Bone Scanning in the Evaluation of Patients with Lung Cancer Antonio T. Donato, M.D., E. Gifford Ammerman, M.D., and Otoniel Sullesta, M.D.

ABSTRACT Sixty patients suspected of having lung cancer were evaluated for bone metastasis by means of technetium 99m stannous-polyphosphate bone scanning and correlative radiographic bone survey. Diagnosis of lung cancer was histologically proved in all patients. Scans demonstrated evidence of bone metastasis in 20 patients (33.4%) and radio- graphs, in 10 patients (16.6%). Twenty-four patients had repeat skeletal evaluation at one to eleven months after the first study. Of these patients, 7 ini- tially demonstrating both negative scans and radio- graphs showed abnormal scans within five months. Bone scans correlated with radiographs in 53.3% and with accompanying bone pain in 33.3% of patients. False negative and false equivocal results were noted in 4 patients.

This study suggests that bone scanning with 99mTc stannous-polyphosphate detected early bone meta- stasis in patients with lung cancer before these le- sions became evident clinically or radiographically. Bone scanning is of value during the initial evalu- ation to determine operability in patients with lung cancer.

Cancer of the lung continues to be a diagnostic and therapeutic challenge to thoracic surgeons despite sophisticated investigative procedures, refined surgical techniques, and improved ra- diotherapy. Surgical resection may offer the highest probability of cure in patients with lung cancer. However, the overall five-year survival rate still exceeds the 18.2% reported recently by Stanford and colleagues [14]. Fre- quently, cancer has spread beyond the confines of the therapeutic field at the time of diagnosis.

From the Departments of Surgery, Radiology, and Nuclear Medicine, Veterans Administration Hospital, Salem, VA.

Presented at the Twenty-third Annual Meeting of the Southern Thoracic Surgical Association, Nov 4-6, 1976, Acapulco, Mexico. Accepted for publication Aug 25, 1978.

Address reprint requests to Dr. Donato, 1215 'Third St, SW, Roanoke, VA 24016.

Paulson [ l l ] reported that only 15% of lung cancer is localized, 30% has regional involve- ment, and more than 55% has distant metas- tasis during initial workup.

Postmortem reports on the incidence of bone metastasis from lung cancer range from 21.3 to 32.5% depending on the extensiveness of the postmortem examination [ l , 91. Rimondi and associates [131 reported an average incidence of 14.4% skeletal involvement in 4,436 patients with lung cancer who had radiographic bone survey. Early identification of latent bone metastasis is of value in the preoperative evalu- ation of patients with cancer of the lung.

This paper reports our clinical experience with 60 consecutive patients with lung cancer. The patients were prospectively evaluated for bone metastasis by means of radioisotope scanning using technetium 99m stannous-poly- phosphate and correlative bone radiography.

Materials and Method From July, 1973, to January, 1975, 60 male pa- tients, suspected of having lung cancer, were evaluated at the Salem Veterans Administration Hospital for diagnosis and operability. The men ranged from 26 to 80 years old. Chest radiographs showed identifiable lung lesions in all of them. Radioisotopic bone scanning and radiographic bone survey were done in addi- tion to the conventional diagnostic lung tumor workup. Follow-up skeletal examinations were performed after one month to eleven months depending on scheduled visits and occurrence of pain. The diagnosis of lung cancer in all pa- tients was histologically proved using the pro- cedures shown in Table 1. Cell type diagnosis demonstrated 40 patients with squamous cell carcinoma, 9 with adenocarcinoma, 1 with giant cell carcinoma, 5 with undifferentiated carcinoma, and 5 with oat cell carcinoma. Pul- monary lesions were successfully resected in 16 patients or 26.6%.

300 0003-4975/79/040300-05$01.25 @ 1978 by Antonio T. Donato

301 Donato, Arnmerman, and Sullesta: Bone Scanning in Lung Cancer Evaluation

Table 1 . Methods of Obtaining Tissue Diagnosis

Procedure Positive Results

Bronchoscopy Scalene node biopsy Mediastinal biopsy Pleural biopsy Percutaneous lung biopsy Bone biopsy Thoracotomy with biopsy Lobectomy Pneumonectomy Postmortem examination

12 7 5 3 1 4 9

14 2 3

Bone scans were performed by the intrave- nous administration of technetium 99m stan- nous-polyphosphate in the dose of 1.2 to 18.8 mCi. Images were made after four hours on a gamma camera (Picker Dynacamera 11). An- terior views of the head, sternum, both shoul- ders, cervical and thoracolumbar spines, and pelvis were obtained. Whole-body image scin- tiscan was substituted for the multiple views during the last six months of our study.

Radiographic bone survey consisted of mul- tiple radiographs of the axial skeleton including the skull, cervical, thoracic, and lumbar verte- brae, pelvis, and both femurs.

Bone scans and radiographs were reported independently as negative or normal, equivocal or questionable, and positive or abnormal. Bone scans were graded on a scale of 1 to 10 according to the pattern and intensity of in- creased activity. Images graded 1+, 2+, or 3+ implied negative results or no probable metas- tasis (Figure, A). Images graded 4+, 5+, 6+, or 7+ were judged equivocal or questionable, as in trauma, inflammatory conditions, or prob- able metastasis (Figure, B), and images graded 8+, 9+, or 10+ were believed to show evi- dence of metastases (Figure, C); the higher the number, the stronger the likelihood of meta- static disease. A grade of l+ meant a normal scan with no evidence of increased activity in bone or joint. A 2+ grade indicated that there was a hint of asymmetrical bone or joint activity over a fairly wide area, suggesting nonunifor- mity of the camera crystal. It also included minimal joint activity, which had to be sym-

metrical and at a joint interface or at a bursa. A 3+ included increased joint activity that was symmetrical and usually involved a bursa. The joints concerned are the weight-bearing joints: hips, knees, and occasionally ankles or shoul- ders. With a 4+ grade multiple joints were in- volved, but with little asymmetry or lack of bursa1 activity. Five plus was an extension of 4+ and was used rarely. A 6+ grade included the possibility of some broad diffuse vertebral column activity that was not clearly delineated, and a 7+ was a slight accentuation of that. A grade of 8+ implied focal activity in the verte- bral column or one lone joint, usually away from the joint surface, while grades of 9+ and 10+ meant rib activity, focal spinal column ac- tivity, pelvic activity, asymmetrical or marked sacroiliac joint activity, as well as any single or multiple changes noted in a lower stage. The last three grades were based on an increasing scale of uptake and also may have been used in lower rated scans if the kidneys were not ade- quately visualized. Definition of adequate kid- ney visualization was visualization of bone and both kidneys to a degree equal to or greater than the adjacent rib cage. If the ribs were not adequately visualized, this portion of the crite- ria was not used.

Results With a bone scan, 20 patients (33.4%) had a result positive for cancer; 28 (46.6%), a negative result; and 12 (20°/0), an equivocal result. With a bone radiograph, 10 patients (16.6%) had a positive result; 46 (76.8%), a negative result; and 4 (6.6%), an equivocal result. Six of 20 pa- tients with positive bone scans and 3 of 10 pa- tients with positive radiographs had bone pain during the initial evaluation. Similarly, 4 of 12 patients with equivocal bone scans had bone pain; however, 4 patients in whom pain de- veloped during the follow-up period had nega- tive bone scans and negative radiographs.

Twenty-five percent of the positive bone scan metastases were proved by postmortem exam- ination while 15% were confirmed by needle bone biopsy.

The comparative results between bone scans and radiographic bone surveys are summarized in Table 2.

302 The Annals of Thoracic Surgery Vol 27 No 4 April 1979

A B

(A) Grade 2 + bone scan, probably normal, showing slight increase of activity in the hips and knees, indi- cating a slight increase in the progression of arthritis. ( B ) Grade 7 + bone scan revealing injury to the cos- tochondral junctions on the right chest, which was evaluated clinically as a posttraumatic injury. (C) Scan graded ZO+ showing multiple lesions in the ribs, vertebral column, head, hips, and pelvis resulting from metastatic disease.

C

Table 2 . Comparative Results between Bone Scans and Bone Radiographs

Bone Radiograph Bone Scan Positive Negative Equivocal

Positive 6 (10%) 14 (23.3%) 0 (0%) Negative 2 (3.3%) 24 (40%) 2 (3.3%) Equivocal 2 (3.3%) 8 (13.3%) 2 (3.3%)

SCAN POSITIVE AND RADIOGRAPH NEGATIVE.

Six of 14 patients with positive bone scans but negative radiographs had repeat skeletal stud- ies between one and two months after the ini- tial study. The results were similar except in 1 patient whose bone radiograph showed evi- dence of metastasis at two months. Bone pain was evident in only 2 patients during the initial assessment. The scans were abnormal in 12 asymptomatic patients with neither clinical nor radiographic evidence of metastatic disease. These patients were all considered inoperable and lived an average of five months. Seven pa- tients would have been considered operable if they had not had a positive scan. These results

indicate that scans can detect early bone metastasis in patients with known primary dis- ease before clinical or radiographic manifesta- tions occur.

Half of the patients with positive bone scans and radiographs complained of bone pain. Bone scans in this group correlated very well with bone radiographs. All of these patients were judged inoperable and were treated with other modalities.

Ten of 24 patients with both negative bone scans and radiographs had follow-up skeletal examination at one, three, six, and twelve

SCAN POSITIVE AND RADIOGRAPH POSITIVE.

SCAN NEGATIVE AND RADIOGRAPH NEGATIVE.

303 Donato, Ammerman, and Sullesta: Bone Scanning in Lung Cancer Evaluation

months, or as indicated. Seven patients demon- strated only positive bone scans within five months, while 1 showed only positive bone radiograph at six months. Seven patients in this group underwent curative pulmonary resec- tion, and 3 of them had positive scans and negative radiographs within five to six months. The remaining 17 patients were considered in- operable because of mediastinal or scalene node metastasis. The change from a negative scan to a positive scan during the follow-up period in- dicated progression of the disease in the skeletal system.

Four of 8 patients with equivocal bone scans and negative radiographs were reevaluated for metastasis at five months. In 1 patient, metas- tasis became evident on the bone scan but not the radiograph. Three patients in this group had bone pain, 2 initially and 1 at follow-up. Pain did not correlate with scans or radio- graphic testing.

Two patients had a false negative bone scan. In 1 patient, diagnosis of poorly differentiated squamous cell carcinoma was made. Radio- graph of the skull showed multiple oval metas- tasis, which was not evident in the scan. The other patient had similar cell type and pain in the left groin. Radiographs of the pelvis and femur demonstrated severe destruction of the bone not seen in the 99mTc stannous-polyphos- phate scan. Subsequently a gallium scan re- vealed positive uptake indicative of metastasis.

Two patients had a false equivocal bone scan and both had definite osteolytic metastasis by radiographs.

SCAN EQUIVOCAL AND RADIOGRAPH NEGATIVE.

SCAN NEGATIVE AND RADIOGRAPH POSITIVE.

SCAN EQUIVOCAL AND RADIOGRAPH POSITIVE.

Comment When correlated with clinical signs and radio- graphs, bone scans specify metastasis in the presence of primary malignancy. In our study, correlation of skeletal radioisotope scans with radiographic survey was 53.3%, and with ac- companying bone pain, 33.3%. Bone scans de- tected metastatic disease earlier than bone radiographs in 23.4% of our patients. Pistenma and co-workers [12] reported that 54% of their patients with lung cancer had positive bone

scans but negative radiographs. The percentage of positive scans is much lower in our series because of the categorical grading of the scan results into normal, abnormal, and equivocal. The appearance of metastasis in a positive scan predated radiographic visualization by two to six months.

Gutierrez and associates [6] demonstrated that bone scans detected osseous metastasis in 56% of their patients, as proved by postmortem examination. They also noted that bone scans correlated with the clinical, radiographic, and postmortem findings in 89% of patients. Corco- ran and colleagues [3] reviewed 266 patients with primary lung cancer of whom 53% with abnormal bone scans had metastatic bone in- volvement. Positive bone scan metastases in our series were demonstrated at postmortem examination in 26% and by needle bone biopsy in 15% of patients. An accurate correlation of bone scans with postmortem findings would require postmortem examination of all bones showing increased radioisotope uptake. This is not performed as a routine procedure. Doubtful bone scans may be confirmed best by open or needle bone biopsy.

The incidence of bone metastasis detected by routine radiographic survey was 16.6% in our series. Le Roux [7] in a retrospective study of 4,000 patients with bronchogenic carcinoma, reported 2% osseous metastasis at the time of initial evaluation. However, his data were based on correlation of clinical bone pain with radiographic findings, instead of routine bone survey. We observed that only 5% of all our patients had bone pain correlated with positive radiographs. Bone metastasis is a well recog- nized frequent late manifestation of lung cancer often identified radiographically in the ad- vanced stage of the disease. Skeletal metastasis often becomes visible by radiographs when there is 30 to 50% bone demineralization [21 or when 50 to 75% cancellous bone destruction is present [5]. With accelerated mineral turnover and new bone formation, scans can detect bone metastasis earlier than radiographs [4].

Follow-up bone scanning for evaluation of possible progression of metastasis should be done within five months in asymptomatic pa- tients with equivocal scans, while those show-

304 The Annals of Thoracic Surgery Vol 27 No 4 April 1979

ing both negative scans and radiographs should have scans repeated within six to twelve months or when bone pain is present. Patients with bone metastasis should be considered for radiotherapy when symptomatic or when tumor is located at weight-bearing areas in asymptomatic patients.

Three to 8% of false negative scan results usually occur in patients with highly anaplastic tumors or purely osteolytic lesions [lo]. Our study showed an occurrence of 3.3% false negative results. Napoli and colleagues [81 noted that osteolytic lesions are due to squa- mous cell and anaplastic cell carcinoma of the lung, whereas osteoblastic lesions may be due to diffused bone marrow invasion associated with oat cell carcinoma and adenocarcinoma.

Although false positive results were not en- countered in our study, false positive scans are likely to result, especially with a solitary scan abnormality of the ribs, particularly in the cos- tochondral junction [31. In this instance, bone biopsy should be done to verify metastasis. The quantitative grading of the scan interpreta- tion may have eliminated false positives by categorically including them in the equivocal results.

At the time of writing, the rough cost of a bone scan in community hospitals was $125.00; a skeletal survey was $53.00; a hospital operat- ing room was $150.00 per hour; and a day's hospital charge was $134.00. Therefore, a week's hospitalization at $938.00 plus 2 hours of operating room time at $300.00 totals $1,238.00 of surgical hospitalization unneces- sarily expended on a patient if a bone scan at $125.00 will rule out operability. One patient thus excluded would cover the cost of bone scan for 10 other patients.

Our study has shown that bone scanning is a more sensitive and reliable tool than bone radiography in the evaluation of patients with lung cancer. Scans detected early bone metas- tasis before the lesions became evident clini- cally and radiographically. That ""'Tc stannous-

polyphosphate scanning is easy to use, is widely available, and is nontoxic with low radiation should make this procedure valuable during the preoperative evaluation of patients with lung cancer to avoid unnecessary opera- tion.

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