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Ann Thorac Surg 1998;65:1426-1432
© 1998 The Society of Thoracic Surgeons

Intraoperative Gamma Probe-Directed Biopsy of Asymptomatic Suspected Bone Metastases

^a Thoracic Oncology Program, Division of Cardiovascular and Thoracic Surgery, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, Florida, USA
^b Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, Florida, USA

Accepted for publication December 9, 1997.

Address reprint requests to Dr Robinson, Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, Tampa, FL 33612-9497

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Radioisotope bone scanning is frequently used in staging malignancies. However, false-positive results are common, and biopsy is usually required. In the absence of plain radiographic abnormalities or local symptoms, localization of the area of abnormal tracer activity at the time of open rib or sternum biopsy may be difficult. It often requires resection of a large portion of one or more ribs or the sternum to assure that biopsy of the target area was performed. In this setting, a small gamma probe underwent evaluation as an aid to precise intraoperative localization of increased tracer activity in the target bone.

Methods. Ten patients with asymptomatic suspected osseous chest metastases by radioisotope bone scanning but with normal plain radiographs underwent open biopsy of 13 ribs and 1 sternum. Six to 12 hours before operation, each received an intravenous injection of 28 mCi of technetium-99m oxidronate. The hand-held, pencil-sized gamma probe in a sterile sleeve was used to localize the area of greatest activity in the target bone, once the bone was exposed through a small incision. Biopsy of a 3-cm length of rib or portion of sternum was performed. In the first two rib biopsies, an intraoperative radiograph with a radiopaque marker on the rib confirmed that the correct rib was selected for biopsy. Intraoperative radiographs were not done on later cases.

Results. The mean ratio of hot spot activity on the targeted rib to background counts on adjacent ribs was 1.65 ± 0.22 (range, 1.35 to 2.05), and the difference was easily discernible intraoperatively. The ratio of hot spot activity on the sternum was somewhat lower (1.22), but the target area was still easy to detect. An abnormal diagnosis to account for the increased tracer activity was found in each of the 13 ribs and 1 sternal biopsy in all 10 patients: metastatic squamous cell carcinoma (1 rib), metastatic prostatic adenocarcinoma (1 rib), lymphoma (2 ribs), localized hypercellular marrow (1 rib), medullary fibrosis/Paget’s disease of the bone (2 ribs), localized fibrosis/granulation tissue (1 rib), enchondroma (3 ribs), and chondroma (2 ribs, 1 sternum). The difference in background counts to hot spot activity was best with injection of the tracer 6 hours before operation.

Conclusions. The intraoperative use of gamma counting is an easy, highly accurate aid (100% sensitivity) to localize areas of abnormal radioisotope uptake in suspected asymptomatic rib and sternal metastases. Use of this technique obviates the need to obtain intraoperative localizing radiographs to confirm accurate rib identification, thereby decreasing operative time.

	Introduction

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Almost any cancer may metastasize to bone, although carcinomas of the breast and prostate account for the majority of cases, with kidney, thyroid, and lung metastases often occurring, in that order of decreasing frequency [1]. Because accurate staging of these or any other malignancies is critically important to make rational therapeutic decisions, any suspected osseous metastases must be fully evaluated. Although bony metastases often cause localizing pain or even a pathologic fracture, occasionally metastases are occult and asymptomatic, and are suspected from abnormalities on a screening radioisotope bone scan.

Favorite sites of osseous metastases are the ribs and occasionally the sternum, which may be readily evaluated and sampled. Radioisotope bone scanning is much more sensitive than plain radiographic studies [2]. Because false-positive bone scan abnormalities are common, histologic confirmation of a suspected bony metastasis is generally necessary. However, in the absence of plain radiographic abnormalities or local signs or symptoms, biopsy of a suspected osseous chest metastasis becomes a challenging problem for the thoracic surgeon. Localization of the exact area of abnormal tracer activity at the time of open biopsy may be difficult, often requiring resection of a large portion of one or more ribs or a large area of sternum to assure that biopsy of the target area was performed. In this setting, a small gamma probe [3] (Fig 1) underwent evaluation as an aid to precise intraoperative localization of increased tracer activity in the target bone.

View larger version (88K): [in this window] [in a new window]   Fig 1. Neoprobe 1000 hand-held gamma counter and the smallest (pediatric) probe.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

View larger version (76K): [in this window] [in a new window]   Fig 2. (A) Radioisotope bone scan showing localized increased uptake of tracer in the left sixth rib anteriorly (left anterior oblique position in patient 6). (B) Rib detail films (left anterior oblique position) of the same patient showing no abnormalities in the left sixth rib (arrow) in the same area of the bone scan abnormality.

After induction of general anesthesia, prepping and draping of the patient, the hand-held gamma probe (Neoprobe 1000; Neoprobe Corporation, Dublin, OH) 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 with background counts on adjacent ribs as well as more distantly on the target rib (Fig 3). In the first 2 patients, an intraoperative cross-table lateral radiograph was obtained with a radiopaque marker on the rib in the wound to verify that biopsy of the correct rib was being performed. As our experience with the gamma probe grew, we eliminated these time-consuming, costly radiographs. A 3-cm portion of the targeted rib or the outer table of the sternum was removed subperiosteally. After a chest radiograph in the recovery room verifying the absence of a pneumothorax and that biopsy of the proper rib was performed, most patients were discharged home. Two patients were kept overnight because of a small pneumothorax requiring chest tube placement in each.

View larger version (130K): [in this window] [in a new window]   Fig 3. Intraoperative view of the gamma probe in a sterile sleeve being used to measure counts directly on a rib.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Patient population
There were 3 women and 7 men in the group (Table 1). The mean age of the patients was 58.4 ± 4.4 years (median 63.5 years; range, 37 to 74 years). Six of the 10 patients had known active cancer in the primary site (carcinoma of the lung in 5, carcinoma of the prostate in 1) and were undergoing staging before treatment. The other 4 patients had their primary tumor in remission. In the 10 patients, the primary diagnosis in 5 is carcinoma of the lung, 2 have carcinoma of the prostate, and 1 each has carcinoma of the breast, lymphoma, and melanoma.

In the first 2 patients, an intraoperative radiograph with a radiopaque marker attached to the target bone (a needle was superficially embedded in the bone by the surgeon through the open wound) was obtained to verify that biopsy of the correct rib was performed. Multiple radiographs were needed in both patients to see enough bony landmarks to count the ribs definitively. After these first 2 patients, confidence was gained in the gamma counting method and intraoperative radiographs were omitted.

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, as intraoperative radiographs were no longer needed and the radioisotope counting was very precise and rapid. A postoperative chest radiograph was obtained and confirmed that biopsy of the correct rib was performed in all patients.

Pathology
An abnormal diagnosis to account for the increased tracer activity was found in each of the 13 rib and 1 sternal biopsy in 10 patients. However, only 30% of the patients (3 of 10 patients, 4 ribs) were found to have a bone metastasis. Figure 4 is a photomicrograph that illustrates one of the rib biopsy specimens containing bone marrow replaced by numerous clusters of malignant epithelial cells, inducing a desmoplastic reaction in the adjacent stroma, diagnostic of metastatic squamous cell carcinoma (patient 3). Figure 5 illustrates islands of mature cartilage with focal mineralization surrounded by fibroblastic proliferation diagnostic of an enchondroma from patient 6. This is one of the most common benign abnormalities found in this setting. Benign cartilaginous tumors (enchondroma or chondroma) accounted for six (43%) of the bone scan abnormalities in this patient population.

View larger version (140K): [in this window] [in a new window]   Fig 4. Photomicrograph of a decalcified rib from patient 3 demonstrating metastatic squamous cell carcinoma. (Hematoxylin and eosin stain; x400 before 50% reduction.)

View larger version (149K): [in this window] [in a new window]   Fig 5. Photomicrograph of a decalcified rib from patient 6 showing benign cartilage growing in the bony trabecular spaces characteristic of an enchondroma. (Hematoxylin and eosin stain; x100 before 50% reduction.)

Enzyme studies
Serum alkaline phosphatase is generally considered to be one of the clinical indicators of metastatic disease, especially to bone [5]. In this series, only 1 patient (no. 2) of the 10 had a slightly elevated alkaline phosphatase, and that patient was found to have lymphoma in the rib biopsy specimen. The other 2 patients with rib biopsy results positive for metastatic disease had normal serum alkaline phosphatase levels.

Prostate-specific antigen is a highly sensitive serum marker for the detection of prostate cancer, although various conditions, such as benign prostatic hypertrophy, may cause false positives [6]. The 2 patients with prostate cancer (nos. 1 and 8) both had elevated prostate-specific antigen levels but only 1 patient (no. 8) had metastatic prostate cancer in the rib biopsy specimen.

Morbidity and mortality
Inadvertent entry into the pleural cavity occurred in 2 patients during rib resection requiring overnight hospitalization after insertion of a small chest catheter. There were no other complications and no mortality. There was no complication from the radioisotope or the use of the small gamma camera.

	Comment

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Accurate staging of cancers is essential in determining rational treatment strategies based on clinical trials. The presence of metastatic disease to bone is considered to be distant metastatic spread in almost all cancers and is classified as stage IV [7]. Treatment for this stage then becomes nonoperative and generally chemotherapy is preferred, with radiotherapy added for localized, symptomatic lesions. Some cancers have a predilection for osseous spread, and the highest incidence is with carcinoma of the prostate and of the breast followed by the kidney, thyroid, and lung [1]. However, because treatment and prognosis are based on stage, which is dependent on the presence or absence of bone metastases, it is critically important to prove that suspected lesions are truly metastatic cancer or otherwise patients may be denied potentially curative therapy.

Bony metastases may be readily evident if they cause localized pain, swelling, or even pathologic fractures. The serum alkaline phosphatase level may be elevated in these patients as a nonspecific clinical indicator of osseous metastases, although nonmalignant causes such as osteomalacia, hyperparathyroidism, osteitis deformans, healing fractures, and various types of hepatobiliary disease may also raise levels of this enzyme [5]. Occasionally, metastases are occult and essentially asymptomatic and are suspected from a screening radioisotope bone scan. With some cancers, bone scanning is routine in the staging workup, and asymptomatic abnormalities may be found. In other cancers, such as non-small cell carcinoma of the lung, bone scanning is recommended only if there is a clinical indicator of bony involvement such as bone pain or elevated levels of serum alkaline phosphatase or calcium. Rarely are bony metastases found in patients with non–small lung cancer who are completely free of any clinical indicators [8, 9].

The most common sites of bony metastases in decreasing frequency are the vertebrae, pelvis and sacrum, femur, and ribs [1]. The typical plain radiographic finding is that of decreased density or osteolytic activity at the site of metastatic disease. Much less common is the finding of increased bone density (osteosclerosis or osteoblastosis), and it is generally associated with prostate cancer or the result of hormone treatment of breast cancer [1]. However, plain bone radiographs are relatively insensitive indicators of metastatic disease as more than 50% of the bony trabecula must be destroyed, such as in a vertebral body, before it is radiographically apparent [2].

Radioisotope bone scanning is a far more sensitive technique to detect osseous metastases than plain radiographs. Only 5% to 15% destruction of bone is necessary before neoplastic deposits are detected by bone scanning, which is appreciated much earlier than with plain radiographs [2]. Only 3% of patients with radiographically documented evidence of metastases have no abnormality on radioisotope bone scanning [2].

For the bone scan to be positive with increased uptake, the 99m-technetium-labeled phosphorous compound will need to localize to areas of increased blood flow or diffuse intraosseous bone formation [10]. Most metastatic tumors will cause both osteoclastic bone resorption as well as new bone formation. The technetium–diphosphonate complex appears to bind to the surface of the hydroxyapitite crystal during new bone formation and not to the tumor itself. However, a variety of normal or benign conditions as well as primary bone tumors may also result in a "hot spot" on bone scan leading to a false-positive result in a search for osseous metastases. Some of these conditions that may cause a false-positive result are as follows [10]:

Normal structures

Base of skull, facial bones, inferior tip of scapula

Sternomanubrial and corpus-manubrial joints

Alae of sacrum

Kidneys and bladder

Variant anatomy

Soft tissue abnormalities

Injection site

Dental abscess

Calcific tendinitis or myositis

Postoperative scar

Hydronephrosis or hydroureter

Soft tissue osseous metaplasia

Bony abnormalities with increased blood flow

Osteomyelitis, osteitis

Fracture (recent or healing)

Increased blood flow and bone formation

Eosinophilic granuloma

Paget’s disease

Fibrous dysplasia

Renal osteodystrophy

Osteoid osteoma

Aseptic necrosis, cysts

Hyperostosis frontalis interna

Osteitis pubis

Sudeck’s atrophy

Benign bone tumors

Chondroma

Fibroma

Primary malignant bone tumors

Osteosarcoma

Ewing’s sarcoma

Chondrosarcoma

Metastatic tumors

The most common abnormality causing a positive bone scan in the current study (6 of 14, 43% of all biopsies) is the benign cartilaginous tumor chondroma [11]. When a chondroma is centrally located in bone it is called an enchondroma, but it is termed a chondroma when it expands through the cortex. Chondromas are relatively common representing 13.4% of benign tumors in bone, although the real incidence is unknown as they are generally asymptomatic. Usually, chondromas 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 (patient 7). Multiple chondromas may occur associated with conditions such as Ollier’s disease, Maffucci’s syndrome, and other rare syndromes. A chondrosarcoma may develop late in patients with these unusual disorders. Unless they become very large, chondromas are asymptomatic and generally are not seen on plain radiographs, or at best all that is seen is a subtle, localized area of central rarefaction in the bone. Most chondromas are found incidentally as a hot spot on a radioisotopic 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.

In the asymptomatic patient, the false-positive rate in routine bone scans is significant, ranging from 55% in lung cancer [9], up to 71% in various cancers (current study). Among radiologists, it is commonly believed that a positive bone scan abnormality in the face of normal plain radiographs in an asymptomatic patient with known cancer indicates a bony metastasis. The current study would suggest just the opposite, that is, the bone scan abnormality in this setting is more likely benign. Magnetic resonance imaging, especially of the spine, appears to be highly sensitive in confirming the presence or absence of metastases if the radiographic results are typical [2]. However, a positive bone scan in a patient with a suspected or known malignancy generally should have histologic confirmation of the metastasis before deciding on the final staging.

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 to sample technically, but localization of the exact site of the bone scan hot spot generally is difficult. Depending on the quality and definition of the bone scan image, it may be challenging to define exactly which rib is hot. Likewise it is often difficult to localize precisely the anteroposterior location of the rib abnormality based on the scan alone 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 just 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 count at operation (within one or two ribs) which is the target rib for removal, especially in the lower ribs posteriorly. Consequently, most patients require many intraoperative radiographs with a radiopaque marker adherent to the rib in the wound to verify that the correct numbered rib will be biopsied. Because a frozen section analysis on bone with a thick cortex, such as rib, is not possible intraoperatively and the final histologic diagnosis awaits lengthy decalcification and processing, 7 to 10 days may pass before the surgeon finds out whether biopsy of the correct area was performed. If the final diagnosis is "normal bone," then there is even more uncertainty about whether the correct area was sampled.

To address this difficult and frustrating clinical problem for the surgeon, Little and associates [12] advocated preoperative injection of the target rib and the overlying skin with methylene blue in the nuclear medicine department guided by the gamma camera, followed by immediate excisional biopsy of the blue portion of the rib in the operating room. Although this tattooing technique appears to work in experienced hands, it prolongs and complicates the operative episode by requiring careful coordination of the nuclear medicine department schedule while keeping an operating room available to immediately accept the rib biopsy patient for operation so that the blue dye does not have time to spread to other ribs.

The technique described in this study requires only an intravenous injection of radioisotope 4 to 12 hours preoperatively followed by a very short operative procedure precisely pinpointing the target hot spot. The extreme accuracy of this technique obviates the need for time-consuming intraoperative localizing radiographs. Use of the gamma probe (Neoprobe) to guide the biopsy of ribs is more direct, far quicker, less cumbersome especially in obese patients, and is likely to allow far more cost-effective bone biopsies. This method has no side effects and has proven in this series to be 100% sensitive in finding bony abnormalities. Because the hand-held, intraoperative gamma counter is gaining widespread application for multiple uses in surgical oncology such as for nodal mapping in breast cancer and melanoma [3, 13], this device is becoming a common fixture in most major hospitals and should be considered by the thoracic surgeon for use in guiding the biopsy of suspected asymptomatic osseous chest metastases.

	References

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1. Clain A. Secondary malignant disease of bone. Brit J Cancer 1965;19:15-29.
2. Rogers L.F. Secondary malignancies of bone. In: Juhl J.H., Crummy A.B., eds. Paul and Juhl’s essentials of radiologic imaging, 6th ed Philadelphia: Lippincott, 1993:164-165.
3. Albertini J.J., Cruse C.W., Rapaport D., et al. Intraoperative radiolympho-scintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg 1996;223:217-224.[Medline]
4. Glantz S. Primer of biostatistics. Version 3.0. New York: McGraw-Hill, 1992.
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6. Stamey T.A., Yang N., Hay A.R., et al. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987;317:909-916.[Abstract]
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8. Michel F., Solèr M., Imhof E., Perruchoud A.P. Initial staging of non–small cell lung cancer: value of routine radioisotope bone scanning. Thorax 1991;46:469-473.[Abstract/Free Full Text]
9. Ichinose Y., Hara N., Ohta M., et al. Preoperative examination to detect distant metastasis is not advocated for asymptomatic patients with stages 1 and 2 non–small cell lung cancer. Chest 1989;96:1104-1109.[Abstract/Free Full Text]
10. Wahner H.W., Brown M.L. Role of bone scanning. In: Sim F.H., ed. Diagnosis and management of metastatic bone disease, 1st ed. New York: Raven, 1988:51-67.
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