CASE REPORT Annals of Nuclear Medicine Vol. 10, No. 2, 261-264, 1996 Intense and prolonged Tl-201 accumulation in a slow growing bronchioloalveolar carcinoma Seigo KINUYA,* Shiro TAKAHASHI,** Motoyasu SAITO,*** Yohei TOFUKU *** Takatoshi MICHIGISHI* and Norihisa TONAMI* *Department of Nuclear Medicine, Kanazawa University School of Medicine Departments of **Radiology and ***Internal Medicine, Saiseihai Kanazawa Hospital Thallium-201 SPECT was performed to evaluate a pulmonary lesion in a 73-year-old male which had been considered to be an inflammatory lesion for two years. The lesion has slowly increased in size on x-CT. Tl-201 was intensely taken up and retained in the lesion, suggesting a malignant lesion. Histological examination revealed that the lesion was bronchioloalveolar carcinoma. This case suggested that Tl-201 uptake of pulmonary carcinoma would not be necessarily related to cell growth rate. Key words : Tl-201 SPECT, lung cancer, cell growth rate INTRODUCTION THALLIUM-201 CHLORIDE has been widely used for the assessment of malignant tumors of various organs. 1-10 Many factors might be involved in the mechanism of Tl-201 accumulation in tumors.11-16 Cell activities such as glucose metabolism and (Na+-K+)ATPase pump activity are considered to be important factors while tumor blood flow, vascular permeability and vascular volume are also important for the initial distribution. There is a report showing that the level of (Na+-K+)ATPase activity is correlated with cell growth.17 Tl-201 uptake in gliomas is reported to be associated with the malignancy grade.8 Furthermore, other reports suggested that Tl-201 uptake by tumors could be related to the cell growth rate.9,10 Recently we saw a case of a slow growing bronchioloalveolar carcinoma with intense and prolonged accumulation of Tl-201 . The lesion has been considered to be an inflammation for two years. CASE REPORT An abnormal pulmonary shadow was pointed out on chest radiography in a screening examination in 1993 in a 73-year-old male with an ex-smoking history (20 cigarettes/ day for 30 years, cessation for 15 years) who had been followed up for prostate cancer at the first hospital since 1991 . He had not complained of any respiratory symptom. Chest x-CT obtained in November, 1993 revealed consolidation with airbronchogram in the right S2. No lymph node swelling was observed. The lesion had been considered to be an inflammation and was followed up with chest x-ray and x-CT. Follow-up x-CT was obtained in June, 1994 and interpreted by the clinician as showing no significant change in size in 7 months. He was referred to our hospital in July, 1995 by a urologist. The lesion was re-examined by x-CT, found to have become enlarged when compared to the previous x-CT and suspected of being alveolar cell carcinoma for the first time. The lesion was found to have somewhat increased in size through 1993 to 1994 when retrospectively checked. Tl-201 SPECT was performed in August, 1995 to characterize the lesion. A dose of 6.5 mCi (240 MBq) of Tl-201 chloride was intravenously injected, and tomographic scans were obtained at 15 min (early) and 3 hr (delayed) postinjection with a dual-headed rotating gamma camera (Prism-2000XP, Picker) with low-energy, high-resolution collimators. Both early and delayed images delineated intense tracer accumulation in the right pulmonary lesion, resulting in a diagnosis of lung cancer.13 The early ratio, delayed ratio and retention index were calculated to be 2.41, 2.72 and 13%, respectively. Specimens obtained by transbronchial lung biopsy and surgical resection confirmed bronchioloalveolar carcinoma. Laboratory examination revealed nothing unusual except mild anemia during the clinical course. DISCUSSION Tl-201 imaging has been suggested to have a potential for the in vivo characterization of various tumors.1-10 It has been used for the differential diagnosis of pulmonary nodular lesions and for the detection of mediastinal lymph node metastases from lung cancer,1-3 based on findings indicating that malignant lesions are likely to show intense and prolonged tracer uptake. This theory could also be adapted to tumors originating in bone and muscle structures.4,5 For brain tumor, Tl-201 SPECT has been reported to be effective for the diagnosis of tumor viability6,7 and be correlated with FDG uptake which has been supposed to depend on the malignancy of the tumor.18 Black et al. showed the correlation of Tl-201 uptake with the malignacy grade of glioma.8 Furthermore, Oriuchi et al.9 and Ishibashi et al.10 recently reported that Tl-201 uptake is associated with the cell proliferative activity of gliomas. The mechanism of Tl-201 accumulation into tumors would include blood flow to the tumor, vascular permeability, vascular volume and cell activities such as glucose metabolism and (Na+-K+)ATPase pump activity. 11-16 Since (Na+-K+)ATPase pump activity is related to cell growth,17 Tl-201 uptake of tumor cells is supposed to be modified by cell growth rate. The case presented in this report had a slow growing lung carcinoma with signs of intense initial uptake and prolonged retention of Tl-201 on the SPECT study. The lesion could be classified as a malignant tumor rather than an inflammatory process, although it had been followed for two years as the latter. Tumor doubling time estimated from the slices showing the biggest diameter of the lesion in each x-CT study by means of the equation of Schwartz 19 was approximately 750 days. The estimation was made with x-CT because previous chest x-rays were not available. The mean doubling time of bronchiolo-alveolar carcinoma has been reported to be 300 days,20 and that of the present case appears to be much longer than the reported length of time. There is as yet no report on the correlation between Tl-201 uptake and cell growth rate for lung cancers. Several papers indicated that the tumor doubling time of adenocarcinoma of lung is longer than that of other cell types.21,22 It was reported that the retention index of adenocarcinoma was not significantly different from that of other cell types and there was no difference in the uptake ratio among the various cell types except between adenocarcinoma and large cell carcinoma.3 These findings suggest that the cell growth rate would not be a major factor regulating Tl-201 uptake not only in the present case but also in lung carcinoma in general. Another example of the poor correlation between cell growth and Tl-201 uptake has been demonstrated for thyroid tumor. It is known that both differentiated adenocarcinoma of the thyroid gland and benign tumors such as adenoma accumulate Tl-201 , and thyroid adenocarcinoma usually grows slowly. Kishida reported that both thyroid adenocarcinoma and adenoma had high (Na+-K+)ATPase activity and Tl-201 uptake was well correlated with (Na+-K+)ATPase activity irrespective of whether the tumor was malignant or benign.23 Interestingly, microfollicular adenoma tended to have rather higher enzyme activity than adenocarcinoma. These results indicate that (Na+-K+)ATPase activity is not necessarily associated with cell growth in thyroid tumor. Although we did not examine (Na+-K+)ATPase activity in the present case or could find any report on (Na+-K+)ATPase activity in lung carcinoma, the findings in the present case suggest either that there would be a poor correlation between cell growth and (Na+-K+)ATPase activity in this case as in thyroid tumor, or that the major mechanism of Tl-201 uptake in this case would not depend on (Na+-K+)ATPase activity. Since alveolar cell carcinoma usually does not have intense vascularization, Tl-201 uptake in this case would not be fully explained by tumor blood circulation. Frankly we do not have a satis-factory explanation for the intense Tl-201 uptake in this case. Since the lesion was resected by surgery, a slow growth rate after the TI-201 study could not be confirmed. It is possible that the lesion would have progressed rapidly if not resected. In conclusion, it can be imagined that there would be a variation in the correlation between Tl-201 uptake and cell growth rate according to the organ in which the tumor originated. Although a correlation between Tl-201 uptake and the proliferation of glioma is reported, it is likely that we could not adapt this theory to malignant lesions of the lungs as to thyroid tumors. We need to get more information about metabolic activities, including (Na+-K+)ATPase activity, in lung carcinoma to better understand the mechanism of Tl-201 accumulation in pulmonary lesions. ACKNOWLEDGMENT The authors thank Mr. Masao Kasamatsu, Mr. Tetsuro lgarashi and Ms. Rie Nakajima for their technical assistance and Ms. Hiroe Yabugishi for her secretarial services. REFERENCES 1. Tonami N, Shuke N, Yokoyama K, Seki H, Takayama T, Kinuya S, et al. Thallium-201 single photon emission computed tomography in the evaluation of suspected lung cancer. J Nucl Med 30: 997-1004, 1989. 2. Tonami N, Yokoyama K, Taki J, Shuke N. Kinuya S, Nakajima K, et al. Tl-201 SPECT in the detection of mediastinal lymph node metastases from lung cancer. Nucl Med Commun 12: 779-792, 1991. 3. Tonami N, Yokoyama K, Shuke N, Taki J, Kinuya S, Miyauchi T, et al. Evaluation of suspected malignant pulmonary lesions with Tl-201 single photon emission computed tomography. Nucl Med Commun 14: 602-610, 1993. 4. Tonami N, Itoh K, Nobuharu Y,Terui S.Torizuka K. Clinical usefulness of thallium-201 chloride in the diagnosis of tumor (Il) -an evaluation in bone, soft tissue and mediastinal tumors. KAKU IGAKU (Jpn J Nucl Med) 31 : 63-73, 1994. 5. Ramanna L, Waxman A, Binney G, Waxman S, Mirra J, Rosen G. Thallium-201 scintigraphy in bone sarcoma: comparison with gallium-67 and thechnetium-MDP in the evaluation of chemotherapeutic response. J Nucl Med 31 : 567-572, 1990. 6. Kaplan WD. Takvorisn T, Morris JH, Rumbaugh CL, Connolly BT, Atkins HL. Thallium-201 brain tumor imag-ing: A comparative study with pathologic correlation. J Nucl Med 28: 47-52, 1987. 7. Yoshii Y, Satou M, Yamamoto T, Yamada Y, Hyodo A, Nose T, et al. The role of thallium-201 single photon emission tomography in the investigation and characterization of brain tomours in man and their response to treatment. Eur J Nucl Med 20: 39-45, 1993. 8. Black KL, Hawkins RA, Kim KT. Becker DP. Lerner C, Marciano D. Use of thallium-201 SPECT to quantitative malignancy grade of gliomas. J Neurosurg 71 : 342-346, 1989. 9. Oriuchi N, Tamura M, Shibazaki T, Ohye C, Watanabe N, Tateno M, et al. Clinical evaluation of thallium-201 SPECT in supratentorial gliomas: relationship to histologic grade, prognosis and proliferative activities. J Nucl Med 34: 2085-2089, 1993. 10. Ishibashi M, Taguchi A, Sugita Y, Morita S, Kawamura S, Umezaki N, et al. Thallium-201 in brain tumors: relation-ship between tumor cell activity in astrocytic tumor and proliferating cell nuclear antigen. J Nucl Med 36: 2201-2206, 1995. 11. Winchell HS. Mechanisms for localization of radiopharmaceuticals in neoplasms. Semin Nucl Med 6: 371-396, 1976. 12. Sehweil A, el-Sayed M, Ziada G. Al-Huda F, Mobarak L, Omar YT, et al. Thallium-201 kinetics in malignant tumors. J Nucl Med 27: 1033, 1986. 13. Ando A, Ando I, Katayama M, Sanada S, Hiraki T, Mori H, et al. Biodistributions of 201Tl in tumor bearing animals and inflammatory lesion induced animals. Eur J Nucl Med 12: 567-572, 1987. 14. Sehweil AM, McKillop JH, Milroy R, Wilson R, AbdelDayem HM. Omar YT. Mechanism of 201Tl uptake in tumors . Eur J Nucl Med 15: 376-379, 1989. 15. Ito Y, Muranaka A, Harada T, Matsudo A, Yokobayashi T, Terashima H. Experimental study on tumor affinity of 201Tl-chloride. Eur J Nucl Med 3: 81-86, 1978, 16. Caulser C, Macapinlac H, Healey J, Ghavimi F, Meyers P, Wollner N, et al. The relationship between thallium uptake, blood flow, and blood pool activity in bone and soft tissue tumors. Clin Nucl Med 17: 565-572, 1992. 17. Elligsen JD, Thompson JE, Frey HE, Kruuv J. Correlation of (Na+-K+)-ATPase activity with growth of normal and transformed cells. Exp Cell Res 87: 233-240, 1974. 18. Hoh CK, Khanna S, Harris GC, Chen Tr, Black KL, Becker DP, et al. Evaluation of brain tumor recurrence with Tl-201 SPECT studies: Correlation with FDG PET and histological result. J Nucl Med 33: 867, 1992. 19. Schwartz M. A biomathematical approach to clinical tumor growth. Cancer 14: 1272-1294, 1961. 20. Heikhila L, Mattila P, Harjula A, Sumalainen RJ, Mattila S. Tumor growth rate and its relationship to prognosis in bron-chiolo-alveolar and pulmonary adenocarcinoma. Ann Chir Gynaecol 74: 210-214, 1985. 21 . Garland LH, Coulson W, Wollin E. The rate of growth and apparent duration of untreated primary bronchial carcinoma. Cancer 16: 694-707, 1963. 22. Spratt JS, Spjut HJ, Roper CL. The frequency distribution of the rates of growth and the estimated duration of primary pulmonary carcinomas. Cancer 16: 687-693, 1963. 23. Kishida T. Mechanisms of thallium-201 accumulation to thyroid gland-clinical usefulness of dynamic study in thallium-201 chloride scintigraphy for differential diagnosis of thyroid nodules. KAKU IGAKU (Jpn J Nucl Med) 24: 991-1004, 1987.