1) Endothelin 1 is known to be involved in which of the following

disease processes?
a. Enchondroma formation
b. Osteochondroma formation
c. RANK ligand induced tumor lysis
d. Osteoblastic bone metastases
e. Physeal bar formation
PREFERRED RESPONSE D
Endothelin 1 has been shown to be a crucial protein involved in the
formation of osteoblastic bone metastases, like those caused by prostate
cancer or certain types of breast cancer. Illustration A shows multiple
osteoblastic type metastases in the spine of a patient with metastatic
breast cancer. While the mechanistic explanation for this process isn't
completely understood, it is known that tumor produced endothelin 1 is a
necessary step in the development of osteoblastic metastasis
Mohammad and Guise describe their cell-culture and mouse experiments
which led to this discovery. Specifically, tumor produced cell media,
containing tumor-produced factors like endothelin 1, had the ability to
induce osteoblastic bone metastases in a mice treated with this culture
media. In addition, this process was specifically inhibited by treatment
with antagonists to endothelin 1, confirming the role of endothelin 1 in
osteoblastic metastases
Endothelin 1 has not been shown to play a role in enchondromas,
osteochondromas, physeal bars, or RANK ligand induced tumor lysis

2) A 65-year-old male is seen for increasing thigh pain and a new

femoral lesion seen by his oncologist. A current radiograph is
shown in Figure A. He has a known diagnosis of lung carcinoma
but no history of metastatic disease. What is the next most
appropriate step in management of this patient?

a.
b.
c.
d.
e.

Biopsy
Intramedullary stabilization
Intramedullary stabilization and send femoral reamings as biopsy
Palliative chemotherapy
Palliative radiotherapy

PREFERRED RESPONSE A
The radiographs show a cortically based lytic lesion in the mid diaphysis of
the left femur, which is consistent with a metastatic lesion from a lung
carcinoma, however without a history of biopsy proven bone metastasis,
this lesion needs to be biopsied prior to definitive treatment. Sending
femoral reamings is not an appropriate biopsy technique as significant
contamination of the abductors, skin, and femoral canal occurs which
compromises limb salvage if this lesion is in fact a sarcoma. The biopsy
may be followed by intramedullary stabilization under the same
anesthetic if the lesion can be confirmed as a carcinoma by the surgical
pathologist. However if carcinoma cannot be confirmed, no further
treatment is indicated until final pathology is available for review.
In both her JAAOS and ICL reviews, Weber et al discuss the evaluation,
biopsy, and treatment of patients who present with destructive bone
lesions, presumed to be related to metastatic disease. Her
recommendations include biopsy of all destructive bone lesions without a
history of known bone metastatic disease.
Rougraff reviews the workup of patients with carcinoma metastatic to
bone. While making this diagnosis is a simple matter of obtaining tissue
for the surgical pathologist, the correct diagnosis can be difficult,
especially in GI lesions which may or may not appear on systemic staging
studies. As such, systemic staging, bone scan, lab work, and physical
examination become crucial to the diagnosis of metastatic carcinoma.

3) All of the following are known steps in the development of a

malignant tumor with the ability to metastasize EXCEPT?
a. Increased apoptosis
b. Sustained angiogenesis
c. Tumor cell intravasation
d. Avoidance of immune surveillance
e. Genomic instability
PREFERRED RESPONSE A
All of the listed options are involved in the development of a malignant
tumor with the ability to metastasize EXCEPT increased apoptosis.
Apoptosis is programmed cell death, and tumor cells are known for their
decreased rate of apoptosis. This allows for tumor cell sustained growth
even after induction of cellular signals known to induce apoptosis in nonneoplastic cells.
the process of apoptosis

4) A 61-year-old female presents with a 6 month history of pain in

the left hip and thigh. A hip radiograph is shown in Figure A.
Serum protein electrophoresis is normal, and a bone scan shows
increased uptake in the left femur only. A biopsy is taken and
shown in Figure B. What is the most likely diagnosis?

a.
b.
c.
d.
e.

Osteosarcoma
Chondrosarcoma
Primary lymphoma of bone
Metastatic carcinoma
Multiple myeloma

PREFERRED RESPONSE D
The clinical presentation, radiographs, and histology are most consistent
with metastatic carcinoma. Metastatic carcinoma is the most common
cause of a destructive bone lesion in older adults. Bone is the third most
common site of metastasis, behind the lung and liver. Osteosarcoma
occurs predominately in the metaphysis, and is often associated with
periosteal reaction. Patients with multiple myeloma will usually show
elevated serum protein electrophoresis levels. The pathology slide shows
a mixture of glandular cells and bone, representing metastatic gastric
cancer. Osteosarcoma, chondrosarcoma, and primary lymphoma of bone
lack the presence of glandular cells on histology
5) Metastatic bony lesions that occur distal to the elbows or knees
are most likely to originate from which one of the following
primary organs?
a. Breast
b. Lung
c. Thyroid
d. Gastrointestinal
e. Prostate
PREFERRED RESPONSE B
Metastatic bony lesions that occur distal to the elbows or knees are most
likely to occur from primary lung and kidney tumors. The exact molecular
mechanism for this metastatic pattern is not known. It is unknown if acral
metastases in isolation confer a negative prognosis, or if it is merely a
reflection of an aggressive tumor; however, when encountered, long term
survival is unlikely

6) You are seeing a 53-year-old female for 1 year of increasing knee

pain. She is otherwise healthy. Based on the imaging studies
below (Figures A-D), what is your diagnosis?

a.
b.
c.
d.
e.

Chondrosarcoma
Giant Cell Tumor
Multiple myeloma
Chordoma
Renal cell carcinoma

PREFERRED RESPONSE E
The history and imaging studies, specifically the high power histology
slide, suggest a metastatic renal cell carcinoma. Specifically the histology
slides show the characteristic clear cell change and the pseudoalveolar
pattern of renal cell carcinoma. The histology is not characteristic of
chondrosarcoma, giant cell tumor, or multiple myeloma. Chordoma, while
similiar in histologic appearance, occurs from cellular remnants of the
notochord, not in the proximal tibia
7) A 70-year-old female has unrelenting lower back pain and severe
left anterior thigh pain. She has hip flexion weakness on the left
that is limiting her ambulation. A representative image from her
abdominal CT is shown below as well as a sagittal MRI of her
spine. Nonoperative management has failed. What is the next
appropriate step before performing an anterior corpectomy and
stabilization of the spine?

a.
b.
c.
d.
e.

CT-guided biopsy of spinal lesion

Percutaneous kyphoplasty
External beam radiation
Intravenous antibiotics
Arteriography and embolization of the spinal lesion

PREFERRED RESPONSE E
The CT of the abdomen shows a renal mass. Renal cell carcinoma is
extremely hypervascular and has a propensity to bleed profusely. Thus,
many authorities recommend arteriography and embolization of the lesion
prior to performing any surgery on a suspected renal metastatic lesion.
The goal is to reduce blood loss in patients undergoing surgery for these
hypervascular tumors. There is no need for a CT guided biopsy for several
reasons: 1) because our suspicion is high for metastatic renal disease 2)
decompression is indicated and we can obtain a biopsy during
decompression 3) biopsies of metastatic renal lesions can lead to
excessive bleeding. Percutaneous kyphoplasty and radiation would not
alleviate her radicular symptoms and are not indicated. Her clinical picture
and MRI are not characteristic of infection, and therefore antibiotics would
not be indicated.
Sundaresan et al performed a case-control study of patients with renal
mets to the spine treated with radiation alone or surgery +/- radiation.
The median survival of the surgically treated patients was 13 months,
compared with 3 months for those treated by radiation alone. In addition,
a greater proportion of the surgically treated patients were benefitted
neurologically (70%) compared with those treated by radiation (45%).
8) A 69-year-old man with known metastatic lung cancer presents
with a pathological fracture after a fall from standing height
(Figure A). Which of the following options is the best choice for
treating this fracture?

a.
b.
c.
d.
e.

Total hip arthroplasty

Hemiarthroplasty
Sliding hip screw
Dynamically locked cephalomedullary nail
Statically locked cephalomedullary nail

PREFERRED RESPONSE E
The best choice of the listed options for treatment of this fracture would
be a statically locked cephalomedullary nail. Note however that either a
statically locked cephalomedullary nail or a proximal femoral replacement
(intentionally not a listed option) would be acceptable treatment for this
lesion.
Based on the location of the lesion, neither a total hip arthroplasty nor a
hemiarthroplasty would be appropriate - unless a cemented long stem
which bypasses the defect is available as a treatment option. A sliding hip
screw is not an appropriate treatment choice because of the
subtrochanteric nature of the fracture and the fact that the sliding hip
screw does not biomechanically address subtrochanteric fractures. As this
patient has significant bone loss, a dynamically locked nail is at risk of
shortening, and only the statically locked nail will provide resistance to the
torsional stress and angular displacement.
Jacofsky and Haidukewych review the management of pathologic fractures
of the proximal femur, "...the most commonly affected bone with
metastatic disease in the appendicular skeleton." While the recommended
treatment for this subtrochanteric pathologic fracture is arguable between
proximal femoral replacement and statically locked cephalomedullary nail,
the authors advocate for internal fixation rather than replacement.
9) A 56-year-old female is referred for a second opinion after
placement of an intramedullary nail through a presumed

metastatic lesion in her proximal femur. Final biopsy results from

the lesion show a high-grade chondrosarcoma and staging studies
show this to be an isolated site of disease. What treatment
should be recommended?
a. Intramedullary nail removal and radiotherapy to the limb
b. Systemic chemotherapy and keep nail in place to prevent fracture
c. Wide proximal femoral resection and hemiarthroplasty followed by
radiotherapy
d. Wide resection including hip disarticulation
e. Palliative care
PREFERRED RESPONSE D
Bone lesions require biopsy prior to treatment as placement of an
intramedullary nail through a tumor contaminates the entire bone. In the
treatment of metastatic lesions with an intramedullary nail, adjuvant
radiotherapy has to be dosed over the entire bone due to implant
contamination of the bone. In the case of chondrosarcoma, which is
chemotherapy and radiotherapy resistant, wide resection will require
some type of resection of the entire bone, meaning either a hip
disarticulation or a total femoral resection - removing all contaminated
tissue
10)
All of the following are necessary steps in bony metastasis
of a malignant cell EXCEPT?
a. Intravasation
b. Avoidance of immune surveillance
c. Target tissue localization
d. Induction of angiogenesis
e. Direct stimulation of osteoclasts
PREFERRED RESPONSE E
Malignant cell metastasis requires at a minimum tumor cell intravasation
(entry into blood vessels), avoidance of immune surveillance, target tissue
localization, and induction of angiogenesis. While tumor cells may
stimulate osteoclasts in the process of tumor cell osteolysis, this is not a
necessary step for metastasis. In addition, tumor cells do not directly
stimulate osteoclasts, they indirectly stimulate them through
osteoblast/stromal cell production of cytokines like RANKL.