Radioisotope-Guided Surgical Biopsy of Suspected Osseous Metastases
Lary A. Robinson, MD
The gamma probe shows promise as an effective technique to locate bone
metastases.
Background: Radioisotope bone scanning is frequently used to stage patients with
suspected or proven malignancies. Since false-positive results are common, especially in
the ribs, open biopsy is often necessary. The conventional approach of visual inspection
of the bone scan image to guide the surgeon usually requires excision of a large area of
one or two ribs to assure that the biopsy was performed on the correct rib. A more precise
method to guide the biopsy is desirable.
Methods: One technique to localize the suspicious area of bone intraoperatively for
accurate biopsy involves percutaneous injection of the bone abnormality with a
radioisotope followed by injection of methylene blue into the periosteum and subsequent
open surgical biopsy. A more recent technique uses a hand-held gamma probe in a sterile
sleeve in the operating room to locate the bone "hot spot" directly in the wound
to guide the biopsy.
Results: Both techniques are effective in pinpointing the bone scan abnormality,
but use of the gamma probe is less cumbersome and consumes less time and fewer resources.
In one series of 10 patients undergoing gamma probe-guided biopsies of 13 rib and 1
sternal bone scan lesions, this technique showed a sensitivity of 100% in locating the
area of abnormal radioisotope uptake. All biopsies yielded an abnormal diagnosis to
account for the bone scan abnormality, but only 4 of 14 (29%) demonstrated metastatic
tumor.
Conclusions: Techniques described for radioisotope-guided localization of areas of
increased tracer uptake in asymptomatic suspected bone metastases are accurate, sensitive
guides to the open biopsy of these bony abnormalities. Due to the high false-positive
rates in these asymptomatic but suspicious bone scan abnormalities, a diagnosis should be
histologically confirmed.
Introduction
Accurate staging of malignancies is essential to guide the clinician in selecting the
most appropriate therapy for that patient. The presence of metastatic disease from solid
tumors in bone is considered as distant metastases and classifies the tumor as advanced
stage IV.1 Since stage and survival are strongly correlated, precise staging is
critical to avoid over- or under-treatment. Special importance is attached to staging with
regard to surgery since the presence of bone metastasis effectively eliminates resection
as a curative option. In addition, the documented presence of bone metastases generally
mandates a chemotherapy-only approach in most malignancies, with radiotherapy being
reserved only for treatment of symptomatic lesions. However, suspected bony metastases
must be histologically confirmed because of the high frequency of false-positive results,
particularly when discovered only on radioisotope bone scans.
Bone Metastases
Although primary bone malignancies are rare, metastatic disease to the bone is common,
particularly in patients over 45 years of age.2 The most common sites of
metastases are sites of persistent red marrow, especially the axial skeleton (spine,
pelvis, ribs, and skull). In a study of 2,001 patients with bone metastases, the most
common eight sites of metastatic disease in descending frequency are the vertebrae, pelvis
and sacrum, femur, ribs, skull, humerus, scapula, and sternum.3
Carcinomas of the breast and prostate account for most of the bone metastases, with
cancers of the kidney, thyroid, and lung following in descending frequency.2 In
all cases, bone metastases will occur in 67% of breast cancer patients, in 50% of prostate
cancer cases, in 25% of lung and kidney cancer patients, and in less than 10% of cases
with all other malignancies.2 Cancers of the gastrointestinal and genital
tracts and sarcomas rarely metastasize to bone.2
Metastases to bone are often symptomatic, presenting with new onset bone pain over the
metastatic site and swelling. An occasional patient presents with a pathologic fracture.
Most metastases are destructive and cause osteolytic changes, with an occasional case
demonstrating increased density that is characteristic of an osteoblastic lesion. An
elevated serum alkaline phosphatase level may be seen in some patients with bone
metastases, but this enzyme may be elevated in a variety of conditions such a
hyperparathyroidism, osteomalacia, osteitis deformans, osteogenic sarcoma, rickets,
healing fractures, pregnancy, normal growth, and various hepatobiliary conditions.4
Some patients have clinically silent bone metastases, and the presence of bony spread
is suspected only from a screening radioisotope bone scan performed during a staging
workup. In some malignancies, bone scanning is routine in the initial workup, and
asymptomatic abnormalities may be found. In other cancers such as non-small-cell lung
cancer, bone scanning is recommended only if there is some clinical indicator of bone
disease such as bone pain, elevated level of serum alkaline phosphatase, or elevated serum
calcium level. Bone metastases are rarely found in non-small-cell lung cancer patients who
are entirely free of clinical indicators.5,6
Most bone metastases are destructive and cause osteolytic changes. Therefore, the
typical plain radiograph appearance is decreased density at the site of the metastasis.
Less common is the finding of increased bone density (osteosclerotic or osteoblastic
changes), generally associated with prostate cancer or the result of hormone treatment in
metastatic breast cancer.3 Nevertheless, plain radiographs are insensitive
indicators of bone metastases since at least 50% of the trabecular bone must be destroyed
in a vertebral body, for example, before it is radiographically visible.
Radioisotope Bone Scan
The radioisotope bone scan is a much more sensitive indicator of metastatic disease.
The scan may be positive when as little as 5% to 15% of trabecular bone is destroyed,
often demonstrating the metastatic tumor much earlier than plain radiographs.2
In fact, only 3% of patients with radiographically proven bone metastases will have no
evidence of increased uptake ("hot spot") on bone scan.
The mechanism leading to an increased uptake of the radiopharmaceutical used in a bone
scan, most commonly 99mtechnetium-labeled diphosphonate, is incompletely
understood and involves multiple steps. Generally, localization of the radioisotope will
occur in areas of increased blood flow and/or areas of increased bone formation.7
Most tumors cause both osteoclastic bone resorption, but there is new bone formation as
well. The technetium-diphosphonate complex appears to bind onto the surface of the
hydroxyapatite crystal during new bone growth and not to the tumor itself.
A localized area of decreased uptake of the radioisotope (photopenic lesion) may be
rarely seen with decreased blood flow or with reduced or absent reactive new bone
formation. In rapidly growing tumors, the bone matrix may be resorbed before
mineralization occurs such that there is no increased uptake of isotope in an area of
metastatic disease. These instances are infrequent, and most bone scan lesions appear as
areas of increased uptake.
Although the bone scan is sensitive in demonstrating metastatic bone involvement, this
test is not especially specific. A number of normal or benign conditions may also result
in a hot spot on bone scan, which can lead to a false-positive result in the staging of
the primary cancer. Some of these benign conditions that cause local increased uptake of
tracer on bone scan are listed in the Table. (Please see hard copy of journal.)
Considering the nonspecific nature of a positive bone scan, particularly when the plain
radiographs are normal, histologic confirmation of the bony metastasis is mandatory prior
to implementing treatment.
Bone Localization Techniques
For the symptomatic patients, the presence of bone metastases will be readily apparent
and proving their existence will be relatively easy. In the patient with bone pain or
local swelling, plain radiographs are usually obtained first, and the bone scan is
obtained only if the radiograph results are negative or equivocal. In addition, a bone
scan may be obtained in a patient with known bone metastases on plain radiographs to look
for asymptomatic metastases in weight-bearing bones such as the femur to locate and treat
prior to a pathologic fracture. Computed tomography (CT) or especially magnetic resonance
imaging (MRI) with gadolinium contrast appears to be a sensitive technique, particularly
in the spine or pelvis, to document bone metastases when the bone scan is positive and the
plain radiographs are negative.2 MRI of the spine also has special use in
patients with neurologic abnormalities or vertebral body collapse to visualize a tumor
mass extending from or around the vertebral body that may impinge on the spinal cord.
Histologic confirmation of the metastasis often can be obtained in symptomatic patients
who have imaging abnormalities by using CT scan-guided percutaneous biopsy of the
vertebral body in question or by a needle biopsy of a lytic lesion or soft-tissue mass in
other bones. However, the possibility of a sampling error exists when the needle biopsy
result returns as negative or nondiagnostic. When treatment and/or a diagnosis depends on
a positive malignant histology, an open biopsy is necessary. In the setting of a locally
symptomatic probable metastasis with a corresponding plain radiograph abnormality,
intraoperative localization of the bony abnormality is generally not difficult,
particularly when the target bone for biopsy is a rib.
Among radiologists, it is commonly believed that a positive bone scan abnormality with
negative plain radiographs in an asymptomatic patient with known cancer indicates a
probable bone metastasis. However, there is a documented high incidence of false-positive
bone scan results seen in this setting, ranging from 47% to 71% in various studies.6,8,9
Therefore, a confirmatory open bone biopsy is mandatory, but increased technical
difficulties are encountered in locating the lesion in these patients when only the bone
scan serves as the guide.
Conventional Open Bone Biopsy
The presence of a positive bone scan in an asymptomatic patient with normal plain
radiographs presents a difficult clinical problem to the surgeon planning a bone biopsy.
Ribs, when positive on bone scan, are probably the easiest bones, technically, on which to
perform a biopsy, but localization of the exact site of the bone scan hot spot is
generally difficult. Depending on the quality and definition of the bone scan image,
establishing exactly which rib is "hot" can be challenging. Likewise, localizing
the precise anterior-posterior location of the rib abnormality based on the scan alone
also can be difficult when the plain bone radiographs are normal. As a result, the surgeon
is often forced to remove a large, grossly normal-appearing area of one or even two ribs
to be sure that the bone scan abnormality is contained in the specimen.
In the muscular or obese patient, it may be difficult to determine and actually count
at surgery (within one or two ribs) which is the target rib for removal, especially in the
lower ribs posteriorly. Consequently, most patients require one or often many
intraoperative radiographs (usually cross-table lateral radiographs, which are technically
difficult to complete on the first try) with a radiopaque marker adherent to the rib in
the wound to verify that the biopsy will be performed on the correct-numbered rib. Since a
frozen section analysis on bone with a thick cortex, such as a rib, is not possible
intraoperatively and the final histologic diagnosis awaits lengthy decalcification and
processing, seven to 10 days may pass before the surgeon can determine if the biopsy was
performed on the correct area. If the final diagnosis is "normal bone," then
there is even more uncertainty about the accuracy of the biopsy site.
Methylene Blue "Tattooing" of the Target Rib
Due to this difficult and often frustrating clinical problem of precisely locating the
rib abnormality by the operating surgeon, Little and associates8 developed a
technique published in 1983 that involves preoperative marking of the target rib. With
this technique, the radioactive tracer (99mtechnetium diphosphonate) is
injected intravenously in the patient six to 12 hours before the patient is brought to the
nuclear medicine department. The patient is positioned below the gamma camera to image the
appropriate area. An external 99mtechnetium point source is placed over the
scan image abnormality and is imaged on the scintiview screen. If the external point
source corresponds to the abnormal scan area, the skin is marked with an indelible pen.
The area is anesthetized with lidocaine, and a needle is inserted to the rib in that area,
followed by injection of a small amount of the tracer to mark the hot spot more deeply.
With the needle still left in place, the patient is repositioned several times under the
gamma camera to ensure that the percutaneously injected tracer is superimposed over the
bone scan abnormality. Several injections may be needed until the correct area is imaged.
Methylene blue is then injected into the same needle to stain the underlying periosteum
and soft tissue up to the skin. The patient is taken promptly to the operating room for an
open biopsy of the methylene blue-stained rib so that the stain does not diffuse away.
In the experience of Little and associates,8 this technique was used
successfully in 15 patients with known cancer (12 lung cancer, one breast carcinoma, and
two gastrointestinal carcinomas) to perform biopsies on 13 ribs, one skull, and one
scapula. An abnormal diagnosis was found in all patients, but only eight of 15 (53%) had
metastatic cancer, and the others (bone scan false-positive rate = 47%) had a variety of
benign diagnoses (two old rib fractures, two hypercellular marrow, one Paget’s
disease, one granuloma, and one osteoporosis). Although this tattooing technique appears
to work in experienced hands, the operative episode is prolonged and complicated. The
nuclear medicine department schedule must be carefully coordinated with the availability
of the operating room in order to immediately accept the patient for surgery before the
blue dye spreads to other ribs. Due to the considerable experience and operative
coordination needed by the nuclear medicine department, the surgeon performing only an
occasional bone biopsy guided by this technique might find it difficult to duplicate the
excellent results of Little and associates.8
Intraoperative Radioscintigraphic Localization
The most direct method to localize the bone scan hot spot for open biopsy in the
asymptomatic patient became possible with the development of a hand-held, high-resolution
gamma camera, which is capable of providing real-time gamma counting from the
intravenously injected tracer. This device has been successfully used for intraoperative
radiolymphoscintigraphy for sentinel lymph node identification in melanoma10
and breast cancer11 patients. It has been adapted at our center for
intraoperative localization of areas of increased uptake of tracer in ribs and the sternum
for open biopsy in 10 patients suspected of having bone metastases.9
Six to twelve hours prior to surgery, each patient received an intravenous injection of
28 mCi technetium-99m oxidronate, the standard dosage for a radioisotope bone scan. The
six-hour interval from injection until surgery provided the best intraoperative results.
After general anesthesia was administered and the patient was prepared and draped, the
hand-held gamma probe in a sterile plastic sleeve was used to localize the area of
greatest tracer activity (measured in counts per second) on the skin of the chest wall. A
3- to 4-cm incision was made over this area, and the targeted rib or sternum was exposed.
The probe in the sterile sleeve was then used to localize precisely in the surgical wound
the area of increased tracer activity in comparison to background counts (Fig 1). In the
initial few patients, an intraoperative cross-table lateral radiograph was obtained with a
radiopaque marker on the rib in the wound to verify that the biopsy was performed on the
correct rib. As the experience with the gamma probe grew, these time-consuming and costly
radiographs were eliminated. A 3-cm portion of the targeted rib or the outer table of the
sternum was removed subperiosteally and was decalcified and histologically studied.
Patients were discharged after obtaining a chest radiograph in the recovery room to verify
the absence of a pneumothorax and to confirm that the biopsy was performed on the proper
rib.
This series9 of 10 patients consisted of a variety of known or suspected
underlying primary cancers (five had carcinoma of the lung, two had carcinoma of the
prostate, and one each had carcinoma of the breast, lymphoma, and melanoma). Biopsies of
14 bones (13 ribs and one sternum) were all positive for pathologic processes, although
metastatic cancer was diagnosed in only four of the 14 (29%) patients. The other 10 bone
biopsies (71% bone scan false-positive rate for diagnosing a malignancy) showed various
benign processes: localized hypercellular marrow (one rib), medullary
fibrosis/Paget’s disease of the bone (two ribs), localized fibrosis/granulation
tissue (one rib), enchondroma (three ribs), and chondroma (two ribs and one sternum).
Using this technique, localization and detection of the bone scan hot spot were easily
accomplished with the gamma probe. A typical radioisotope bone scan from this population
of patients is shown in Fig 2. Intraoperatively, the rib or sternum appeared grossly
normal to the surgeon, even after resection of the abnormal area. When using the gamma
probe to count directly on the rib in the wound, the mean ratio of hot spot activity
measured in counts per second in the targeted rib to background counts (count ratio) on
other ribs or elsewhere on the same rib was 1.63 ± 0.06 (range = 1.35.-2.05; median =
1.59), and the difference was easily discernible intraoperatively. That is, the number of
counts measured over the hot spot was a mean 63% higher than background counts.
Interestingly, six of the 14 biopsies (43%) in this series demonstrated the benign
cartilaginous tumor, a chondroma.9 Chondromas are relatively common,
representing 13.4% of benign tumors in bone, although the real incidence is unknown since
they are generally asymptomatic.12 Chondromas usually occur sporadically, most
commonly in the small bones of the hands and feet, although they may occur in thin bones
such as the ribs or scapulae and rarely in the sternum. Unless they become very large,
chondromas are asymptomatic and generally are either not seen on plain radiographs or are
seen as a subtle, localized area of central rarefaction in the bone. Most chondromas are
found incidentally as a hot spot on a radioisotope bone scan performed during the
metastatic workup of a patient with a known or suspected malignancy. A biopsy often
follows, and the diagnosis of chondroma is made. Fig 2 shows the radioisotope bone scan
from one patient from this series who had biopsy-proven chondromas.
No mortality or morbidity was specifically associated with this intraoperative
radioscintigraphy technique. With the open rib biopsy, inadvertent entry into the pleural
cavity in two patients during rib resection required overnight hospitalization following
insertion of a small chest catheter. After the experience of using this technique in only
a few patients, the total operative time for these cases decreased to 20 to 40 minutes
since intraoperative radiographs were no longer needed, and the radioisotope counting was
precise and rapid.
Conclusions
The presence of an asymptomatic area of increased uptake of tracer in a bone scan of a
patient with a malignancy does not necessarily indicate the presence of metastatic tumor
in the bone. Histologic confirmation of metastatic disease is necessary since the
incidence of false-positive bone scan abnormalities is high, ranging from 46% to 71% in
this setting.
The technique of methylene blue tattooing of the rib for biopsy8 appears to
be effective but is much more time consuming than the more recently described
intraoperative gamma probe method.9 This latter technique requires only an
intravenous injection of radioisotope four to 12 hours preoperatively, followed by a short
operative procedure to precisely pinpoint the target hot spot. The extreme accuracy of
this technique obviates the need for time-consuming intraoperative localizing radiographs.
Use of the gamma probe to guide the biopsy of ribs is quicker, more direct, less
cumbersome (especially in obese patients), and likely to provide more cost-effective bone
biopsies. Although the technique was used in this study9 only to localize rib
or sternal abnormalities for biopsy, this same gamma probe method could no doubt be
adapted by orthopedic surgeons to localize bone lesions for biopsy in other areas (eg, the
long bones of the appendicular skeleton). This method has no side effects and is 100%
sensitive in finding bony abnormalities. The hand-held intraoperative gamma counter is
gaining widespread application for multiple uses in surgical oncology such as nodal
mapping in breast cancer and melanoma8,9 and is becoming a common fixture in
most major hospitals. The gamma probe appears to be the most accurate and cost-effective
technique to localize bone scan abnormalities and should be considered for use by the
surgeon in guiding the open biopsy of suspected asymptomatic osseous chest metastases.
References
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Juhl’s Essentials of Radiologic Imaging. 6th ed. Philadelphia, Pa: JB Lippincott
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3. Clain A. Secondary malignant disease of bone. Br J Cancer. 1965;19:15-29.
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Management of Metastatic Bone Disease. 1st ed. New York, NY: Raven Press; 1988:51-67.
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nuclear bone scans: techniques and indications. J Thorac Cardiovasc Surg. 1983;85:396-403.
9. Robinson LA, Preksto D, Muro-Cacho C, et al. Intraoperative gamma probe localization
of abnormal tracer activity to aid in the biopsy of suspected asymptomatic osseous
metastases. Ann Thorac Surg. 1997. In press.
10. Albertini JJ, Cruse CW, Rapaport D, et al. Intraoperative radio-lymphoscintigraphy
improves sentinel lymph node identification for patients with melanoma. Ann Surg.
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11. Albertini JJ, Lyman GH, Cox C, et al. Lymphatic mapping and sentinel node biopsy in
the patient with breast cancer. JAMA. 1996;276:1818-1822.
12. Unni KK. Chondroma. In: Unni KK, ed. Dahlin’s Bone Tumors. 5th ed.
Philadelphia, Pa: Lippincott-Raven; 1996:25-45.
From the Thoracic Oncology Program at H. Lee Moffitt Cancer Center & Research
Institute, Tampa, Fla.
Address reprint requests to Dr Robinson at the Division of Cardiovascular and Thoracic
Surgery, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Dr, Tampa,
FL 33612.
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