Orthopaedic Oncology

Tumor Growth and Metastasis

1.	Tumor cells secrete what substance?	1.	Parathyroid hormone-related peptide (PTHrP)
2.	PTHrP then stimulates what cells?	2.	Osteoblasts
3.	What do the osteoblasts secrete when stimulated?	3.	RANK ligand
4.	This ligand then binds to osteoclasts and stimulates the secretion of what two substances?	4.	Transforming growth factor-β (TGF-β) Insulin-derived growth factor (IGF)
5.	What is the net effect of these growth factors?	5.	Tumor growth Release of more PTHrP (cycle repeats itself)
6.	What cofactor is required to facilitate the RANK-RANK ligand interaction?	6.	Macrophage colony-stimulating factor (M-CSF)
7.	What is the cause of osteogenic rickets?	7.	Secretion of fibroblast growth factor-23 (FGF-23)
8.	What is the resultant effect?	8.	Decreased renal reabsorption of calcium
9.	What is the sequence of five events leading to metastasis?	9.	Tumor growth and increased vascularity Metalloproteinases degrade type IV collagen (present within the basement membrane) Tumor cells enter the bloodstream Tumor cells embolize Tumor invades vessel wall to grow at a new location
10.	What are the five most common tumors that metastasize to bone?	10.	Breast Prostate Lung Kidney Thyroid
11.	What type of thyroid cancer is especially likely to metastasize to bone?	11.	Follicular
12.	What is the No. 1 location to which bony metastases go?	12.	Thoracic vertebral body
13.	Besides lung cancer, what other cancer also metastasizes distally (e.g., to hands)?	13.	Renal cell
14.	What four sarcomas classically metastasize to lymph nodes?	14.	Rhabdomyosarcoma Synovial sarcoma Epithelioid sarcoma Clear cell sarcoma
15.	What is the usual function of P-glycoprotein?	15.	Pumps out cellular toxins
16.	What is the significance of P-glycoprotein and chemotherapy?	16.	Pumps out chemotherapeutic agents and may contribute to chemotherapy resistance

Key Genetic and Immunohistochemical Concepts

DNA: Normal Physiology

17.	Approximately how many genes are there in human DNA?	17.	30,000
18.	What is the difference between an intron and an exon?	18.	Intron: noncoding sequence within DNA Exon: directly codes for protein
19.	What is an oncogene?	19.	Tumor-inducing agent Arises from proto-oncogenes after mutation or increased expression
20.	What is a proto-oncogene?	20.	Normal gene Codes for proteins that regulate cell growth and differentiation
21.	What is an anti-oncogene?	21.	Tumor suppression gene Suppresses growth in damaged cells to inhibit tumors If function is lost, allows tumor growth
22.	What is a gene promoter?	22.	DNA sequence required for transcription
23.	What is a gene enhancer?	23.	Region of DNA that provides a binding site for transcription factors
24.	What happens after a transcription factor binds to a region of DNA?	24.	Recruits RNA polymerase Enables RNA synthesis from the coding region of the gene
25.	What is a consensus sequence?	25.	Shared sequence of nucleotides in different DNA and RNA sequences Plays the same role in different locations (e.g., binding site for regulatory proteins)
26.	What transcription factor is critical for enchondral ossification?	26.	SOX-9
27.	A deficiency of this transcription factor results in which dysplasia?	27.	Camptomelic dysplasia
28.	What transcription factor is associated with intramedullary ossification?	28.	CBFA-1 (core binding factor 1)
29.	What dysplasia is associated with deficiency of this factor?	29.	Cleidocranial dysostosis

Laboratory Techniques for Manipulating DNA

30.	What is DNA ligation? What is an example of a clinical application?	30.	Joining linear DNA fragments together with covalent bonds Example: attachment of human genes to plasmids
31.	Two fragments of DNA can be linked to form what?	31.	Recombinant DNA
32.	What is transformation? What is an example of an application where transformation is used?	32.	The genetic alteration of a cell resulting from uptake and expression of foreign material Example: Inserting a recombinant plasmid into a bacteria
33.	What is the difference between therapeutic cloning, reproductive cloning, and embryo cloning?	33.	Therapeutic: a specific organ or tissue is produced from a stem cell Reproductive: an animal is produced that is genetically identical to the host Embryo: several genetically identical animals are produced
34.	How is a transgenic animal made?	34.	A foreign gene is inserted into a one-cell embryo Transgene is then represented in every cell of the animal
35.	What is the difference between Southern, Northern, and Western hybridization?	35.	Southern hybridization can identify a DNA sequence Northern hybridization can identify an RNA sequence Western hybridization can identify proteins expressed after translation

Genetics in Orthopaedic Oncology

36.	What is gene translocation? What is the clinical significance?	36.	Movement of a gene fragment from one chromosomal location to another May alter or abolish gene expression
37.	What are the two methods by which translocations are identified?	37.	Polymerase chain reaction (PCR) Fluorescence in situ
38.	PCR is used for the amplification of what?	38.	DNA
39.	Real-time PCR is used for the amplification of what?	39.	RNA
40.	What translocation is associated with Ewing sarcoma?	40.	11:22
41.	What translocation is associated with myxoid liposarcoma?	41.	12:16
42.	What translocation is associated with clear cell sarcoma?	42.	12:22
43.	What translocation is associated with synovial sarcoma?	43.	X:18
44.	What translocation is associated with rhabdomyosarcoma?	44.	2:13
45.	What translocation is associated with myxoid chondrosarcoma?	45.	9:22
46.	What gene is associated with osteosarcoma and retinoblastoma?	46.	Rb1
47.	With what syndrome is a p53 mutation associated?	47.	Li-Fraumeni
48.	What is the inheritance pattern of this genetic mutation?	48.	Autosomal dominant (AD)
49.	What four other classes of tumors have been associated with p53 mutations?	49.	Adrenal tumors Brain tumors Soft tissue sarcomas (e.g., rhabdomyosarcoma) Breast cancer

Key Immunohistochemistry Concepts

50.	Lymphoma stains positive for what marker?	50.	Leukocyte common antigen (LCA)
51.	What other disorder also stains positive for this marker?	51.	Leukemia
52.	What three disorders are associated with a positive keratin stain?	52.	Metastatic carcinoma Synovial sarcoma Adamantinoma
53.	What disorder is associated with a positive vimentin stain? Example?	53.	Mesothelial tumors Example: sarcoma
54.	What disorder is associated with positive desmin and actin stains? Example?	54.	Tumors with myodifferentiation (stains for muscle components) Example: rhabdomyosarcoma
55.	What disorder is associated with a positive smooth muscle actin stain?	55.	Leiomyosarcoma
56.	What three disorders are associated with S-100 positivity?	56.	Chondroid tumors and chordoma Neural tumors (for example, neurofibromatosis) Melanocytic tumors
57.	What two disorders are associated with factor VIII antigen positivity?	57.	Hemangioma Hemangioendothelioma
58.	What four disorders are associated with α-fetoprotein positivity?	58.	Nephroblastoma (Wilms’) Testicular cancer Ovarian cancer Malignant teratoma
59.	What four disorders are associated with high α-fetoprotein levels in pregnancy?	59.	Spina bifida Anencephaly Chromosomal abnormalities (e.g., trisomy 21 and trisomy 18) Omphalocele
60.	What disorder is associated with CD138?	60.	Myeloma
61.	What disorder is associated with a ring chromosome/giant marker?	61.	Liposarcoma
62.	What disorder is associated with CA-125?	62.	Metastatic ovarian cancer
63.	What disorder is associated with CK-7?	63.	Metastatic brain/lung cancer
64.	What disorder is associated with CK-20?	64.	Metastatic colon cancer

Basic Orthopaedic Tumor Principles

Workup and Staging

65.

What is the role of computed tomography (CT), magnetic resonance imaging (MRI), and technetium (Tc) bone scan in evaluating bony lesions?

65.

CT: determines amount of bone destruction and soft tissue calcification
MRI: determines lesion extent, edema, and presence of soft tissue extension
Tc bone scan: determines total number of lesions

New Soft Tissue Mass Workup

66.	What is the imaging study of choice for evaluation of a soft tissue mass?	66.	MRI with contrast
67.	What is the classic MRI appearance of a malignant tumor on T1? T2?	67.	Low T1 High T2
68.	Quick review: what is the typical MRI appearance of a hemangioma on T1? T2?	68.	High T1 High T2
69.	What does rim enhancement suggest?	69.	Mass is likely a cyst
70.	What if the entire mass enhances?	70.	Mass is likely a tumor
71.	If the mass is indeterminate in appearance (benign versus malignant), what is the next study?	71.	Needle or open biopsy
72.	What does a positron emission tomography (PET) scanner measure?	72.	Fluorodeoxyglucose (FDG) accumulation
73.	This is an indirect measure of what?	73.	Glucose utilization rate
74.	Why does a suspected hematoma require careful follow-up?	74.	May be clinically difficult to differentiate hematoma and developing sarcoma Must follow patient regularly until mass has resolved
75.	From what tissue line do sarcomas originate?	75.	Mesenchyme
76.	In general, what is the significance of sarcoma size?	76.	>5 cm is more likely to metastasize
77.	What is the significance of sarcoma location?	77.	If sarcoma is below the deep fascia, the prognosis is poorer
78.	In general, which study is ordered to evaluate for sarcomatous metastases?	78.	CT chest
79.	What studies are ordered to evaluate for liposarcoma metastases?	79.	CT chest/abdomen/pelvis

Additional Evaluation of Bony Tumors

80.	Complete staging of osteosarcoma requires what two imaging studies?	80.	CT chest Bone scan
81.	What additional test is routinely performed for Ewing sarcoma?	81.	Bone marrow biopsy
82.	What additional test is routinely performed for rhabdomyosarcoma? Why?	82.	Local node biopsy One of four sarcomas that metastasizes to lymph nodes

Stage and Grade

83.	What are the three stages of benign tumors?	83.	Latent Active Aggressive
84.	In the Enneking staging of malignant tumors, what do I and II refer to?	84.	Whether the tumor is low grade (I) or high grade (II)
85.	What is the significance of grade?	85.	High-grade tumors are more likely to metastasize
86.	What is the 5-year survival rate for high-grade sarcomas?	86.	50%
87.	What do A, B, and C refer to?	87.	Whether the tumor is intracompartmental (A), extracompartmental (B), or metastatic (C)
88.	What other system is commonly employed to stage malignant tumors?	88.	American Joint Committee on Cancer (AJCC) system
89.	What is the major difference in this system?	89.	Includes a classification for “skip” metastases
90.	What are the four key prognostic factors for malignant tumors in descending order of importance?	90.	Stage (includes grade and metastases) Whether metastases are present Grade Size greater than or less than 8 cm
91.	For what can flow cytometry be used?	91.	To quantify the amount of abnormal DNA present
92.	What are Mirel’s four criteria?	92.	Site Pain Lesion type Size
93.	What is the clinical application of Mirel’s score?	93	To predict the likelihood that a metastatic bony lesion will go on to fracture
94.	How are lesions scored based on site?	94.	1: upper limb
			2: lower limb
			3: trochanteric
95.	How are lesions scored based on pain?	95.	1: mild
			2: moderate
			3: pain with activity
96.	How are lesions scored based on type of lesion?	96.	1: blastic
			2: mixed
			3: lytic
97.	How are lesions scored based on size?	97.	1: <1/3 diameter
			2: 1/3 to 2/3 diameter
			3: >2/3 diameter
98.	What was the mean score for the population that went on to fracture?	98.	10
99.	What was the mean score for the nonfracture population?	99.	7

Radiographic Examination Pearls

100.	What are the five key differential diagnoses for destructive lesions of bone in young patients?	100.	Osteosarcoma Ewing sarcoma Leukemia/lymphoma Osteomyelitis Eosinophilic granuloma
101.	What are the five key differential diagnoses for destructive lesions of bone in older patients?	101.	Metastases Myeloma Lymphoma Chondrosarcoma Malignant fibrous histiocytoma (MFH)
102.	What are the five key differential diagnoses for processes that affect both sides of a joint?	102.	Bone infarcts (x-ray: smoke signal; histology: empty lacunae) Tuberculosis/coccidioidomycosis (histology: spores, Langerhans’ cells) Pigmented villonodular synovitis (PVNS; x-ray: lytic) Gout (histology: tophaceous material) Rheumatoid arthritis
103.	What are the three key differential diagnoses for eccentric metaphyseal lesions?	103.	Nonossifying fibroma (NOF): “bubbly” x-ray appearance Chondromyxoid fibroma (CMF): “bubbly” Aneurysmal bone cyst (ABC): not bubbly
104.	What are the six key differential diagnoses for a calcified lesion on the surface of bone?	104.	Osteochondroma Periosteal osteosarcoma Parosteal osteosarcoma Myositis ossificans Periosteal chondroma Periosteal chondrosarcoma
105.	If you see a multiple-lesion process, what are the three most likely etiologies in children <5 years of age?	105.	Metastases from neuroblastoma Metastases from nephroblastoma Histiocytosis
106.	What is the most likely etiology at ages 15 to 40?	106.	Vascular tumor (e.g., hemangioendothelioma)
107.	What are the three most likely etiologies at age >40?	107.	Metastases Multiple myeloma Lymphoma
108.	What two other multiple-lesion processes can affect patients at a variety of ages?	108.	Fibrous dysplasia Paget’s disease
109.	What three tumors often demonstrate predominantly cortical involvement or tunneling?	109.	Ewing sarcoma (occasionally) Osteomyelitis (cortical tunneling classically) Osseofibrous dysplasia
110.	What are the five key differential diagnoses for a lytic lesion within the sacrum?	110.	Chordoma Chondrosarcoma Giant cell tumor Metastasis Myeloma
111.	What is the key differential diagnosis for a centrally located lytic lesion in a pediatric humeral shaft without periosteal reaction?	111.	Unicameral bone cyst
112.	What are the three key differential diagnoses for a pagetoid-looking pelvis and unilateral femoral involvement?	112.	Polyostotic fibrous dysplasia Ollier disease Paget’s disease
113.	A widened femoral metaphysis may suggest what disorder?	113.	Multiple hereditary exostoses (MHE)
114.	What six tumors classically involve the anterior vertebral body?	114.	Eosinophilic granuloma Giant cell tumor Osteosarcoma Hemangioma Metastases Myeloma
115.	What three tumors classically involve the posterior spinal elements?	115.	Aneurysmal bone cyst (ABC) Osteoid osteoma/blastoma Osteochondroma
116.	What tumors classically involve the neuroforamina?	116.	Neurofibromatosis (NF)
117.	What are the five components of the differential diagnosis of an intramedullary destructive lesion of the hand or foot?	117.	Enchondroma Giant cell tumor (no bone on histology) Giant cell reactive granuloma (bone present on histology)
			Aneurysmal bone cyst (ABC) Metastases
118.	What are punched-out lytic lesions?	118.	Lytic lesions that look as if they were created by a hole punch in bone
119.	Among younger patients, what lesion classically has this appearance?	119.	Eosinophilic granuloma
120.	What lesion classically has this appearance among older patients?	120.	Multiple myeloma

Histologic Examination Pearls

121.	When interpreting the histology of a bony tumor, what does lamellar bone indicate?	121.	A section that is not part of the tumor
122.	How do you go about evaluating the histology of a bony tumor with woven bone present?	122.	First, look for osteoblastic rimming If osteoblastic rimming is present, then the bone is reactive If no osteoblastic rimming is present, then the bone is neoplastic Second, look at stroma to determine if the neoplasm is benign or malignant
123.	What are the two features of malignant stroma?	123.	High cellularity and necrosis High mitotic rate and atypia
124.	What are three examples of lesions with woven bone and osteoblastic rimming?	124.	Osseofibrous dysplasia Osteoblastoma Paget’s disease (also see coarse trabeculae on x-ray)
125.	If the histology resembles osseofibrous dysplasia but no osteoblastic rimming is present, consider what lesion?	125.	Fibrous dysplasia
126.	Metastases often have what cells on histology? How do they generally appear?	126.	Epithelial cells Appear as clumps (stuck together) or as glands
127.	What are the three aspects of the histologic appearance of normal cartilage?	127.	Relatively sparse cells One nucleus per cell One cell per lacuna
128.	Myxoid lesions are characterized by what two areas of distinct histologic appearance?	128.	White (myxoid) area Dense or cartilage looking area
129.	When present in bone, such lesions often represent what?	129.	CMF
130.	When present in soft tissue, a myxoid lesion often represents what?	130.	Schwannoma with Antoni A and Antoni B areas
131.	What is the acronym and what are the five components of the differential diagnosis for a tumor that has small round cells on histology?	131.	Acronym: La HEIM Lymphoma Histiocytosis Ewing sarcoma Infection Metastases/myeloma
132.	If you see a giant cell tumor with bone present, consider what lesion in what location?	132.	Giant cell reactive granuloma Hands
133.	Nuclear inclusions on electron microscopy are suggestive of what two tumors?	133.	Paget’s disease Eosinophilic granuloma
134.	In eosinophilic granuloma, what are the nuclear inclusions called?	134.	Birbeck granules

General Treatment Concepts: Resection, Reconstruction, Chemotherapy, and Radiation

135.	What are the two major drawbacks to plate-and-screw fixation of allograft to native bone for reconstruction after tumor surgery?	135.	High allograft fracture rate 10% deep infection rate
136.	What anatomic location is particularly prone to complications with this method?	136.	Proximal tibia
137.	What is the relative advantage of this method of fixation?	137.	Relatively high rates of union
138.	What three tumors are the classic low-grade malignant tumors of bone?	138.	Adamantinoma Parosteal osteosarcoma Chordoma
139.	Because they are low grade, how are these tumors generally treated?	139.	Wide resection only
140.	Chemotherapy is generally helpful for what four tumors?	140.	Acronym: MOLE Metastases Osteosarcoma Lymphoma Ewing sarcoma
141.	Radiation therapy is generally helpful for what five tumors?	141.	Acronym: ELMMS Ewing sarcoma Lymphoma Multiple myeloma Metastases Soft tissue sarcoma
142.	By what mechanism is radiation therapy thought to act?	142.	Oxygenates intracellular water Damages DNA of tumor cells
143.	What are the two potential therapeutic uses of strontium in patients with neoplasms?	143.	Control pain from bony metastases Localizes selectively within bone and irradiates bony metastases from within
144.	What complication is classically associated with doxorubicin?	144.	Cardiac toxicity