ORIGINAL Annals of Nuclear Medicine Vol. 6, No. 4, 215-220, 1992 Accumulation of 99mTc-HM-PAO in photon deficient areas in bone scan of bone metastasis from hepatocellular carcinoma Nobuaki OTSUKA,* Masao FUKUNAGA,* Koichi MORITA,* Shimato ONO,* Kiyohisa NAGAI,* Tatsushi TOMOMITSU,* Shinichi YANAGIMOTO,* Hiroaki MIMURA,* Shinichiro YAMAMOTO** and Yutaka HIRANO** Departments of *Nuclear Medicine and **Gastroenterology, Kawasaki Medical School, Okayama, Japan To evaluate bone metastasis from hepatocellular carcinoma (HCC), both bone and 99mTc-HM-PAO scintigraphies were performed in six patients with clinically and pathologically confirmed HCC. Two patients had a bone scintigram which revealed abnormal accumulation in the skull base, pelvic bone and thoracic spine. The 99mTc-HM-PAO scans of both these patients also showed abnormal accumulation in the same sites. The bone scintigrams in one patient revealed not only abnormal accumulation in the ribs but also photon deficient areas in the sternum, thoracic spine and femur, while 99mTc-HM-PAO scans showed abnormal accumulation in all these sites. In three patients, bone scintigraphy revealed photon deficient areas in the ribs, pelvic bone and femur, and their 99mTc-HM-PAO scintigrams showed abnormal accumulation in the same sites. Thus, it was shown that, in the detection of bone metastasis from HCC by means of bone scintigraphy, it was necessary to pay attention to hot and cold lesions, and that a combination study with 99mTc-phosphorous compounds and 99mTc-HM-PAO was useful in evaluating these lesions. Key words : hepatocellular carcinoma, bone metastasis, bone scintigraphy, 99mTc-HM-PAO scintigraphy INTRODUCTION HEPATOCELLULAR CARCINOMA (HCC) often metastasizes to the bone. It is well known that bone scintigraphy with 99mTc-phosphorous compounds is an excellent method for the detection of bone metastasis.1-3 However, since the accumulation of q¥ 99mTc-phosphorous compounds in bone lesions does not directly indicate the presence of tumor cells but rather accelerated bone formation following osteolysis,4,5 bone scintigraphy frequently presents photon deficient findings when tumor growth is not accompanied by bone formation.6 Although photon deficient findings of bone metastases on bone scintigraphy have been reported previously in differenti- Received February 7, 1992, revision accepted April 8, 1992. For reprints contact : Nobuaki Otsuka, M.D., Department of Nuclear Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-01, JAPAN. ated thyroid cancer7 and myeloma,8 such findings have not been emphasized in HCC.9 99mTc-hexa-methylpropyleneamine oxime (99mTc-HM-PAO), which is mainly used for the evaluation of the cerebral blood flow, has also been reported to be useful in detecting bone metastasis.10 However, such "filling-in" of photon deficient areas in the skeletal metastatic sites with 99mTc-HM-PAO has not been described reported in the case of HCC. In the present study, the usefulness of bone and 99mTc-HM-PAO scintigraphy for the detection of bone metastasis from HCC has been evaluated. MATERIALS AND METHODS We studied six patients (age range 50-69) with histologically proven HCC. Bone scintigraphy was performed 3 hr after the administration of 740 MBq (20 mCi) 99mTc-HMDP. Within one week of the bone scan, planar images obtained with a conventional gamma camera and, in some cases, single photon emission computed tomographic images with a rotating gamma camera were scintigraphied 60 min after intravenous administration of 370 MBq (10 mCi) 99mTc-HM-PAO. RESULTS The results of bone and 99mTc-HM-PAO scans of the six patients are shown in Table 1 . Two patients (cases 1 and 3) had bone scintigrams which revealed abnormal accumulation in the skull base, pelvic bone and thoracic spine. The 99mTc-HM-PAO scans in both these patients showed abnormal accumulation in the same sites. The bone scintigram of one patient (case 2) revealed not only abnormal accumulation in the ribs but also photon deficient areas in the sternum, thoracic spine and femur, while 99mTc-HM-PAO showed abnormal accumulation in all these sites. In three patients (cases 4-6), bone scintigraphy revealed photon deficient areas in the ribs, pelvic bone and femur, and their 99mTc-HM-PAO scintigrams showed abnormal accumulation in the same sites. In three cases, bone metastasis was diagnosed histologically, while in the other four cases it was diagnosed frcm abnormalities on X-rays and computed tomography. CASE REPORTS Case 2 A 62-year-old man was admitted to our hospital with lumbago and anterior chest pain. A chest X-ray film revealed a mass lesion in his left upper lung field (Fig. 1a). Bone scintigraphy showed a cold lesion in the sternum (Fig. 1b). 99mTc-HM-PAO scintigraphy showed increased accumulation of radioactivity in the sternum (Fig. 1c, d). Six months after admission, he died of gastrointestinal bleeding and liver dysfunction. Findings at autopsy revealed metastatic lesions of the left first and second ribs and the sternum from well-differentiated HCC. Case 3 A 59-year-old man has been treated with TAE for HCC. Bone scintigraphy showed a small hot spot in the lower thoracic spine (Fig. 2a). 99mTc-HM-PAO scintigraphy showed increased accumulation of radioactivity in the thoracic spine (Fig. 2b) and computed tomography (CT) showed slight osteolytic change in the same site (Fig. 2c). Six months after the scintlgraphy, he died of the liver dysfunction. Findings at autopsy revealed metastatic lesion of the thoracic spine from HCC. Case 4 A 55-year-old man was treated with TAE for HCC. Six months after this treatment, as the patient complained of left rib pain, bone scintlgraphy was performed. The bone scan disclosed a defect in the 8th left rib (Fig. 3a). On 99mTc-HM-PAO scintigraphy, increased radioactivity was found in the left 8th rib (Fig. 3b). CT showed osteolytic change in the 8th left rib (Fig. 3c). Case 5 A 69-year-old man was admitted to our hospital for treatment with TAE for HCC. The patient complained of right rib pain. On bone roentgenogram osteolytic change in the right 10th rib was shown. Bone scintigraphy showed a photon deficient area in the rib (arrow), and a doughnut sign in the left ilium (Fig. 4a). On 99mTc-HM-PAO scintigraphy, increased radioactivity was found in the right 10th rib and left ilium (Fig. 4b). However, no accumulation was noted in the lower spine. Bone roentgenogram showed senile change in the 5th lumbar vertebra. CT showed liver mass and osteolytic change in the right rib (Fig. 4c). DISCUSSION Metastases of HCC occur in approximately half of the patients. The most common site of hematogenous spread is the lung, followed by bone. Scintigraphy with 67Ga and 99mTc-PMT (99mTc-Sn-N-pyridoxyl-5-methyltryptophan) is widely used in the imaging of HCC and its metastatic lesions. Imaging of metastatic bone tumor by bone scintigraphy greatly facilitates its early diagnosis, as com-pared with bone radiography,1-3 which generally required 30-50% decalcificationl2 prior to the recongnition of bone destruction by bone X-ray. However, 99mTc-phosphorous compounds accumulated specifically not in malignant bone tumors but in areas of rapid bone renewal, which reflected the process of repairing bone destruction due directly to a tumor or indirectly to the activation of osteoclasts.4,5 When bone formation, resulting from osteosclerotic changes in a metastatic lesion on skeletal radiography, occurs there is strong accumulation of the radionuclide. However, when there occurs minimal bone formation in malignant tumors such as HCC, little accumulation is usually evident on bone scintigraphy, even if tumor cells are present. This results in an appearance of osteolytic change on skeletal radiography. Thus, normal or photon deficient images are often obtained on bone scans. Therefore, bone scintigraphy alone is not a reliable technique for the detection and diagnosis of metastasis. In 1987, Hammersley et al reported that Tc-99m-HM-PAO could be used for the estimation of tumor blood flow in experimental models.13 Recently, it has been reported that Tc-99m-HM-PAO is taken up by various tumors.14 To confirm whether this scintigraphy, is useful for the detection of HCC or not, 99mTc-HM-PAO scintigraphy was performed in six cases with HCC. Increased accumulation of the radioisotope was shown in all the bone metastatic lesions. Although increased uptake was observed in four sites, and photon deficient areas were noted in seven sites in the metastatic lesions on bone scintigraphy, the increased uptake of 99mTc-HMDP in benign senile bone lesions made it difficult to differentiate them from metastatic lesions. On 99mTc-HM-PAO scintigraphy, the bone metastatic lesions were clearly delineated, while the benign bone lesions were not. This is most important in diagnosing bone metastasis. It is well known that bone metastases in HCC produced photon deficient areas on bone scintigraphy.9 In our experience, "filling-in" of such areas with 99mTc-HM-PAO in metastatic sternum, rib, thoracic spine and femur lesions from HCC was observed in four patients. While the precise mechanism of the accumulation of 99mTc-HM-PAO into the metastatic lesions is not clear, it might be attributed to the fact that tumor accumulation of 99mTc-HM-PAO was correlated with 86Rb uptake in experimental models,13 and that, in a clinical study, the intensity of 99mTc-HM-PAO uptake correlated well with that of the radioactivity at the tumor site in the arterial phase on radionuclide angiography.14 In our patients with HCC, 99mTc-HM-PAO might have shown greater activity in the metastatic lesions to the bone, because bone metastatic lesions from HCC are more hypervascular.15 This intense vascularity is a common feature shared with renal cell carcinomas and their bone metastatic lesions, and these tumors exhibit similar radiographic and scintigraphic changes : Osteolytic change with an expanded cortex and finding of photon deficient defects on the bone scan. Therefore, 99mTc-HM-PAO might accumulate in bone metastasis from renal cell carcinomas. In this study, the images were obtained at 60 min after i.v. injection of 99mTc-HM-PAO, and lung uptakes were dominant in some cases. Early and delayed imagings of rib lesions are therefore needed in further study. In conclusion, it was shown that, in the detection of bone metastasis from HCC, it was necessary to pay attention to photon deficient areas, and that combination studies with 99mTc-phosphorous compounds and 99mTc-HM-PAO were useful for the evaluation of such metastasis. This study was supported in part by a Research Project Grant (No. 1-801) from Kawasaki Medical School. REFERENCES 1 . Osmond JD, Pendergrass HP, Potsaid MS : Accuracy of 99mTc-diphosphonate bone scans and roentgenograms in the detection of prostate, breast and lung carcinoma metastases. Am J Roentgenol Radium Ther Nucl Med 125: 972-977, 1975 2. Sy WM. Patel K, Faunce H : Significance of absent or faint kidney sign on bone scan. J Nucl Med 16: 454-456, 1975 3. 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