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

Question 1

A 14-year-old boy presents with progressive pain in the diaphysis of the femur. Radiographs show a permeative, destructive lesion with a wide zone of transition and an 'onion-skin' periosteal reaction. Biopsy reveals uniform sheets of small round blue cells. Immunohistochemistry is strongly positive for CD99 in a membranous pattern.

Which of the following chromosomal translocations is most characteristic of this patient's diagnosis?

Explanation

This is a classic presentation of Ewing Sarcoma. Characteristic features include diaphyseal location, onion-skin periosteal reaction, and sheets of small round blue cells that express CD99. The most common genetic alteration is the t(11;22)(q24;q12) translocation, which produces the EWS-FLI1 fusion protein. Synovial sarcoma is associated with t(X;18). Myxoid liposarcoma has t(12;16). Alveolar rhabdomyosarcoma has t(2;13).

Question 2

A 32-year-old female presents with knee pain. Radiographs demonstrate an eccentric, entirely lytic lesion located in the epiphysis of the proximal tibia, extending to the subchondral bone plate. Biopsy reveals a proliferation of uniform mononuclear cells interspersed with numerous osteoclast-like giant cells. What genetic mutation is most commonly associated with the pathogenesis of this tumor?

Explanation

The clinical scenario describes a Giant Cell Tumor (GCT) of bone, classically presenting as an eccentric epiphyseal lesion in a skeletally mature patient. The neoplastic cells are the mononuclear cells, which express RANKL and recruit the reactive osteoclast-like giant cells. Over 90% of GCTs harbor a mutation in the H3F3A gene (typically G34W). USP6 translocations are seen in aneurysmal bone cysts.

Question 3

A 16-year-old girl presents with swelling in her distal femur. MRI reveals an expansile, multiloculated cystic lesion with prominent fluid-fluid levels. Core needle biopsy confirms multiple blood-filled spaces lacking an endothelial lining, surrounded by fibrous septa containing giant cells and woven bone.

Which of the following genetic alterations is the primary driver of this lesion?

Explanation

The lesion described is a primary Aneurysmal Bone Cyst (ABC). The presence of fluid-fluid levels on MRI is highly characteristic. While ABCs can be secondary to other tumors (like GCT, chondroblastoma, or osteoblastoma), primary ABCs are driven by rearrangements of the USP6 gene (most commonly t(16;17) fusing CDH11 to USP6).

Question 4

A 28-year-old male presents with a slow-growing, painful mass near his knee joint, though imaging confirms the lesion is extra-articular. Biopsy demonstrates a biphasic pattern consisting of sheets of uniform spindle cells and scattered glandular structures lined by cuboidal epithelial cells. Which of the following represents the characteristic genetic translocation for this soft tissue sarcoma?

Explanation

This is the classic presentation and histology of a biphasic Synovial Sarcoma. Despite its name, it rarely involves the synovial tissue directly, but rather arises near joints. The pathognomonic translocation is t(X;18)(p11;q11), resulting in the SYT-SSX (or SS18-SSX) fusion gene.

Question 5

A 15-year-old boy is diagnosed with conventional high-grade osteosarcoma of the distal femur. Biopsy displays an overtly malignant stroma with high pleomorphism.

Regardless of whether the subtype is osteoblastic, chondroblastic, or fibroblastic, what is the absolute requisite histological hallmark required to establish this diagnosis?

Explanation

The defining diagnostic feature of all conventional osteosarcomas is the production of osteoid (unmineralized bone matrix) directly by the malignant neoplastic cells. Without the demonstration of malignant osteoid, the diagnosis of osteosarcoma cannot be definitively made.

Question 6

A 55-year-old man presents with a painful mass in the proximal humerus. Radiographs show a lytic lesion with intralesional stippled and 'popcorn' calcifications. Biopsy demonstrates a cartilaginous matrix with moderate cellularity, atypical chondrocytes, binucleation, and permeation into surrounding marrow spaces. Which of the following genetic mutations is frequently observed in this neoplasm?

Explanation

The lesion is a conventional Chondrosarcoma. Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are frequently found in enchondromas and central chondrosarcomas. EXT1/2 mutations are characteristic of multiple hereditary exostoses (osteochondromas).

Question 7

A 65-year-old man presents with severe lower back pain. Radiographs reveal multiple punched-out lytic lesions in the vertebral bodies and skull. A technetium-99m bone scan is surprisingly normal (cold) in these affected areas.

Biopsy of a vertebral lesion would most likely reveal which of the following?

Explanation

The presentation of punched-out lytic lesions with a cold bone scan (due to purely osteolytic activity with no osteoblastic reactive bone formation) in an older adult is classic for Multiple Myeloma. Histology will show a monoclonal proliferation of plasma cells, which characteristically express CD138 and CD38.

Question 8

A 12-year-old girl is evaluated for a limp and a leg length discrepancy. Radiographs demonstrate a well-defined 'ground-glass' appearance in the metaphysis and diaphysis of the proximal femur, accompanied by a shepherd's crook deformity. What is the underlying pathogenesis of this condition?

Explanation

The clinical and radiographic features are diagnostic of Fibrous Dysplasia. The underlying cause is an activating missense mutation in the GNAS gene (typically occurring post-zygotically), which encodes the alpha subunit of the Gs G-protein. This leads to constitutive activation of adenylate cyclase and increased cAMP, causing abnormal proliferation and differentiation of skeletal progenitor cells.

Question 9

A 50-year-old man presents with chronic, insidious sacral pain and recent onset of bowel/bladder dysfunction. MRI reveals a large, destructive midline mass in the sacrum. Biopsy reveals lobules of large cells with prominent intracytoplasmic vacuoles (physaliferous cells) set within a rich myxoid stroma.

Which immunohistochemical marker is highly specific for this tumor?

Explanation

The tumor described is a Chordoma, which originates from embryonic notochordal remnants. It most commonly occurs in the sacrum and the spheno-occipital region. The presence of 'physaliferous' (bubbly) cells is characteristic. Brachyury is a transcription factor essential for notochord development and serves as a highly sensitive and specific immunohistochemical marker for chordoma.

Question 10

A 25-year-old female presents with a deep-seated, slowly enlarging mass in the plantar aspect of her foot, which appears attached to the plantar aponeurosis. Biopsy reveals nests of clear and pale cells with prominent nucleoli. Immunohistochemistry is strongly positive for HMB-45, Melan-A, and S100. Which of the following translocations is diagnostic of this entity?

Explanation

The tumor is Clear Cell Sarcoma of soft tissue (also historically known as malignant melanoma of soft parts). Due to its neural crest differentiation, it stains positive for melanocytic markers (HMB-45, Melan-A, S100). The pathognomonic translocation is t(12;22)(q13;q12) which fuses the EWSR1 gene with ATF1.

Question 11

A 5-year-old boy presents with a painful lytic lesion in his parietal skull. Biopsy reveals a proliferation of mononuclear cells exhibiting folded, grooved nuclei (resembling coffee beans), admixed with a dense infiltrate of eosinophils. Electron microscopy of the lesional cells demonstrates intracytoplasmic 'tennis-racket' shaped Birbeck granules. These cells will characteristically express which of the following markers?

Explanation

The diagnosis is Langerhans Cell Histiocytosis (LCH). Classical histological features include grooved nuclei ('coffee bean' appearance), abundant background eosinophils (hence the older term 'eosinophilic granuloma'), and Birbeck granules on EM. The Langerhans cells are reliably positive for S100, CD1a, and Langerin (CD207). Approximately 50-60% of LCH cases harbor a BRAF V600E mutation.

Question 12

A 16-year-old boy presents with knee pain. Radiographs demonstrate a 2 cm lytic lesion with a thin sclerotic rim confined entirely to the epiphysis of the proximal tibia. Biopsy shows mononuclear cells, scattered osteoclast-like giant cells, and distinctive areas of 'chicken-wire' intercellular calcification. What is the underlying genetic mutation most commonly associated with this tumor?

Explanation

This is a Chondroblastoma, a rare benign cartilaginous tumor characteristically arising in the epiphysis of growing long bones. Histology features mononuclear chondroblasts, giant cells, and classic 'chicken-wire' calcifications. Genetically, over 90% have mutations in the histone H3.3 gene H3F3B (typically K36M), distinguishing it from Giant Cell Tumor of bone which predominantly harbors mutations in H3F3A (typically G34W).

Question 13

A 35-year-old man presents with chronic dull pain and swelling in the anterior mid-shaft of his leg. Radiographs reveal a multilocular, expansile, eccentric osteolytic lesion with a 'soap-bubble' appearance. Biopsy demonstrates a biphasic tumor with nests and cords of epithelial cells surrounded by a bland fibrous stroma.

This specific tumor occurs almost exclusively in which of the following bones?

Explanation

The diagnosis is Adamantinoma, a low-grade malignant bone tumor. It exhibits a biphasic histological pattern consisting of epithelial islands (positive for cytokeratins) within an osteofibrous stroma. Clinically, 80-90% of adamantinomas occur in the diaphysis of the tibia, typically in the anterior cortex.

Question 14

A 22-year-old male presents with dull, aching pain in his mid-back that does not completely resolve with NSAIDs. Imaging reveals a 2.8 cm radiolucent lesion in the posterior elements of the L3 vertebra with an surrounding zone of reactive sclerosis. Histological evaluation shows a nidus of irregular, interconnected woven bone trabeculae lined by prominent osteoblasts, highly vascular loose connective tissue, and no atypical cells. Based on clinical and pathologic features, what is the most likely diagnosis?

Explanation

The histology described (woven bone trabeculae lined by osteoblasts in a vascular stroma) is identical for both osteoid osteoma and osteoblastoma. However, the distinction is made clinically and radiographically: osteoblastomas are larger (> 2.0 cm), often have a less dramatic response to NSAIDs/aspirin, and have a predilection for the posterior elements of the spine.

Question 15

An asymptomatic 10-year-old boy undergoes a radiograph after a minor knee sprain. The plain film reveals an incidental finding: an eccentric, cortically based, multilocular radiolucency with a well-defined sclerotic border in the distal femur metaphysis.

Which of the following is the most appropriate management for this lesion?

Explanation

The radiograph describes a Non-Ossifying Fibroma (NOF) or Fibrous Cortical Defect. These are benign, asymptomatic, self-limiting developmental defects of bone rather than true neoplasms. They typically present as eccentric, cortically based, 'bubbly' metaphyseal lesions with sclerotic margins. The standard of care is observation and reassurance, as the vast majority will ossify and resolve spontaneously as the child reaches skeletal maturity.

Question 16

A 65-year-old male presents with a large, deep intramuscular mass in his proximal thigh. Biopsy reveals two distinct components: one area shows well-differentiated liposarcoma (atypical lipomatous tumor) with lipoblasts, and abruptly transitioning adjacent areas show a high-grade, non-lipogenic pleomorphic sarcoma. Which of the following genetic alterations is the hallmark of this condition?

Explanation

The lesion is a Dedifferentiated Liposarcoma, which arises from a well-differentiated liposarcoma. Both well-differentiated and dedifferentiated liposarcomas are defined by a characteristic supernumerary ring or giant marker chromosome containing amplification of the 12q13-15 region, which includes the MDM2 and CDK4 genes. MDM2 overexpression inhibits p53 function.

Question 17

A 35-year-old female presents with chronic knee swelling, stiffness, and recurrent hemarthrosis without any history of trauma. MRI displays a nodular and frond-like synovial mass with extensive 'blooming' artifact on gradient-echo sequences due to hemosiderin deposition.

Which genetic alteration is primarily implicated in the pathogenesis of this disease?

Explanation

The patient has Pigmented Villonodular Synovitis (PVNS), now more accurately termed Tenosynovial Giant Cell Tumor (TGCT). The blooming artifact on MRI is classic for hemosiderin. The neoplastic driver is a t(1;2) translocation fusing the CSF1 gene to COL6A3, causing an overexpression of Colony Stimulating Factor 1 (CSF1). This acts in a paracrine fashion to attract a massive non-neoplastic inflammatory infiltrate of macrophages and multinucleated giant cells.

Question 18

A 40-year-old man presents with a painless, deep, intramuscular mass in the thigh. Biopsy shows a proliferation of small, uniform, round-to-oval cells set in an abundant myxoid stroma, accompanied by a prominent delicate arborizing 'chicken-wire' capillary network and scattered signet-ring lipoblasts. What is the characteristic translocation associated with this tumor?

Explanation

This is a Myxoid Liposarcoma. Typical histologic hallmarks include a myxoid matrix, a delicate 'chicken-wire' branching capillary vasculature, and lipoblasts. Over 90% of myxoid liposarcomas contain the t(12;16)(q13;p11) translocation, which fuses the FUS gene with the DDIT3 (CHOP) gene.

Question 19

A 15-year-old boy presents with a rapidly growing, deep soft tissue mass in his forearm. Biopsy reveals a dense proliferation of primitive small round blue cells. The cells are divided into discrete nests by fibrous septa, with central discohesion of cells creating spaces that mimic pulmonary alveoli. Which genetic fusion is most characteristic of this aggressive sarcoma?

Explanation

The histology is classic for Alveolar Rhabdomyosarcoma, characterized by small round blue cells arranged in pseudo-alveolar spaces. It is highly associated with the t(2;13) translocation forming the PAX3-FOXO1 fusion gene, or less commonly t(1;13) forming PAX7-FOXO1. EWS-FLI1 is seen in Ewing Sarcoma.

Question 20

A 30-year-old female presents with a painless, slow-growing mass on the posterior aspect of the distal femur. Radiographs reveal a dense, heavily ossified mass broadly attached to the posterior cortex. Notably, a thin radiolucent line ('string sign') separates a portion of the tumor from the underlying cortex.

Histologically, the lesion consists of low-grade spindle cells interspersed among parallel trabeculae of woven and lamellar bone. Which genetic abnormality is characteristic of this tumor?

Explanation

The clinical, radiographic (posterior distal femur, string sign), and histologic (low-grade spindle cells with mature bone trabeculae) findings are classic for Parosteal Osteosarcoma, a low-grade surface osteosarcoma. Like well-differentiated liposarcomas, parosteal osteosarcomas are characterized genetically by supernumerary ring chromosomes leading to amplification of the 12q13-15 region, specifically amplifying MDM2 and CDK4.

Question 21

A 35-year-old male presents with a painless, slowly enlarging swelling over his right shin. Radiographs reveal an eccentric, multi-loculated osteolytic lesion in the anterior cortex of the tibial diaphysis. Biopsy demonstrates a biphasic tumor with nests of epithelial cells surrounded by a bland fibrous stroma. Which of the following immunohistochemical markers is most characteristically positive in the neoplastic cellular nests of this lesion?

Explanation

The clinical and histological presentation is classic for Adamantinoma. Adamantinoma typically occurs in the anterior cortex of the tibial diaphysis in young adults. Histologically, it has a biphasic appearance with epithelial cells interspersed in a fibrous stroma. The epithelial cells are strongly positive for cytokeratins (CK14, CK19). CD99 is for Ewing sarcoma, S-100 for neural/chondroid tumors, and Desmin/SMA for myogenic tumors.

Question 22

A 42-year-old male presents with persistent shoulder pain. Radiographs show a lytic lesion in the proximal humeral epiphysis. Histological examination reveals sheets of neoplastic cells with abundant clear cytoplasm, distinct cell membranes, scattered osteoclast-like multinucleated giant cells, and areas of chondroid matrix. What is the most likely diagnosis?

Explanation

Clear cell chondrosarcoma is a rare, low-grade malignant bone tumor that characteristically involves the epiphysis of long bones (typically proximal femur or humerus) in adults (30-50 years). Histologically, it shows large cells with clear cytoplasm (glycogen-rich), interspersed giant cells, and islands of chondroid matrix. While Chondroblastoma is also epiphyseal and contains giant cells, it occurs in skeletally immature patients and features "chicken-wire" calcification rather than extensive clear cells. Metastatic RCC has clear cells but lacks chondroid matrix.

Question 23

An 8-year-old boy presents with polyuria and a solitary lytic skull lesion. Biopsy of the lesion shows sheets of large, pale mononuclear cells with grooved (coffee-bean) nuclei, mixed with eosinophils. Electron microscopy reveals Birbeck granules. Which of the following immunohistochemical profiles best characterizes the lesional cells?

Explanation

The patient has Langerhans Cell Histiocytosis (LCH), likely presenting as Hand-Schüller-Christian triad (diabetes insipidus, exophthalmos, lytic skull lesions). The characteristic cells are Langerhans cells, which possess grooved nuclei and Birbeck granules (tennis-racket shaped) on EM. Immunophenotypically, they are uniformly positive for S-100, CD1a, and CD207 (Langerin).

Question 24

A 25-year-old male presents with a slow-growing soft tissue mass in the plantar aspect of his foot. Radiographs show a soft tissue density with focal stippled calcifications. Biopsy reveals a biphasic tumor consisting of spindle cells and glandular epithelial structures. Which of the following translocations is diagnostic for this tumor?

Explanation

The diagnosis is Synovial Sarcoma. Despite its name, it rarely arises within a joint, often occurring in periarticular soft tissues of the extremities (especially foot/ankle). Radiographs show calcifications in about 30% of cases. The pathognomonic translocation is t(X;18)(p11;q11), leading to the SYT-SSX fusion gene. t(11;22) is Ewing sarcoma; t(12;16) is Myxoid liposarcoma; t(2;13) is Alveolar rhabdomyosarcoma; t(9;22) is Extraskeletal myxoid chondrosarcoma.

Question 25

A 30-year-old female presents with recurrent, painful swelling of her knee. Joint aspiration yields brownish fluid. MRI reveals a thickened synovium with prominent blooming artifact on gradient-echo sequences. The pathogenesis of this condition is primarily driven by a t(1;2) translocation leading to the overexpression of which of the following?

Explanation

The clinical picture and MRI (blooming artifact indicating hemosiderin) are classic for Pigmented Villonodular Synovitis (PVNS), also known as Tenosynovial Giant Cell Tumor (TGCT). The driver mutation is a t(1;2) translocation involving the COL6A3 and CSF1 genes, leading to an overproduction of CSF1 (M-CSF). This attracts a massive non-neoplastic inflammatory infiltrate of macrophages and multinucleated giant cells, which make up the bulk of the tumor mass.

Question 26

A 62-year-old male presents with chronic constipation and lower back pain. Imaging reveals a large, destructive, midline mass in the sacrum. Biopsy demonstrates lobules of large cells with prominent intracytoplasmic vacuoles (physaliferous cells) in a myxoid background. Which immunohistochemical marker is highly sensitive and specific for distinguishing this tumor from chondrosarcoma?

Explanation

The diagnosis is Chordoma, a primary malignant bone tumor arising from notochordal remnants, most commonly located in the sacrum or clivus. It features 'physaliferous' (bubbly) cells. While chordomas, like chondrosarcomas, can be positive for S-100, Brachyury (a transcription factor crucial for notochord development) is highly sensitive and specific for chordoma and differentiates it from chondrosarcoma.

Question 27

A 32-year-old male presents with a slowly enlarging, ulcerated nodule on the volar aspect of his wrist. Initial biopsy was misinterpreted as a necrotizing granuloma. Re-evaluation reveals a proliferation of plump epithelioid cells surrounding central areas of necrosis. Immunohistochemistry shows loss of nuclear expression of INI1 (SMARCB1). What is the diagnosis?

Explanation

Epithelioid sarcoma classically presents in the distal extremities (hand/wrist) of young adults as a firm, slow-growing nodule that may ulcerate. Histologically, it exhibits a nodular pattern of epithelioid cells surrounding central necrosis, closely mimicking a benign granuloma (like a rheumatoid nodule or caseating granuloma). The diagnostic molecular hallmark is the loss of INI1 (SMARCB1) nuclear expression.

Question 28

A 28-year-old male has an expansile, multiloculated radiolucent lesion in the body of the mandible. Histology shows interlacing fascicles of uniform, bland spindle cells with abundant collagen production and no cytologic atypia or mitotic figures. The lesion is locally aggressive. Mutations in which of the following signaling pathways are most commonly implicated in this tumor?

Explanation

The presentation and histology describe a Desmoplastic Fibroma of bone. This rare, locally aggressive intraosseous tumor is the bone counterpart of soft tissue fibromatosis (desmoid tumor). Like soft tissue desmoids, desmoplastic fibroma is driven by mutations in the Wnt/beta-catenin signaling pathway (often CTNNB1 mutations), leading to nuclear accumulation of beta-catenin.

Question 29

A 72-year-old male with a long history of bone pain, increasing head size, and progressive hearing loss suddenly develops severe pain and swelling in his right thigh. Radiographs reveal a highly destructive diaphyseal lesion with cortical breakthrough and a wide zone of transition. His alkaline phosphatase is markedly elevated. The underlying disease process that predisposed him to this malignancy primarily begins with the dysfunction of which cell type?

Explanation

The clinical history strongly suggests Paget's disease of bone (increasing head size, hearing loss, very high Alk Phos) complicated by secondary osteosarcoma. Paget's disease begins with a primary localized phase of excessive and abnormal bone resorption mediated by dysfunctional, overly active, and enlarged osteoclasts (often containing viral-like nuclear inclusions). This is followed by a compensatory but disorganized (woven bone) osteoblastic response.

Question 30

A 16-year-old boy presents with mild, chronic knee pain. Radiographs demonstrate an eccentric, sharply circumscribed, well-demarcated osteolytic lesion with a sclerotic margin in the metaphysis of the proximal tibia. Histology shows a lobulated architecture with hypocellular centers containing stellate/spindle cells in a myxoid stroma, and hypercellular peripheries containing multinucleated osteoclast-like giant cells. What is the diagnosis?

Explanation

Chondromyxoid fibroma (CMF) is a rare, benign cartilaginous tumor. It characteristically presents as an eccentric metaphyseal lytic lesion with a sclerotic rim in the lower extremity (especially proximal tibia). Histologically, it is highly characteristic: distinct lobules with myxoid/chondroid hypocellular centers containing stellate cells, and hypercellular fibrous septa/peripheries housing osteoclast-like giant cells. Chondroblastoma is epiphyseal. NOF is cortical and purely fibroblastic/histiocytic.

Question 31

A 15-year-old male undergoes curettage of a 3 cm lytic lesion located exclusively in the greater tuberosity epiphysis of the proximal humerus. Histological analysis reveals sheets of mononuclear cells with characteristic nuclear grooves, prominent eosinophilic cytoplasm, and focal areas of fine, intercellular pericellular calcifications. Molecular testing of this lesion is most likely to reveal a mutation in which of the following genes?

Explanation

The lesion is a Chondroblastoma (epiphyseal location in a teenager, mononuclear cells with grooved nuclei, and "chicken-wire" pericellular calcification). Almost all chondroblastomas harbor a highly specific mutation in the H3F3A gene, specifically an H3.3 K36M substitution. A different substitution in the same gene, H3.3 G34W, is characteristic of Giant Cell Tumor of Bone. GNAS is associated with fibrous dysplasia. EXT1/EXT2 with osteochondromas.

Question 32

A 34-year-old female presents with an expansile, eccentric lytic lesion in the distal radius that extends to the subchondral bone plate. A biopsy confirms Giant Cell Tumor (GCT) of bone. Regarding the cellular constituents of this tumor, which of the following statements is most accurate regarding its pathogenesis and targeted medical treatment?

Explanation

In Giant Cell Tumor of Bone, the actual neoplastic cells are the spindle-shaped mononuclear stromal cells. These neoplastic stromal cells overexpress RANKL. The multinucleated giant cells are non-neoplastic, reactive osteoclast-like cells that express the RANK receptor. Denosumab is a monoclonal antibody that binds to RANKL (produced by the mononuclear cells), preventing it from activating RANK on the giant cells, thus halting bone destruction. The H3F3A G34W mutation is found only in the neoplastic mononuclear cells, not the giant cells.

Question 33

A 55-year-old male is referred for an asymptomatic calcified lesion discovered incidentally on a radiograph of his proximal humerus. The radiologist suggests distinguishing between an enchondroma and a low-grade (Grade 1) central chondrosarcoma. Which of the following MRI or radiographic findings is the most reliable indicator favoring a diagnosis of low-grade chondrosarcoma over enchondroma?

Explanation

Differentiating enchondroma from low-grade central chondrosarcoma is notoriously difficult. Radiographic features that suggest malignancy (low-grade chondrosarcoma) include deep endosteal scalloping (>2/3 of the cortical thickness), cortical thickening, soft tissue extension, and pain (clinical feature). Both lesions can have popcorn calcifications, metaphyseal/diaphyseal locations, and lobular T2 hyperintensity. Size >5 cm favors malignancy, so <4 cm favors enchondroma.

Question 34

A 48-year-old female presents with generalized weakness, recurrent nephrolithiasis, and bilateral multi-focal lytic bone lesions. A biopsy of a femoral lesion demonstrates a highly vascularized stroma containing plump spindle cells, areas of hemorrhage, and clusters of osteoclast-like multinucleated giant cells. Which of the following laboratory profiles is most likely to be found in this patient?

Explanation

The clinical scenario (stones, bones, groans) and the histology (hemorrhage, spindle cells, giant cells) describe a Brown Tumor (osteitis fibrosa cystica) resulting from primary hyperparathyroidism. Brown tumors are non-neoplastic, reactive lesions mimicking giant cell tumors. Primary hyperparathyroidism is characterized by elevated parathyroid hormone (PTH), hypercalcemia, and hypophosphatemia. The "brown" color macroscopically is due to hemosiderin from hemorrhage.

Question 35

A 22-year-old female presents with a slow-growing, painless mass deep in the vastus lateralis. Staging reveals multiple small brain metastases. Biopsy of the primary tumor shows large, polygonal cells with abundant granular eosinophilic cytoplasm arranged in a nested, pseudoalveolar pattern. PAS staining reveals diastase-resistant rhomboid crystals in the cytoplasm. What is the specific genetic alteration driving this tumor?

Explanation

The diagnosis is Alveolar Soft Part Sarcoma (ASPS). It typically affects young adults, often arising in the deep tissues of the thigh/leg. It has a high propensity for early metastasis to the brain and lungs. Histologically, it shows large cells with granular eosinophilic cytoplasm in pseudoalveolar nests, containing PAS-positive, diastase-resistant, rhomboid-shaped crystals. The pathognomonic mutation is an unbalanced translocation der(17)t(X;17)(p11;q25), yielding an ASPSCR1-TFE3 fusion protein.

Question 36

A 52-year-old male undergoes MRI for chronic lumbar radiculopathy. An incidental lesion is noted in the L3 vertebral body. Sagittal T1- and T2-weighted MRI both show high signal intensity in the lesion, and axial CT shows a "polka-dot" pattern of thickened trabeculae. What is the most appropriate management for this specific lesion?

Explanation

The lesion is a vertebral Hemangioma. It is the most common benign tumor of the spine. The radiographic findings are pathognomonic: a "corduroy" or vertically striated appearance on lateral plain films/sagittal CT, a "polka-dot" pattern on axial CT (representing thickened vertical trabeculae in cross-section), and high signal intensity on both T1 and T2-weighted MRI (due to fat content interspersed with vascular channels). Since it is incidental and asymptomatic, observation is the standard of care.

Question 37

A 6-year-old boy presents with painless anterolateral bowing of his left tibia. Radiographs show multiple anterior intracortical lytic lesions in the tibial diaphysis. Histology shows a fibroblastic stroma surrounding trabeculae of woven bone that are lined by a prominent layer of active osteoblasts. No epithelial cells are identified on extensive sectioning. This lesion has a known clinical association with, and must be carefully distinguished from, which of the following malignancies?

Explanation

The diagnosis is Osteofibrous Dysplasia (Campanacci disease). It occurs almost exclusively in the tibia and fibula of children <10 years, causing anterolateral bowing and anterior intracortical lytic lesions. Histologically, it resembles fibrous dysplasia but is distinguished by the presence of prominent osteoblastic rimming around the bone trabeculae. Osteofibrous dysplasia is intimately related to Adamantinoma (which occurs in older patients in the exact same location) and some consider it a precursor or a regressive form. Some cases thought to be OFD are actually "differentiated adamantinomas" if epithelial cells are found.

Question 38

A 68-year-old male with a history of fatigue and normocytic anemia presents with severe, acute onset back pain. Radiographs reveal multiple 'punched-out' lytic lesions in his skull and a compression fracture of T10. Serum protein electrophoresis (SPEP) demonstrates an M-spike. If a biopsy of the skull lesion were performed, what would be the most prominent immunohistochemical finding?

Explanation

The diagnosis is Multiple Myeloma, characterized by CRAB symptoms (hyperCalcemia, Renal involvement, Anemia, Bone lytic lesions/back pain) and a monoclonal paraproteinemia (M-spike). The lytic bone lesions are plasmacytomas, consisting of clonal plasma cells. Neoplastic plasma cells characteristically have "clock-face" eccentric nuclei with a perinuclear halo (Golgi zone) and are immunohistochemically positive for CD138 (syndecan-1) and CD38.

Question 39

A 32-year-old female presents with a slowly enlarging, hard mass on the posterior aspect of her distal femur. Plain radiographs display a heavily ossified, dense, lobulated mass arising from the cortex, with a radiolucent line (cleft) separating parts of the tumor from the underlying bone cortex. Histological examination shows bland, well-differentiated spindle cells arranged between parallel trabeculae of mature woven and lamellar bone. Molecular analysis is most likely to show amplification of which genomic region?

Explanation

The clinical, radiographic (posterior distal femur, dense mass, "string sign" or radiolucent cleft), and histologic features (low cellularity, bland spindle cells, parallel trabeculae) are classic for Parosteal Osteosarcoma, a low-grade surface osteosarcoma. Biologically, parosteal osteosarcoma (like low-grade central osteosarcoma and well-differentiated liposarcoma) is characterized by supernumerary ring chromosomes containing amplified sequences of the 12q13-15 region, leading to overexpression of MDM2 and CDK4.

Question 40

An 18-year-old female presents with a deep thigh mass. Biopsy reveals a primitive, small round cell tumor. Molecular analysis demonstrates a t(11;22)(q24;q12) translocation resulting in an EWSR1-FLI1 fusion transcript. Although this tumor typically arises in bone, when it presents as a primary soft tissue mass (extraskeletal), it must be differentiated from which morphologically identical tumor that belongs to the same family and shares the identical genetic driver?

Explanation

Ewing sarcoma and Primitive Neuroectodermal Tumor (PNET) belong to the same Ewing Sarcoma Family of Tumors (ESFT). They are morphologically and genetically virtually identical, both driven by the t(11;22) translocation creating the EWSR1-FLI1 fusion. Historically, tumors showing more neural differentiation (Homer-Wright rosettes, expression of neural markers) were termed PNETs, while more undifferentiated ones were called Ewing sarcoma. They are now considered a single biologic spectrum.

Question 41

A 15-year-old boy presents with knee pain and swelling. Radiographs reveal a lytic and blastic lesion in the distal femoral metaphysis with a 'sunburst' periosteal reaction. Biopsy demonstrates malignant cells producing osteoid matrix. Which of the following tumor suppressor genes are most frequently inactivated in the pathogenesis of this primary bone tumor?

Explanation

Conventional osteosarcoma is highly associated with mutations in the RB1 and TP53 tumor suppressor genes. Inactivation of these pathways leads to unchecked cellular proliferation and is foundational to its pathogenesis.

Question 42

A 55-year-old man presents with chronic, progressively worsening thigh pain. Radiographs demonstrate a large radiolucent lesion with 'popcorn' calcifications in the proximal femur and prominent endosteal scalloping. Histological evaluation shows lobules of hyaline cartilage with atypical, binucleated cells within lacunae. What is the most important histologic predictor of prognosis and metastasis for this patient's lesion?

Explanation

In chondrosarcoma, histologic grade (based on cellularity, nuclear atypia, and mitotic activity) is the single most reliable predictor of clinical behavior, local recurrence, and metastatic potential. Low-grade lesions rarely metastasize, whereas high-grade lesions have a high metastatic rate.

Question 43

A 30-year-old woman presents with a slow-growing, painful mass around her ankle. Imaging reveals an extra-articular soft-tissue mass with stippled calcifications. Biopsy demonstrates a biphasic pattern consisting of both epithelial and spindle cells. Cytogenetic testing of the lesion is most likely to reveal which of the following translocations?

Explanation

The clinical and histological presentation is classic for synovial sarcoma, which frequently demonstrates stippled calcifications on imaging. It is genetically defined by the t(X;18)(p11;q11) translocation, resulting in the SYT-SSX fusion gene.

Question 44

A 60-year-old man presents with bowel and bladder dysfunction and sacral pain. MRI shows a destructive, lobulated mass centered in the sacrum. Histopathology shows lobules of myxoid tissue containing large cells with vacuolated cytoplasm (physaliferous cells). Immunohistochemistry for this tumor will characteristically be positive for cytokeratin, EMA, S-100, and which of the following highly specific markers?

Explanation

This patient has a chordoma, a locally aggressive tumor arising from notochordal remnants. Brachyury is a transcription factor essential for notochord development and is a highly sensitive and specific immunohistochemical marker for chordoma.

Question 45

A 24-year-old man presents with a nodular lesion on the volar aspect of his finger that has slowly ulcerated, mimicking a chronic infection or granuloma. Biopsy reveals epithelioid and spindle cells arranged in a nodular pattern with central necrosis. Immunohistochemistry demonstrates a loss of SMARCB1 (INI1) expression. What is the most likely diagnosis?

Explanation

Epithelioid sarcoma often presents in young adults as a superficial nodule in the distal extremities that can ulcerate. It is characterized molecularly by the loss of INI1 (SMARCB1) protein expression on immunohistochemistry.

Question 46

A 28-year-old female presents with a palpable, painless mass on the posterior aspect of her distal thigh. Radiographs demonstrate a dense, lobulated, ossified mass attached to the posterior cortex of the distal femur with a 'string sign' (radiolucent cleft). Biopsy confirms a low-grade spindle cell stroma interspersed with well-formed woven bone trabeculae. Which genetic alteration is characteristic of this tumor?

Explanation

Parosteal osteosarcoma is a low-grade, surface osteosarcoma typically found on the posterior distal femur. It is characterized genetically by ring chromosomes leading to the amplification of the MDM2 and CDK4 genes on chromosome 12q13-15.

Question 47

A 15-year-old boy presents with shoulder pain. Radiographs reveal a well-circumscribed, lytic lesion in the epiphysis of the proximal humerus with a thin sclerotic margin. Histological examination shows mononuclear cells with grooved nuclei and areas of 'chicken-wire' calcification. Which specific genetic mutation drives this neoplasm?

Explanation

The clinical presentation and histology (chicken-wire calcification) are diagnostic of a chondroblastoma. Chondroblastomas are uniquely driven by a specific K36M mutation in the H3F3B histone gene.

Question 48

A 12-year-old girl is evaluated for a pathological fracture of the proximal femur. Radiographs reveal a large, diaphyseal expansile lesion with a 'ground-glass' matrix and a 'shepherd's crook' deformity. A biopsy shows irregular, C-shaped trabeculae of woven bone lacking prominent osteoblastic rimming in a fibrous stroma. What is the underlying molecular mechanism of this disorder?

Explanation

Fibrous dysplasia is caused by a post-zygotic somatic missense mutation in the GNAS gene, leading to an inherently active Gs-alpha protein. This causes constitutive activation of adenylyl cyclase and high levels of intracellular cAMP, altering osteoblast differentiation.

Question 49

A 45-year-old man undergoes excision of a large, deep soft-tissue mass in his thigh. Pathology reveals a uniform proliferation of primitive mesenchymal cells, small signet-ring lipoblasts, and a prominent plexiform ('chicken-wire') capillary network within a myxoid stroma. Which cytogenetic abnormality is pathognomonic for this tumor?

Explanation

Myxoid liposarcoma is characterized histologically by a myxoid stroma, lipoblasts, and a plexiform capillary network. It is defined by the t(12;16)(q13;p11) translocation, which creates the FUS-DDIT3 (or FUS-CHOP) fusion transcript.

Question 50

A 32-year-old man presents with chronic anterior tibial pain. Radiographs show a multiloculated, eccentric, osteolytic lesion in the anterior diaphysis of the tibia. Histopathology demonstrates a biphasic tumor with nests of basaloid epithelial cells surrounded by an osteofibrous stroma. Immunohistochemistry is positive for broad-spectrum cytokeratins. What is the most likely diagnosis?

Explanation

Adamantinoma is a low-grade malignant bone tumor that almost exclusively occurs in the anterior tibia. It exhibits a distinct biphasic histology with cytokeratin-positive epithelial cells and a fibrous stroma.

Question 51

A 5-year-old boy presents with anterior bowing of the tibia. Imaging shows a radiolucent, intracortical lesion along the anterior tibial diaphysis. Biopsy reveals fibroblastic tissue with trabeculae of woven bone that are characteristically rimmed by active, plump osteoblasts. Cytokeratin staining is negative. Patients with this condition require clinical follow-up primarily to monitor for progression into which of the following entities?

Explanation

The lesion described is osteofibrous dysplasia (OFD), distinguished from fibrous dysplasia by the prominent osteoblastic rimming of bone trabeculae. OFD can be contiguous with or progress to adamantinoma, thus requiring careful observation.

Question 52

A 40-year-old man presents with hip pain. Radiographs reveal a well-defined lytic lesion in the epiphysis of the proximal femur. Biopsy demonstrates sheets of cells with abundant, clear cytoplasm and distinct cell membranes, interspersed with areas of woven bone and chondroid matrix. What is the most appropriate management for this lesion?

Explanation

Clear cell chondrosarcoma is a low-grade malignant tumor that uniquely prefers the epiphysis of long bones in adults (unlike conventional chondrosarcoma or chondroblastoma). Being a chondrosarcoma, it is resistant to chemotherapy and radiation, making wide surgical resection the treatment of choice to prevent local recurrence.

Question 53

A 12-year-old boy is found to have an incidental eccentric, multiloculated, radiolucent lesion with a sclerotic rim in the distal femoral metaphysis following minor trauma. A biopsy of a similar lesion would characteristically demonstrate spindle cells in a storiform pattern, multinucleated giant cells, and lipid-laden foamy macrophages. Multiple such lesions, combined with café-au-lait spots, are associated with which of the following syndromes?

Explanation

The lesion is a non-ossifying fibroma (NOF). The association of multiple NOFs with café-au-lait macules, mental retardation, and cardiovascular anomalies is known as Jaffe-Campanacci syndrome.

Question 54

A 68-year-old man presents with severe back pain and fatigue. Radiographs show multiple punched-out lytic lesions in his skull and vertebrae. Laboratory studies reveal hypercalcemia and a monoclonal spike on serum protein electrophoresis. A bone marrow biopsy confirms the diagnosis. Which immunohistochemical marker is characteristically strongly positive on the neoplastic cells?

Explanation

The patient has multiple myeloma, a plasma cell dyscrasia. CD138 (syndecan-1) is a highly specific and sensitive cell surface marker for plasma cells and is classically positive in multiple myeloma.

Question 55

An 18-year-old male presents with persistent night pain in his thigh that is dramatically relieved by aspirin. Radiographs show a 1 cm radiolucent nidus surrounded by dense reactive cortical sclerosis in the proximal femoral diaphysis. The profound pain experienced by the patient is primarily due to local production of which of the following mediators?

Explanation

The clinical and radiographic picture is pathognomonic for an osteoid osteoma. The extreme pain, particularly at night, is mediated by high levels of Prostaglandin E2 (PGE2) produced by osteoblasts within the nidus, which explains the dramatic response to NSAIDs.

Question 56

A 70-year-old man presents with increasing head size, hearing loss, and anterior bowing of the tibiae. Laboratory testing reveals a markedly elevated serum alkaline phosphatase with normal calcium and phosphorus levels. A biopsy of the tibia would most likely show a mosaic pattern of lamellar bone. Mutations in which gene are most strongly implicated in the familial form of this condition?

Explanation

The clinical scenario is classic for Paget's disease of bone. Up to 50% of familial cases and 10-20% of sporadic cases are associated with mutations in the SQSTM1 gene, which encodes the p62 protein involved in osteoclastogenesis.

Question 57

A 35-year-old woman presents with chronic knee swelling, pain, and catching. MRI demonstrates a large, nodular intra-articular mass with dark signal intensity on T1 and T2-weighted images due to hemosiderin deposition. A biopsy confirms tenosynovial giant cell tumor (pigmented villonodular synovitis). What is the underlying molecular pathogenesis driving the proliferation of this lesion?

Explanation

Tenosynovial giant cell tumor (PVNS) is driven by a t(1;2)(p13;q37) translocation that fuses the CSF1 gene to a highly active promoter. This causes an overproduction of CSF1 (M-CSF), which recruits non-neoplastic macrophages and multinucleated giant cells that form the bulk of the tumor.

Question 58

A 40-year-old male with a history of numerous cutaneous neurofibromas and café-au-lait spots presents with a rapidly enlarging, painful mass in his sciatic nerve. Biopsy reveals a highly cellular, pleomorphic spindle cell tumor with brisk mitotic activity and geographic necrosis. Immunohistochemistry shows patchy, weak S-100 positivity. The malignant transformation in this patient is most closely linked to loss of heterozygosity in which of the following?

Explanation

This patient has a Malignant Peripheral Nerve Sheath Tumor (MPNST) arising in the setting of Neurofibromatosis type 1. This condition is caused by mutations in the NF1 gene on chromosome 17q11.2, which encodes the tumor suppressor protein neurofibromin.

Question 59

A 4-year-old boy presents with a painful, lytic lesion in the skull vault. Biopsy demonstrates a proliferation of mononuclear histiocyte-like cells with grooved, 'coffee-bean' nuclei, admixed with eosinophils. Electron microscopy identifies characteristic tennis-racket-shaped cytoplasmic organelles. Recent targeted therapies for this disease successfully inhibit which of the following commonly mutated kinases?

Explanation

The clinical and histological features describe Langerhans cell histiocytosis (LCH), characterized by Birbeck granules on EM. More than 50% of LCH cases harbor an activating BRAF V600E mutation, making BRAF inhibitors highly effective in refractory disease.

Question 60

A 6-year-old girl presents with a rapidly expanding soft tissue mass in her forearm. Biopsy reveals sheets of primitive small round blue cells with prominent fibrovascular septa lacking central cellularity, creating an 'alveolar' pattern. Strong desmin and myogenin positivity is noted. Which specific chromosomal translocation is most frequently identified in this malignancy?

Explanation

Alveolar rhabdomyosarcoma is a highly aggressive soft tissue sarcoma in pediatric populations. It is molecularly characterized by the t(2;13)(q35;q14) translocation resulting in the PAX3-FOXO1 fusion gene, which correlates with a poorer prognosis compared to embryonal variants.

Question 61

A 28-year-old male presents with a slowly enlarging, painless mass around his ankle. MRI shows a soft tissue mass adjacent to the Achilles tendon. Core biopsy reveals a biphasic tumor with both epithelial-like glandular structures and uniform spindle cells. Which of the following cytogenetic abnormalities is pathognomonic for this tumor?

Explanation

This patient has a synovial sarcoma, which classically occurs in the extremities of young adults and can exhibit biphasic histology. The pathognomonic translocation is t(X;18)(p11;q11), which fuses the SS18 (SYT) gene with an SSX gene.

Question 62

A 65-year-old man presents with dull pelvic pain. Radiographs reveal a bulky, destructive lesion in the ilium with 'ring-and-arc' calcifications. Biopsy demonstrates atypical chondrocytes with binucleation and permeation of the host trabecular bone. Mutations in which of the following genes are most frequently implicated in the pathogenesis of this primary bone tumor?

Explanation

The clinical and radiographic presentation is consistent with a conventional chondrosarcoma. Mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) are found in over 50% of conventional central chondrosarcomas.

Question 63

A 12-year-old girl is evaluated for a leg length discrepancy and a 'shepherd's crook' deformity of her proximal femur. Radiographs show an expansile, ground-glass intramedullary lesion. Histological analysis demonstrates irregular trabeculae of woven bone lacking prominent osteoblastic rimming, set in a fibrous stroma. This condition is driven by an activating mutation in a gene encoding which of the following?

Explanation

The patient has fibrous dysplasia, characterized histologically by 'Chinese letter' woven bone lacking osteoblastic rimming. It is caused by an activating post-zygotic missense mutation in the GNAS gene, which encodes the stimulatory G-protein alpha subunit (Gs-alpha).

Question 64

A 55-year-old woman complains of chronic sacral pain and bowel dysfunction. MRI shows a midline, destructive sacral mass. Biopsy reveals lobules of large, vacuolated cells with bubbly cytoplasm arranged in a myxoid stroma. Immunohistochemistry is positive for S100, cytokeratin, and a highly specific nuclear transcription factor. What is this specific immunohistochemical marker?

Explanation

This lesion is a chordoma, characterized histologically by physaliferous (bubbly) cells. Brachyury is a crucial transcription factor for notochord development and is a highly sensitive and specific immunohistochemical marker for chordoma.

Question 65

A 6-year-old boy presents with back pain. Radiographs demonstrate vertebra plana of T8. A biopsy of the vertebral body shows a proliferation of mononuclear cells with folded, 'coffee-bean' nuclei, admixed with numerous eosinophils. These neoplastic cells are most likely to harbor a mutation in which of the following?

Explanation

The patient's presentation and histology (coffee-bean nuclei, eosinophils) are classic for Langerhans Cell Histiocytosis (LCH). Approximately 50-60% of LCH cases are driven by an activating BRAF V600E mutation.

Question 66

A 30-year-old male presents with chronic anterior knee pain and intermittent swelling. MRI reveals a nodular intra-articular mass with low signal intensity on both T1 and T2 weighted sequences, along with blooming artifact on gradient-echo imaging. Histology shows mononuclear cells, multinucleated giant cells, and hemosiderin-laden macrophages. Which of the following drives the pathogenesis of this lesion?

Explanation

The patient has Tenosynovial Giant Cell Tumor (formerly PVNS), known for hemosiderin deposition causing blooming artifact on MRI. It is a neoplastic process driven by a t(1;2) translocation resulting in overexpression of Colony Stimulating Factor 1 (CSF1).

Question 67

A 35-year-old male presents with an anterior shin mass. Radiographs show a multiloculated, expansile, eccentric radiolucency in the anterior cortex of the tibial diaphysis. Histology exhibits a biphasic pattern of uniform epithelial cells forming nests and tubules within a bland spindle-cell fibrous stroma. Which immunohistochemical stain will best differentiate the prominent cell nests in this tumor from surrounding osteofibrous tissue?

Explanation

This classic presentation represents an adamantinoma, which typically occurs in the anterior tibial diaphysis. It is a biphasic tumor, and the epithelial nests strongly stain positive for pan-cytokeratin.

Question 68

A 68-year-old woman presents with severe back pain. Radiographs reveal multiple 'punched-out' lytic lesions in her skull and spine. Bone marrow biopsy shows sheets of eccentric cells with abundant basophilic cytoplasm, a perinuclear halo (hof), and clock-face chromatin. Which cytokine is primarily responsible for the osteoclast activation and subsequent lytic bone destruction in this disease?

Explanation

The patient has multiple myeloma, characterized by sheets of clonal plasma cells. The myeloma cells secrete various factors, most notably Interleukin-6 (IL-6) and MIP-1 alpha, which powerfully stimulate RANKL expression and subsequent osteoclast-mediated bone resorption.

Question 69

A 25-year-old woman presents with a deep, firm mass in her plantar fascia. Excisional biopsy reveals nests of pale, uniform cells separated by delicate fibrous septa. Immunohistochemistry is strongly positive for S100, HMB-45, and Melan-A. Cytogenetics reveals a t(12;22)(q13;q12) translocation. What is the diagnosis?

Explanation

Clear cell sarcoma (melanoma of soft parts) presents in young adults, often involving the tendons/aponeuroses of the foot and ankle. It shares immunohistochemical markers with melanoma but is uniquely defined by the t(12;22) EWSR1-ATF1 translocation.

Question 70

A 22-year-old male presents with a slowly growing, ulcerating nodule on his volar wrist. It was initially excised at an outside clinic under the assumption it was a necrotizing granuloma, but it rapidly recurred. Histology shows epithelioid cells arranged in nodules with central necrosis. Which immunohistochemical finding is a diagnostic hallmark of this malignancy?

Explanation

Epithelioid sarcoma typically affects the distal extremities of young adults and frequently mimics benign granulomatous processes clinically and histologically. A key diagnostic hallmark is the loss of INI-1 (SMARCB1) nuclear expression due to gene deletion or mutation.

Question 71

A 35-year-old female presents with a painless mass on the posterior aspect of her distal femur. Imaging shows a densely ossified mass attached to the cortex with a broad base, showing no medullary involvement. Biopsy reveals well-formed trabeculae of mature woven bone within a bland, low-grade spindle cell stroma. Which genetic alteration is characteristic of this lesion?

Explanation

This is a parosteal osteosarcoma, a low-grade surface osteosarcoma predominantly found on the posterior distal femur. It is cytogenetically characterized by supernumerary ring chromosomes containing amplifications of the MDM2 and CDK4 genes.

Question 72

A 16-year-old boy presents with pain in his shoulder. Radiographs show an epiphyseal lytic lesion in the proximal humerus with subtle internal calcifications. Biopsy demonstrates mononuclear cells with longitudinal nuclear grooves and areas of eosinophilic matrix with a 'chicken-wire' pattern of calcification. What genetic mutation is specifically associated with this tumor?

Explanation

The clinical picture and chicken-wire calcification define a chondroblastoma, typically occurring in the epiphyses of skeletally immature patients. It is characteristically driven by the H3F3B K36M mutation, distinguishing it from giant cell tumors which have H3F3A mutations.

Question 73

A 45-year-old man presents with a large, painless mass in his deep thigh musculature. MRI demonstrates a lipomatous tumor with thick, nodular septations. Histologic examination reveals mature adipocytes alongside atypical, hyperchromatic spindle cells. Which molecular finding confirms the diagnosis of Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma?

Explanation

Atypical lipomatous tumor (ALT) / well-differentiated liposarcoma is characterized by atypical spindle cells within a mature fat background. The molecular hallmark is the presence of ring chromosomes leading to MDM2 and CDK4 gene amplification.

Question 74

A 15-year-old male presents with a rapidly enlarging mass in his forearm. Biopsy reveals a primitive malignant neoplasm with small round blue cells arranged in clusters separated by dense fibrous septa, forming cleft-like spaces. Immunohistochemistry is strongly positive for desmin and myogenin. Which translocation is most likely present?

Explanation

The histology (alveolar spaces, small round blue cells) and positive myogenic markers (desmin, myogenin) identify alveolar rhabdomyosarcoma. This aggressive sarcoma is characterized by the t(2;13) translocation resulting in a PAX3-FOXO1 fusion gene.

Question 75

A 10-year-old girl is evaluated for multiple bony deformities and multiple dark, compressible soft tissue masses on her hands. Radiographs reveal numerous cartilaginous lesions within the medullary canals of the phalanges, and multiple phleboliths in the adjacent soft tissues. This patient is at a significantly increased risk for which of the following complications?

Explanation

This patient has Maffucci syndrome, distinguished from Ollier disease by the presence of multiple enchondromas and soft tissue spindle cell hemangiomas (with phleboliths). Patients with Maffucci syndrome have a high risk of malignant transformation to chondrosarcoma, as well as a significantly increased risk of various visceral malignancies.

Question 76

A 19-year-old male complains of severe, throbbing pain in his proximal tibia that is worse at night and dramatically relieved by ibuprofen. Imaging shows a cortical lucency measuring 8 mm, surrounded by dense reactive sclerosis. The intense pain associated with this lesion is primarily mediated by which of the following mechanisms?

Explanation

The clinical scenario is classic for an osteoid osteoma. The central nidus contains osteoblasts that highly overexpress Cyclooxygenase-2 (COX-2), leading to massive local production of Prostaglandin E2 (PGE2), which causes the characteristic night pain that is responsive to NSAIDs.

Question 77

A 24-year-old female presents with a destructive, lytic lesion in her distal femur. Biopsy shows an intraosseous proliferation of uniform, bland spindle cells with abundant collagen bundles, resembling a soft-tissue desmoid tumor. There is no cytological atypia or pleomorphism. This lesion is most commonly associated with mutations in which of the following genes?

Explanation

The lesion described is a desmoplastic fibroma of bone, the intraosseous counterpart to soft-tissue fibromatosis (desmoid tumor). Both entities are frequently driven by mutations in the CTNNB1 gene, leading to abnormal beta-catenin accumulation.

Question 78

A 70-year-old man with advanced prostate cancer develops new, diffuse osteoblastic metastases in his lumbar spine and pelvis. The mechanism of this profound osteoblastic response is primarily mediated by the secretion of which of the following factors by the metastatic tumor cells?

Explanation

Prostate cancer uniquely produces predominantly osteoblastic (sclerotic) bony metastases. This osteoblastic reaction is heavily driven by the tumor's secretion of Endothelin-1 (ET-1), which potently stimulates osteoblast proliferation and bone formation.

Question 79

A 40-year-old male presents with a deep mass in his thigh. Histology reveals a pattern of atypical spindle cells arranged in a 'staghorn' or hemangiopericytoma-like vascular pattern, interspersed with thick bands of collagen. Immunohistochemistry demonstrates strong nuclear expression of STAT6. What is the most likely diagnosis?

Explanation

The staghorn vascular pattern and strong nuclear STAT6 expression are characteristic of a Solitary Fibrous Tumor (formerly hemangiopericytoma). This nuclear STAT6 positivity is a direct result of the defining NAB2-STAT6 gene fusion.

Question 80

A 68-year-old man presents with progressively increasing hat size, hearing loss, and bowing of his tibiae. Radiographs show thickened cortices and a coarse trabecular pattern. Bone biopsy reveals a mosaic pattern of lamellar bone with prominent cement lines. Which of the following gene mutations is most strongly associated with the familial form of this condition?

Explanation

The patient has Paget disease of bone (osteitis deformans), characterized by a mosaic pattern of woven and lamellar bone due to dysregulated bone remodeling. Mutations in the SQSTM1 gene (encoding p62) are identified in 40-50% of familial cases, leading to increased NF-kB activation in osteoclasts.

Question 81

A 25-year-old male presents with a deep, painless mass in his posterior thigh. MRI shows a well-circumscribed soft tissue mass adjacent to the knee joint. Biopsy reveals a biphasic tumor consisting of epithelial cells forming glandular structures and a spindle cell stromal component. Which of the following chromosomal translocations is diagnostic for this malignancy?

Explanation

This patient has a synovial sarcoma, which classically presents in young adults near large joints and exhibits biphasic (epithelial and spindle cell) histology. It is defined by the t(X;18) translocation, resulting in the SYT-SSX fusion gene.

Question 82

A 14-year-old boy presents with chronic shoulder pain. Radiographs reveal a well-defined, lytic epiphyseal lesion in the proximal humerus with a sclerotic margin. Biopsy shows mononuclear cells with grooved nuclei and areas of "chicken-wire" calcification. Which of the following genetic mutations is most characteristic of this lesion?

Explanation

The clinical and histological findings describe a chondroblastoma, a benign cartilage-producing tumor of the epiphysis in pediatric patients. It is almost exclusively associated with the H3F3B mutation, distinguishing it from giant cell tumors which have H3F3A mutations.

Question 83

A 40-year-old male undergoes excision of a large thigh mass. Histopathological examination demonstrates a multinodular tumor with a myxoid stroma, scattered lipoblasts, and a prominent "chicken-wire" capillary network. Which translocation drives the pathogenesis of this tumor?

Explanation

Myxoid liposarcoma is characterized histologically by a myxoid background, signet-ring lipoblasts, and a delicate arborizing capillary network. It is genetically driven by the t(12;16) translocation, which produces the FUS-DDIT3 (also known as TLS-CHOP) fusion transcript.

Question 84

A 10-year-old girl is evaluated for a limp. Radiographs show a "shepherd's crook" deformity of the proximal femur with a ground-glass appearance. Biopsy reveals curvilinear woven bone trabeculae lacking osteoblastic rimming set in a fibrous stroma. A mutation in which of the following genes is responsible for this condition?

Explanation

This is fibrous dysplasia, which features "Chinese character" trabeculae without osteoblastic rimming and can cause a shepherd's crook deformity. It is caused by an activating post-zygotic mutation in the GNAS gene, leading to increased cAMP production.

Question 85

A 22-year-old male presents with a firm, ulcerating nodule on the volar aspect of his right wrist. Biopsy demonstrates nodular proliferations of epithelioid and spindle cells with central areas of necrosis, mimicking a granuloma. Which of the following immunohistochemical or molecular findings is most specific for this diagnosis?

Explanation

Epithelioid sarcoma typically affects the distal extremities of young adults and histologically mimics a necrotizing granuloma. A diagnostic hallmark is the loss of INI-1 (SMARCB1) expression on immunohistochemistry.

Question 86

A 15-year-old boy presents with progressive distal femur pain. Radiographs show a sclerotic metaphyseal lesion with a "sunburst" periosteal reaction. Biopsy confirms pleomorphic cells producing malignant osteoid. The patient's family history is significant for multiple early-onset cancers. A germline mutation in which gene is most likely present?

Explanation

Conventional osteosarcoma is highly associated with Li-Fraumeni syndrome, a cancer predisposition syndrome caused by germline mutations in the TP53 tumor suppressor gene. It is also associated with germline RB1 mutations (hereditary retinoblastoma).

Question 87

A 60-year-old male presents with progressive constipation and urinary incontinence. Imaging reveals a large, destructive midline mass involving the sacrum. Biopsy demonstrates lobules of vacuolated cells with a bubbly appearance embedded in a myxoid stroma. Which of the following immunohistochemical markers is most specific for this tumor?

Explanation

Chordoma is a malignant bone tumor derived from notochordal remnants, most commonly occurring in the sacrococcygeal region and clivus. It features characteristic physaliferous (bubbly) cells and is uniquely positive for the nuclear transcription factor Brachyury.

Question 88

A 30-year-old female presents with a slowly enlarging mass on her plantar foot deep to the plantar fascia. Biopsy shows nests of uniform cells with clear cytoplasm and prominent nucleoli, divided by fibrous septa. Immunohistochemistry is strongly positive for HMB-45 and S-100. Which chromosomal abnormality is diagnostic?

Explanation

Clear cell sarcoma (melanoma of soft parts) typically arises in the foot/ankle of young adults and shares immunophenotypic features with melanoma (S-100, HMB-45). Unlike cutaneous melanoma, it is defined by the t(12;22) translocation creating the EWSR1-ATF1 fusion.

Question 89

A 35-year-old male presents with a dull ache in his lower leg. Radiographs show a well-circumscribed, multilobular, osteolytic lesion in the anterior diaphysis of the tibia. Biopsy reveals a biphasic pattern consisting of nests of basaloid cells surrounded by a bland fibrous stroma. Which of the following markers will the epithelial-like cells express?

Explanation

Adamantinoma is a rare, low-grade malignant bone tumor that predominantly occurs in the tibial diaphysis. It has a biphasic histology characterized by epithelial nests that are strongly positive for cytokeratin, distinguishing it from purely mesenchymal tumors.

Question 90

A 28-year-old female presents with a painless mass in her abdominal wall. Excision is performed, and pathology shows a proliferation of uniform spindle cells in a collagenous stroma with deep infiltration into adjacent skeletal muscle. Immunohistochemistry shows nuclear beta-catenin accumulation. Patients with multiple such tumors should be screened for which of the following syndromes?

Explanation

Desmoid tumors (aggressive fibromatosis) feature mutations in the Wnt/beta-catenin pathway, leading to nuclear beta-catenin accumulation. When multiple desmoid tumors are present, it is highly suggestive of Gardner syndrome, a variant of Familial Adenomatous Polyposis (FAP) caused by APC gene mutations.

Question 91

A 18-year-old male presents with severe, progressive thigh pain that awakens him at night but is dramatically relieved by ibuprofen.

Imaging reveals a thick area of cortical sclerosis containing a 7-millimeter central radiolucent nidus. The intense pain experienced by this patient is primarily mediated by excessive local production of which substance?

Explanation

Osteoid osteoma is a benign bone-forming tumor characterized by a small nidus (<1.5 cm) surrounded by dense sclerotic bone. The nidus secretes high levels of Prostaglandin E2 (PGE2), explaining both the severe nocturnal pain and the dramatic response to NSAIDs.

Question 92

An 8-year-old boy presents with back pain. Radiographs demonstrate vertebra plana of T8. Biopsy reveals a proliferation of mononuclear cells with indented, "coffee-bean" shaped nuclei mixed with eosinophils. Electron microscopy identifies tennis-racket shaped Birbeck granules. Which genetic mutation is most frequently identified in this disease?

Explanation

Langerhans Cell Histiocytosis (LCH), formerly known as eosinophilic granuloma when localized to bone, features cells with "coffee-bean" nuclei and Birbeck granules. Over 50% of LCH cases are driven by the activating BRAF V600E mutation.

Question 93

A 65-year-old male presents with hypercalcemia, renal insufficiency, anemia, and low back pain. Radiographs of the skull reveal multiple "punched-out" lytic lesions. Bone marrow biopsy demonstrates sheets of cells with an eccentric nucleus, clumped "clock-face" chromatin, and a perinuclear halo. These neoplastic cells will strongly express which of the following surface markers?

Explanation

The clinical presentation and histology are classic for multiple myeloma. The neoplastic plasma cells in multiple myeloma universally express CD138 (syndecan-1), which is used as a highly specific diagnostic marker.

Question 94

A 55-year-old male presents with deep groin pain. Radiographs of the proximal femur show a poorly marginated radiolucent lesion with stippled "rings and arcs" calcifications and endosteal scalloping. Biopsy demonstrates malignant cartilage permeating between preexisting host bone trabeculae. Which of the following gene mutations is most commonly implicated in this primary bone tumor?

Explanation

Conventional central chondrosarcoma frequently demonstrates characteristic "rings and arcs" calcification and histologic permeation of host bone. Mutations in the isocitrate dehydrogenase genes (IDH1 or IDH2) are found in >50% of central chondrosarcomas.

Question 95

A 12-year-old boy is evaluated for multiple painless, bony bumps around his knees and shoulders. Radiographs show multiple pedunculated excrescences pointing away from the joint line. Genetic testing reveals a loss-of-function mutation in EXT1. The normal product of this gene is essential for 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 that are essential for the synthesis of heparan sulfate, which regulates normal chondrocyte proliferation and differentiation.

Question 96

A 14-year-old girl presents with a rapidly enlarging mass deep in her calf. Biopsy reveals a proliferation of small round blue cells with eosinophilic cytoplasm, separated by fibrous septa into spaces resembling pulmonary alveoli. Which translocation is diagnostic and confers an unfavorable prognosis in this sarcoma?

Explanation

Alveolar rhabdomyosarcoma is an aggressive pediatric soft tissue sarcoma characterized by small round blue cells with alveolar architecture. It is defined by the t(2;13) translocation, generating the PAX3-FOXO1 fusion protein, which drives aggressive tumor growth.

Question 97

A 35-year-old male undergoes wide local excision of a slow-growing, multi-nodular mass on his trunk. Histology reveals bland spindle cells arranged in a "storiform" or cartwheel pattern, deeply infiltrating the subcutaneous fat in a "honeycomb" pattern. The tumor cells are strongly positive for CD34. Which cytogenetic abnormality is characteristic of this lesion?

Explanation

Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive cutaneous tumor with storiform histology and prominent CD34 positivity. It is driven by the t(17;22) translocation, resulting in the COL1A1-PDGFB fusion gene, which causes autocrine overstimulation of the PDGF receptor.

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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