conventional osteosarcoma following neoadjuvant chemotherapy is the percentage of tumor necrosis in the resection specimen. Necrosis greater than 90% (Huvos Grade III/IV) indicates a good response and correlates with improved survival.

Question 92

A 22-year-old man presents with an eccentric, radiolucent lesion in the proximal tibial metaphysis with a well-defined sclerotic rim. Biopsy reveals a lobular architecture with stellate and spindle cells embedded in an abundant myxoid and chondroid background. Multinucleated giant cells are present at the lobular peripheries. Which diagnosis is most consistent with these findings?

Explanation

Chondromyxoid fibroma is a rare benign bone tumor presenting as an eccentric metaphyseal lesion with sclerotic margins. Histologically, it features a characteristic lobular pattern with stellate cells in a myxochondroid background and osteoclast-like giant cells at the periphery.

Question 93

A 9-year-old boy with multiple café-au-lait macules with irregular borders ('coast of Maine') presents with a limp. Radiographs demonstrate a classic 'shepherd’s crook' deformity of the proximal femur with a ground-glass appearance of the medullary canal. The fundamental cellular defect in this condition leads to which intracellular abnormality?

Explanation

McCune-Albright syndrome features polyostotic fibrous dysplasia, café-au-lait spots, and endocrinopathies. It is caused by a somatic activating mutation in GNAS1, causing constitutive adenylyl cyclase activity and elevated intracellular cAMP, impairing normal osteoblast differentiation.

Question 94

An 8-year-old child presents with multiple painless bony masses near the joints of the knees, ankles, and shoulders. Radiographs reveal multiple broad-based, cartilage-capped bony outgrowths continuous with the medullary cavity of the parent bone. The pathogenesis of this condition most directly involves abnormal function in which signaling pathway component?

Explanation

Multiple hereditary exostoses (osteochondromatosis) is caused by mutations in EXT1 or EXT2. These genes encode glycosyltransferases essential for heparan sulfate polymerization, which normally regulates chondrocyte proliferation and differentiation in the growth plate.

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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