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Imaging of head and neck tumors with positron emission tomography and [11C]methionine
Int. J. Radiation Oncology Biol. Phys., Vol. 30, No. 5, pp. 1195-I199, I994 Copyright 0 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0360-3016/94 $6.00 + .OO
Pergamon
0360-3016(94)E0186-N
??Therapeutic Imaging
IMAGING
SIRKKU
OF HEAD AND NECK TUMORS WITH POSITRON TOMOGRAPHY AND [“CIMETHIONINE
LESKINEN-KALLIO, HEIKKI
M.D.,*+ PAULA JOENSUU,
M.D.*
LINDHOLM, AND EEVA
M.D.,*+
MARIA
NORDMAN,
M.D.*
EMISSION
LAPELA
M.D.,*+
*Department of Oncology and Radiotherapy, Turku University Central Hospital, 20520 Turku, Finland +Turku University Cyclotron/PET Center; PET unit, Turku University Central Hospital, 20520 Turku, Finland Purpose: To evaluate the value of positron emission tomography and [“Cjmethionine in imaging of malignant tumors of the head and neck region. Methods and Materials: Forty-seven tumors of the head and neck were investigated with “C-labeled methionine and positron emission tomography before treatment. Because of the resolution limits of the positron emission tomography scanner, all tumors selected for the study were larger than 1 cm in diameter. Results: Forty-two (91%) of the 46 malignant tumors were clearly visible in the positron emission tomography imagesquamous cell carcinoma, n = 26, lymphoma, n = 9, adenocystic carcinoma, n = 2; lymphoepithelioma, n = 1; adenocarcinoma, n = 1; transitional cell carcinoma, n = 1; esthesioneuroblastoma, n = 1; plasmocytoma, n = l), while three (7%) squamous cell carcinomas were visible, but less easy to detect due to physiological accumulation of the tracer in the area under observation. Only one (2%) squamous cell carcinoma could not be delineated from the positron emission tomography image, and there was no uptake of [“Cjmethionine in a benign pleomorphic adenoma. No correlation was found between the uptake of [“Cjmethionine and the histological grade in the subset of squamous cell carcinoma (n = 30). High physiological uptake of [“CJmethionine was observed in the salivary glands and the bone marrow. Conclusions: Malignant head and neck tumors can be effectively imaged with positron emission tomography using [“CJmethionine as the tracer. Positron emission tomography, [“C]Methionine,
Head and neck tumors.
accurately than computed tomography or magnetic resonance imaging ( 13, 14). A PET study may also give information about the proliferation rate of the tumor (10, 18). In the present article we describe our current experience in imaging malignant tumors of the head and neck region with PET and [’‘Clmethionine.
INTRODUCTION
It is occasionally difficult to localize the tumor and to assess its volume accurately with the currently available methods for radiotherapy, and, therefore, new imaging modalities of cancer are welcome ( 16). It is also desirable to know the proliferation rate of the tumor when the fraction size, the number of daily fractions, and the total treatment time are being planned (1). Positron emission tomography (PET) provides quantitative information on tissue physiology. Sugars, amino acids, and a wide variety of other molecules can be labeled with short-lived positron emitting isotopes, such as 18F, “C, or 150, and their accumulation in cancer can be measured with PET successfully (21). For example, carbon11 labeled L-methionine ([’'Clmethionine) has been reported to delineate brain tumors in PET images more
METHODS
AND
MATERIALS
Forty-seven patients with a head and neck tumor with a diameter larger than 10 mm were studied with PET and [“Clmethionine prior to any treatment between March 1989 and April 1993. The characteristics of the patients are given in Table 1. Thirty-eight (8 1%) of the patients were male, and the median age was 62.5 years (range, from 32 to 85 years). Most of the tumors studied were
Reprint requests to: Sirkku Leskinen-Kallio, M.D., Department of Oncology and Radiotherapy, Turku University Central Hospital, FIN-20520 Turku, Finland. Acknowledgements-We thank Prof. Uno Wegelius for valuable support and the personnel of the Turku Cyclotron/PET Center and the Department of Nuclear Medicine for pleasant cooper-
ation. The cooperation with the Departments of Otorhinolaryngology and Pathology is greatly appreciated. This study was financially supported by the Finnish Cancer Society and Turku University Foundation. Accepted for publication 24 March 1994.
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I. J. Radiation Oncology 0 Biology 0 Physics
Volume 30, Number 5, 1994
Table 1. Characteristics of 47 patients with the head and neck tumor Patient 1
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47
Sex
Age
M M F M M M M M M M M M M M M M F M M M M M M M M M M M M F M F M F F M M M M M F F M F M M M
63 62 49 64 75 83 63 71 66 36 70 65 66 67 41 58 58 65 62 38 62 56 70 50 56 73 79 71 73 77 58 81 63 59 41 56 48 41 32 52 71 59 42 85 80 68 60
PAD
see see see see see see see see see
see see
see see see see see
see see see see see see
see see
see see
see see see
see L L L L L L L L Mb H.ns pleom.aden 1ymfoep.c ACC est.n.blast TCC ACC AC plasmocyt
G
Region
TNM/Size
suvtu
SUVm
1
gingiva gingiva hypopharynx tongue lower lip facial skin hypopharynx maxill. sinus maxill. sinus hard palate neck larynx neck parotis floor of mouth tonsilla floor of mouth lower lip larynx tongue gingiva gingiva neck hypopharynx hypopharynx larynx nasopharynx gingiva maxill. sinus neck neck neck neck neck neck neck neck neck neck parotis nasopharynx nasopharynx maxilla maxilla facial skin nose maxill. sinus
T2NlMO T2NOMO T4NOMO T3N2MO T3N2cMO R 70X80 T4N2MO T4NOMO T4NOMO T2NOMO R 30X20 T2NOMO TXN3MO T3N2MO TZNOMO T4N 1MO TlNOMO TINOMO T3NlMO T4NlMO T4N2MO T3NlMO R 80X60 T4N 1MO TlNOMO T3NOMO T4N2MO T2NOMO T4NOMO TXN2MO 50x40 70X60 20x30 30x30 20x15 70x60 40x20 140x100
6.7 7.3 7.4 7.4 8 9.2 10.6 12.5 14.6 2.9 4.2 4.7 5.6 6.2 6.9 8.5 8.8 9 9.2 9.3 9.4 9.8 9.8 11.7 11.7 12.3 8.4 8.7 18.3
7.2
1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 X 1 1 1
1 2 2 2 3
3 X
1 2
30x30 T3N2cMO T4NlMO TlNOMO T4NOMO R 25X25 T2NOMO 70x50
8.6 d5.1; ~5.5 3.7
2.7
4.4 3.24 7.8 NFV NFV
6
sl 1.5; d6.4
3.1 4.0 5.9 7.7 2.2 5.2 6 7.6 4.1 0 12.4 6 4.1 8.2 8.1 4.4 14.3
d9.5; ~9.5 3
PAD = pathological anatomic diagnosis, G = grade, SCC = squamous cell carcinoma, L = lymphoma, Mb H.ns = Morbus Hodgkin nodular sclerosis type, ACC = adenocystic carcinoma, TCC = transitional cell carcinoma, AC = adeno carcinoma, R = recurrent, NFV = not in the field of view, d = right; s = left, SUVtu = standardized uptake value of the primary tumor, SUVm = SUV of metastasis. Tumor size is given in millimeters.
histologically malignant squamous cell carcinomas (n = 30,of which 27 were primary tumors and three recurrent tumors); and the rest consisted of non-Hodgkin’s lymphoma (n = 8;of which 4,3, and 1 were low, intermediate, and high grade malignant by the Working Formulation, respectively) ( 15), Hodgkin’s disease (nodular sclerosis type) (n = I), adenocystic carcinoma (n = 2), lymphoepithelioma (n = l), adenocarcinoma (n = l), transitional
cell carcinoma (n = l), esthesioneuroblastoma (n = l), plasmocytoma (n = 1), or benign pleomorphic adenoma of the parotid gland (n = 1). Histological grading of the squamous cell carcinomas was done according to the World Health Organization classification (17), and staging according to the Intemational Union Against Cancer TNM classification (6). Staging examinations consisted of full otorhinolaryngo-
PET in head and neck tumors 0 S.
LESKINEN-KALLIO et al.
1197
logical status including fiberoscopy in most cases, chest x-ray, computed tomography (n = 25), and occasionally magnetic resonance imaging and/or cervical ultrasonography. After a surgical biopsy, the patients with squamous cell carcinoma were treated with preoperative irradiation to the total tumor dose of 50 to 65 Gy with 2 Gy daily fractions followed by surgery, or with radiotherapy alone. All patients gave a written informed consent. The study was approved by the Ethical Committee of Turku University Central Hospital. PET imaging An ECAT PET scanner’ was used for PET imaging. The device acquires 15 contiguous slices simultaneously with a slice thickness of 6.7 mm; the full width of half maximum is 6.1 mm transaxially in the center of the field of view ( 19). Transmission and dynamic emission scannings were carried out as described by us in detail else(7.4 * 1.6 mCi) was inwhere (10, 11). [’'C]Methionine jected to a cubital vein after the transmission scanning immediately before the dynamic emission scanning of 40 min (4 X 30, 3 X 60, 5X 180, and 4 X 300 s). Data analysis Regions of interest (ROI) were drawn on the hot spots of the PET images so that the standard deviation of the radioactivity concentration of the ROI in the last frames of the study was under 15%. The “hot spot” ROI represents the most metabolically active portion of the tumor. The standardized uptake value (SUV)
suv
= Radioactivity Injected
concentration
in tissue [Bq/mL]
dose [Bq]/Patient’s
Fig. 1. (a) The PET image of patient No. 29 with squamous cell carcinoma of the left maxillary sinus. There is also slight uptake of [“Clmethionine in the parotid glands. (b) The PET image of patient No. 7 with squamous cell carcinoma of the hypopharynx and a lymph node metastasis on the right side of the neck (arrow).
weight [g] (Eq. 1)
was calculated from the last frame of each study, which represents the time 35-40 min from the injection. The body mass index (the body weight in kilograms divided by the square of length given in meters) of the patients was within the normal range (range, from 16.5 to 33.6; mean, 24.3 + 3.8) which is important for the validity of the WV (11). RESULTS Forty-two (9 1W) out of the 46 malignant tumors were clearly visible in the PET image (squamous cell carcinoma, n = 26; lymphoma, n = 9; adenocystic carcinoma, n = 2; lymphoepithelioma, IZ = 1; adenocarcinoma, n = 1; transitional cell carcinoma, n = 1; esthesioneuroblastoma, y1= 1; plasmocytoma, y1= 1) (Fig. 1). Delineation of three squamous cell carcinomas was somewhat impaired be-
’ CT1 PET Systems,
Inc. Knoxville,
TN, type 931/08-12.
cause of the physiological accumulation of the tracer in the adjacent structures (patients 2, 15, and 28). However, the tumors could still be delineated from the image when the anatomical location of the tumor was known by the investigators before image interpretation. One squamous cell carcinoma could not be clearly delineated from the PET image (patient 1 I), and there was no uptake of [“Clmethionine in a benign pleomorphic adenoma. All 17 clinically detected cervical lymph node metastases were detected also by PET. Patient No. 25 had some uptake of [“Clmethionine in the cervical lymph nodes, although there was no evidence of metastatic spread of the disease with other methods of investigation (clinical examination. magnetic resonance imaging, ultrasound). In patient No. 29, delineation of the tumor was clearly defined in the PET image only, and the radiation treatment plan was altered accordingly.
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The SUVs for [’'Clmethionine of the malignant tumors varied from 2.2 to 18.3 [mean, 8.1; standard deviation (SD) 3.31. In addition to tumors, high uptake of [“Clmethionine was found to be present in the salivary glands. The SUVs of the submandibular glands ranged from 3.7 to 6.6 (mean, 4.7; SD 1.0, n = 26), and those of the parotid glands from 3.1 to 5.9 (mean, 4.4; SD 1.O, n = 20). [“ClMethionine accumulated also avidly in the bone marrow of the maxilla and the mandible (mean, 6.8; SD 2.1, n = 17) and the vertebrae (mean, 4.9; SD, 1.O, it = 5). There was also some uptake of [“Clmethionine in the small salivary glands of mouth and the lymphoid tissue of Waldeyer ring. Uptake of [’'Clmethionine was somewhat higher in the squamous cell carcinoma (mean, 8.8; SD, 3.1; IZ = 30) than in lymphomas (mean, 5.1; SD, 1.9; n = 9) in the present series. No correlation was found between the uptake of [“Clmethionine and the histological grade in the subgroup of squamous cell carcinoma (n = 29, Fig. 2). Patient No. 2 had a gingival tumor that was visible neither in computed tomography nor in magnetic resonance imaging, but the extensions of the tumor could still be verified in a PET study. DISCUSSION Positron emission tomography appears to be the most effective method in nuclear medicine to image head and neck tumors. Forty-two (9 1%) out of 46 malignant head and neck tumors were clearly visible in PET imaging in the present series. The smallest tumor included was 10 X 1.5mm in size, and because of the resolution limits of our PET device it is difficult to image smaller tumors than this. Small tumors may also be difficult to detect with [’‘Clmethionine if they are located next to the major salivary glands or the bone marrow tissue, which was the
0
15 -
0
lo-
o a 1
??
suv
5-
a I
0
i 8 ??
I
II
III
GRADE Fig. 2. Lack of correlation between histological grade (horizontal axis) and [“Clmethionine uptake (vertical axis) in squamous cell carcinoma of the head and neck (n = 29).
Volume 30, Number 5, 1994
case in four patients in this series. Despite these limitations, PET imaging may complement information obtained by other imaging modalities, such as computed tomography. Methionine is an essential amino acid that is needed for protein synthesis, polyamine synthesis, transmethylation reactions, and the transsulphuration pathway, and malignant transformation accelerates all these reactions (4). Uptake of glucose is also enhanced in most malignant tumors, and both accelerated methionine and glucose metabolism seem to take place simultaneously. We have recently measured a high uptake of [“Clmethionine in those head and neck tumors that also have a high uptake of [‘*F]fluorodeoxyglucose, which is the most commonly used PET tracer (12). According to our experience, both tracers are suitable for imaging head and neck cancer. The resolution limits of PET and the physiological accumulations of the tracer may limit the visualization of small tumors. There are few data available on how well PET imaging with [’‘Clmethionine is able to differentiate between histologically malignant and benign tumors. According to Kubota et al., PET may provide a method to differentiate between benign and malignant lung lesions (7). There was only one histologically clearly benign tumor (a pleomorphic adenoma) in our series, and it did not accumulate [“Clmethionine. Similarly, we have studied a patient with a mediastinal sarcoidosis, where the tumors did not accumulate [’‘Clmethionine (unpublished data). On the other hand, we found slight accumulation of [I ‘Clmethionine in another patient with a breast abscess ( 10). Hence, high uptake of [’'Clmethionine may reflect malignant transformation of the tissue, whereas slightly increased uptake may also be found in benign lesions, such as infections. However, further information regarding the uptake of [“Clmethionine in benign lesions is needed. Malignant tissue is metabolically more active than fibrous tissue, and there is evidence that PET imaging may be useful in differentiating viable tumor tissue from scar tissue after cancer treatment (9, 20). Such information may be particularly useful when a recurrent tumor is suspected. [’'C]Methionine may also provide a tool for the follow-up of cancer treatment. Early metabolical changes detected by PET have been found to correlate with the treatment response in lung and breast cancer (5, 8). The uptake of [’‘Clmethionine in hypophyseal adenomas has been shown to decrease in hours after effective treament, while the volume of the adenomas shrinks in weeks (2). The histological grade of squamous cell carcinoma did not correlate with the uptake of [“Clmethionine in this series of patients. The histological grade may be subjective, and there is some evidence that high uptake of [’‘Clmethionine may be associated with high proliferative activity in the tumor (10) or with survival (3). Malignant head and neck tumors can be effectively imaged with PET and [’‘Clmethionine. Positron emission tomography with[“C]methionine may help to delineate
PET in head and neck tumors 0 S. LESKINEN-KALLIO er a/.
a tumor not well defined by the conventional imaging methods, e.g., maxillary neoplasms, while the value of PET and [“Clmethionine in providing information regarding the clinical behavior and prognosis of cancer is not yet known. Only few benign head and neck tumors
1199
have been studied by PET, and it is not currently known if changes in [“Clmethionine uptake are useful in predieting response to radiotherapy. Similarly, the prognostic value of [“Clmethionine uptake in head and neck cancer needs to be evaluated.
REFERENCES 1. Begg, A. C.; Hofland, I.; Moonen, L.; Bartelink, H; Schraub, S.; Bontemps, P.; Le Fur, R.; Van Den Bogaert, W.; Caspers, R.; Van Glabbeke, M.; Horiot, J. C. The predictive value of cell kinetic measurements in a European trial of accelerated fractionation in advanced head and neck tumors: An interim report. Int. J. Radiat. Oncol. Biol. Phys. 19:14491453; 1990. 2. Bergstrom, M.; Muhr, C.; Lundberg, P. 0.; L&tgstrGm, B. PET as a tool in the clinical evaluation of pituitary adenomas. J. Nucl. Med. 32:610-615; 1991. 3. Fujiwara T. Reply to letter by Shih, W.-J.; Ryo, U. Y.; Dillon, M. L. J. Nucl. Med. 30:1421-1422; 1989. 4. Hoffman, R. M. Altered methionine metabolism, DNA methylation and oncogenic expression in carcinogenesis. Biochem. Biophys. Acta 738:49-87; 1984. 5. Huovinen, R.; Leskinen-Kallio, S.; Nagren, K.; Lehikoinen, P.; Ruotsalainen, U.; Teras, M. Carbon-l I-methionine and PET in evaluation of treatment response of breast cancer. Br. J. Cancer 67:787-791; 1993. 6. International Union Against Cancer: TNM. Classification of malignant tumours. Hermanek, P.; Sobin, L. H., eds. 4th edition. Berlin: Springer Verlag; 1987. 7. Kubota, K.; Matsuzawa, T.; Fujiwara T.; Ito, M.; Hatazawa, J.; Ishiwata, K.; Iwata, R.; Ido, T. Differential diagnosis of lung tumor with positron emission tomography: A prospective study. J. Nucl. Med. 3 1: 1927-1933; 1990. 8. Kubota, K.; Yamada, S.; Ishiwata, K.; Ito, M.; Fujiwara, T.; Fukuda, H.; Tada, M.; Ido, T. Evaluation of treatment response of lung cancer with positron emission tomography and L-[methyl-“Clmethionine: A preliminary study. Eur. J. Nucl. Med. 20:495-501; 1993. S.; Minn, H.; Joensuu, H. PET and 9. Leskinen-Kallio, [“Clmethionine in assessment of response in nonHodgkin lymphoma. [Letter] Lancet 336: 1188; 1990. S.; Nagren, K.; Lehikoinen, P.; Ruotsa10. Leskinen-Kallio, lainen, U.; Joensuu, H. Uptake of [“Clmethionine in breast cancer studied by PET. Br. J. Cancer 64: 112 I- 1124; 199 1. 11. Leskinen-Kallio, S.; Huovinen, R.; N&en, K.; Lehikoinen, P.; Ruotsalainen, U.; Teras, M.; Joensuu, H. Methods of [’'Clmethionine quantitation in cancer PET studies. J. Comput. Assist. Tomogr. 16:468-474; 1992.
12. Lindholm, P.; Leskinen-Kallio, S.; Minn, H.; Bergman, J.; Haaparanta, M.; Lehikoinen, P.; Nagren, K.; Ruotsalainen, U.; Terls, M.; Joensuu, H. Comparison of fluorine-l 8 fluorodeoxyglucose and [“Clmethionine in head and neck cancer. J. Nucl. Med. 34:171 l-1716; 1993. 13. Mosskin, M.; von Holst, H.; Bergstrom, M.; Collins, V. P.; Eriksson, L., Johnstrom, P.; Noren, G. Positron emission tomography with “C-methionine and computed tomography of intracranial tumours compared with histopathologic examination of multiple biopsies. Acta Radiol. 28:673-68 1; 1987. 14. Mosskin, M.; Ericson, K.; Hindmarsh, T.; von Holst, H.; Collins, V. P.; Bergstrom, M.; Eriksson, L.; Johnstrom, P. Positron emission tomography compared with magnetic resonance imaging and computed tomography in supratentorial gliomas using multiple stereotactic biopsies as reference. Acta Radio]. 30:225-232; 1989. 15. National Cancer Institute sponsored study on classification of nonHodgkin’s lymphomas. Summary and description of a working formulation for clinical usage. Cancer 49:2 1122135; 1982. 16. Photon treatment planning collaborative working group. State-of-the-art of external photon beam radiation treatment planning. Int. J. Radiat. Oncol. Biol. Phys. 21:9-23; 199 1. 17. Shamugaratnam, K.; Sobin, L. H. Histological typing of upper respiratory tract tumors. Geneva: WHO; 1978: 1433. 18. Shields, A. F.; Coonrood, D. V.; Quackenbush, R. C.; Crowley, J. J.; Cellular sources of thymidine nucleotides: Studies for PET. J. Nucl. Med. 28:1435-1440; 1987. 19. Spinks, T. J.; Jones, T.; Gilardi, M. C.; Heather, J. D. Physical performance of the latest generation of commercial positron scanner. IEEE Trans. Nucl. Sci. 35:721-725; 1988. 20. Strauss, L. G.; Clorius, J. H.; Schlag, P.; Lehner, B; Kimmig, B.; Engenhart, R.; Marin-Grez, M.; Helus, F.; Oberdorfer, F.; Schmidlin, P. Recurrence of colorectal tumors: PET evaluation. Radiology 170:329-332; 1989. 21. Strauss, L. G.; Conti, P. S. The application of PET in clinical oncology. J. Nucl. Med. 32:623-648; 1991.
Pergamon
0360-3016(94)E0186-N
??Therapeutic Imaging
IMAGING
SIRKKU
OF HEAD AND NECK TUMORS WITH POSITRON TOMOGRAPHY AND [“CIMETHIONINE
LESKINEN-KALLIO, HEIKKI
M.D.,*+ PAULA JOENSUU,
M.D.*
LINDHOLM, AND EEVA
M.D.,*+
MARIA
NORDMAN,
M.D.*
EMISSION
LAPELA
M.D.,*+
*Department of Oncology and Radiotherapy, Turku University Central Hospital, 20520 Turku, Finland +Turku University Cyclotron/PET Center; PET unit, Turku University Central Hospital, 20520 Turku, Finland Purpose: To evaluate the value of positron emission tomography and [“Cjmethionine in imaging of malignant tumors of the head and neck region. Methods and Materials: Forty-seven tumors of the head and neck were investigated with “C-labeled methionine and positron emission tomography before treatment. Because of the resolution limits of the positron emission tomography scanner, all tumors selected for the study were larger than 1 cm in diameter. Results: Forty-two (91%) of the 46 malignant tumors were clearly visible in the positron emission tomography imagesquamous cell carcinoma, n = 26, lymphoma, n = 9, adenocystic carcinoma, n = 2; lymphoepithelioma, n = 1; adenocarcinoma, n = 1; transitional cell carcinoma, n = 1; esthesioneuroblastoma, n = 1; plasmocytoma, n = l), while three (7%) squamous cell carcinomas were visible, but less easy to detect due to physiological accumulation of the tracer in the area under observation. Only one (2%) squamous cell carcinoma could not be delineated from the positron emission tomography image, and there was no uptake of [“Cjmethionine in a benign pleomorphic adenoma. No correlation was found between the uptake of [“Cjmethionine and the histological grade in the subset of squamous cell carcinoma (n = 30). High physiological uptake of [“CJmethionine was observed in the salivary glands and the bone marrow. Conclusions: Malignant head and neck tumors can be effectively imaged with positron emission tomography using [“CJmethionine as the tracer. Positron emission tomography, [“C]Methionine,
Head and neck tumors.
accurately than computed tomography or magnetic resonance imaging ( 13, 14). A PET study may also give information about the proliferation rate of the tumor (10, 18). In the present article we describe our current experience in imaging malignant tumors of the head and neck region with PET and [’‘Clmethionine.
INTRODUCTION
It is occasionally difficult to localize the tumor and to assess its volume accurately with the currently available methods for radiotherapy, and, therefore, new imaging modalities of cancer are welcome ( 16). It is also desirable to know the proliferation rate of the tumor when the fraction size, the number of daily fractions, and the total treatment time are being planned (1). Positron emission tomography (PET) provides quantitative information on tissue physiology. Sugars, amino acids, and a wide variety of other molecules can be labeled with short-lived positron emitting isotopes, such as 18F, “C, or 150, and their accumulation in cancer can be measured with PET successfully (21). For example, carbon11 labeled L-methionine ([’'Clmethionine) has been reported to delineate brain tumors in PET images more
METHODS
AND
MATERIALS
Forty-seven patients with a head and neck tumor with a diameter larger than 10 mm were studied with PET and [“Clmethionine prior to any treatment between March 1989 and April 1993. The characteristics of the patients are given in Table 1. Thirty-eight (8 1%) of the patients were male, and the median age was 62.5 years (range, from 32 to 85 years). Most of the tumors studied were
Reprint requests to: Sirkku Leskinen-Kallio, M.D., Department of Oncology and Radiotherapy, Turku University Central Hospital, FIN-20520 Turku, Finland. Acknowledgements-We thank Prof. Uno Wegelius for valuable support and the personnel of the Turku Cyclotron/PET Center and the Department of Nuclear Medicine for pleasant cooper-
ation. The cooperation with the Departments of Otorhinolaryngology and Pathology is greatly appreciated. This study was financially supported by the Finnish Cancer Society and Turku University Foundation. Accepted for publication 24 March 1994.
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Table 1. Characteristics of 47 patients with the head and neck tumor Patient 1
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47
Sex
Age
M M F M M M M M M M M M M M M M F M M M M M M M M M M M M F M F M F F M M M M M F F M F M M M
63 62 49 64 75 83 63 71 66 36 70 65 66 67 41 58 58 65 62 38 62 56 70 50 56 73 79 71 73 77 58 81 63 59 41 56 48 41 32 52 71 59 42 85 80 68 60
PAD
see see see see see see see see see
see see
see see see see see
see see see see see see
see see
see see
see see see
see L L L L L L L L Mb H.ns pleom.aden 1ymfoep.c ACC est.n.blast TCC ACC AC plasmocyt
G
Region
TNM/Size
suvtu
SUVm
1
gingiva gingiva hypopharynx tongue lower lip facial skin hypopharynx maxill. sinus maxill. sinus hard palate neck larynx neck parotis floor of mouth tonsilla floor of mouth lower lip larynx tongue gingiva gingiva neck hypopharynx hypopharynx larynx nasopharynx gingiva maxill. sinus neck neck neck neck neck neck neck neck neck neck parotis nasopharynx nasopharynx maxilla maxilla facial skin nose maxill. sinus
T2NlMO T2NOMO T4NOMO T3N2MO T3N2cMO R 70X80 T4N2MO T4NOMO T4NOMO T2NOMO R 30X20 T2NOMO TXN3MO T3N2MO TZNOMO T4N 1MO TlNOMO TINOMO T3NlMO T4NlMO T4N2MO T3NlMO R 80X60 T4N 1MO TlNOMO T3NOMO T4N2MO T2NOMO T4NOMO TXN2MO 50x40 70X60 20x30 30x30 20x15 70x60 40x20 140x100
6.7 7.3 7.4 7.4 8 9.2 10.6 12.5 14.6 2.9 4.2 4.7 5.6 6.2 6.9 8.5 8.8 9 9.2 9.3 9.4 9.8 9.8 11.7 11.7 12.3 8.4 8.7 18.3
7.2
1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 X 1 1 1
1 2 2 2 3
3 X
1 2
30x30 T3N2cMO T4NlMO TlNOMO T4NOMO R 25X25 T2NOMO 70x50
8.6 d5.1; ~5.5 3.7
2.7
4.4 3.24 7.8 NFV NFV
6
sl 1.5; d6.4
3.1 4.0 5.9 7.7 2.2 5.2 6 7.6 4.1 0 12.4 6 4.1 8.2 8.1 4.4 14.3
d9.5; ~9.5 3
PAD = pathological anatomic diagnosis, G = grade, SCC = squamous cell carcinoma, L = lymphoma, Mb H.ns = Morbus Hodgkin nodular sclerosis type, ACC = adenocystic carcinoma, TCC = transitional cell carcinoma, AC = adeno carcinoma, R = recurrent, NFV = not in the field of view, d = right; s = left, SUVtu = standardized uptake value of the primary tumor, SUVm = SUV of metastasis. Tumor size is given in millimeters.
histologically malignant squamous cell carcinomas (n = 30,of which 27 were primary tumors and three recurrent tumors); and the rest consisted of non-Hodgkin’s lymphoma (n = 8;of which 4,3, and 1 were low, intermediate, and high grade malignant by the Working Formulation, respectively) ( 15), Hodgkin’s disease (nodular sclerosis type) (n = I), adenocystic carcinoma (n = 2), lymphoepithelioma (n = l), adenocarcinoma (n = l), transitional
cell carcinoma (n = l), esthesioneuroblastoma (n = l), plasmocytoma (n = 1), or benign pleomorphic adenoma of the parotid gland (n = 1). Histological grading of the squamous cell carcinomas was done according to the World Health Organization classification (17), and staging according to the Intemational Union Against Cancer TNM classification (6). Staging examinations consisted of full otorhinolaryngo-
PET in head and neck tumors 0 S.
LESKINEN-KALLIO et al.
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logical status including fiberoscopy in most cases, chest x-ray, computed tomography (n = 25), and occasionally magnetic resonance imaging and/or cervical ultrasonography. After a surgical biopsy, the patients with squamous cell carcinoma were treated with preoperative irradiation to the total tumor dose of 50 to 65 Gy with 2 Gy daily fractions followed by surgery, or with radiotherapy alone. All patients gave a written informed consent. The study was approved by the Ethical Committee of Turku University Central Hospital. PET imaging An ECAT PET scanner’ was used for PET imaging. The device acquires 15 contiguous slices simultaneously with a slice thickness of 6.7 mm; the full width of half maximum is 6.1 mm transaxially in the center of the field of view ( 19). Transmission and dynamic emission scannings were carried out as described by us in detail else(7.4 * 1.6 mCi) was inwhere (10, 11). [’'C]Methionine jected to a cubital vein after the transmission scanning immediately before the dynamic emission scanning of 40 min (4 X 30, 3 X 60, 5X 180, and 4 X 300 s). Data analysis Regions of interest (ROI) were drawn on the hot spots of the PET images so that the standard deviation of the radioactivity concentration of the ROI in the last frames of the study was under 15%. The “hot spot” ROI represents the most metabolically active portion of the tumor. The standardized uptake value (SUV)
suv
= Radioactivity Injected
concentration
in tissue [Bq/mL]
dose [Bq]/Patient’s
Fig. 1. (a) The PET image of patient No. 29 with squamous cell carcinoma of the left maxillary sinus. There is also slight uptake of [“Clmethionine in the parotid glands. (b) The PET image of patient No. 7 with squamous cell carcinoma of the hypopharynx and a lymph node metastasis on the right side of the neck (arrow).
weight [g] (Eq. 1)
was calculated from the last frame of each study, which represents the time 35-40 min from the injection. The body mass index (the body weight in kilograms divided by the square of length given in meters) of the patients was within the normal range (range, from 16.5 to 33.6; mean, 24.3 + 3.8) which is important for the validity of the WV (11). RESULTS Forty-two (9 1W) out of the 46 malignant tumors were clearly visible in the PET image (squamous cell carcinoma, n = 26; lymphoma, n = 9; adenocystic carcinoma, n = 2; lymphoepithelioma, IZ = 1; adenocarcinoma, n = 1; transitional cell carcinoma, n = 1; esthesioneuroblastoma, y1= 1; plasmocytoma, y1= 1) (Fig. 1). Delineation of three squamous cell carcinomas was somewhat impaired be-
’ CT1 PET Systems,
Inc. Knoxville,
TN, type 931/08-12.
cause of the physiological accumulation of the tracer in the adjacent structures (patients 2, 15, and 28). However, the tumors could still be delineated from the image when the anatomical location of the tumor was known by the investigators before image interpretation. One squamous cell carcinoma could not be clearly delineated from the PET image (patient 1 I), and there was no uptake of [“Clmethionine in a benign pleomorphic adenoma. All 17 clinically detected cervical lymph node metastases were detected also by PET. Patient No. 25 had some uptake of [“Clmethionine in the cervical lymph nodes, although there was no evidence of metastatic spread of the disease with other methods of investigation (clinical examination. magnetic resonance imaging, ultrasound). In patient No. 29, delineation of the tumor was clearly defined in the PET image only, and the radiation treatment plan was altered accordingly.
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I. J. Radiation Oncology 0 Biology 0 Physics
The SUVs for [’'Clmethionine of the malignant tumors varied from 2.2 to 18.3 [mean, 8.1; standard deviation (SD) 3.31. In addition to tumors, high uptake of [“Clmethionine was found to be present in the salivary glands. The SUVs of the submandibular glands ranged from 3.7 to 6.6 (mean, 4.7; SD 1.0, n = 26), and those of the parotid glands from 3.1 to 5.9 (mean, 4.4; SD 1.O, n = 20). [“ClMethionine accumulated also avidly in the bone marrow of the maxilla and the mandible (mean, 6.8; SD 2.1, n = 17) and the vertebrae (mean, 4.9; SD, 1.O, it = 5). There was also some uptake of [“Clmethionine in the small salivary glands of mouth and the lymphoid tissue of Waldeyer ring. Uptake of [’'Clmethionine was somewhat higher in the squamous cell carcinoma (mean, 8.8; SD, 3.1; IZ = 30) than in lymphomas (mean, 5.1; SD, 1.9; n = 9) in the present series. No correlation was found between the uptake of [“Clmethionine and the histological grade in the subgroup of squamous cell carcinoma (n = 29, Fig. 2). Patient No. 2 had a gingival tumor that was visible neither in computed tomography nor in magnetic resonance imaging, but the extensions of the tumor could still be verified in a PET study. DISCUSSION Positron emission tomography appears to be the most effective method in nuclear medicine to image head and neck tumors. Forty-two (9 1%) out of 46 malignant head and neck tumors were clearly visible in PET imaging in the present series. The smallest tumor included was 10 X 1.5mm in size, and because of the resolution limits of our PET device it is difficult to image smaller tumors than this. Small tumors may also be difficult to detect with [’‘Clmethionine if they are located next to the major salivary glands or the bone marrow tissue, which was the
0
15 -
0
lo-
o a 1
??
suv
5-
a I
0
i 8 ??
I
II
III
GRADE Fig. 2. Lack of correlation between histological grade (horizontal axis) and [“Clmethionine uptake (vertical axis) in squamous cell carcinoma of the head and neck (n = 29).
Volume 30, Number 5, 1994
case in four patients in this series. Despite these limitations, PET imaging may complement information obtained by other imaging modalities, such as computed tomography. Methionine is an essential amino acid that is needed for protein synthesis, polyamine synthesis, transmethylation reactions, and the transsulphuration pathway, and malignant transformation accelerates all these reactions (4). Uptake of glucose is also enhanced in most malignant tumors, and both accelerated methionine and glucose metabolism seem to take place simultaneously. We have recently measured a high uptake of [“Clmethionine in those head and neck tumors that also have a high uptake of [‘*F]fluorodeoxyglucose, which is the most commonly used PET tracer (12). According to our experience, both tracers are suitable for imaging head and neck cancer. The resolution limits of PET and the physiological accumulations of the tracer may limit the visualization of small tumors. There are few data available on how well PET imaging with [’‘Clmethionine is able to differentiate between histologically malignant and benign tumors. According to Kubota et al., PET may provide a method to differentiate between benign and malignant lung lesions (7). There was only one histologically clearly benign tumor (a pleomorphic adenoma) in our series, and it did not accumulate [“Clmethionine. Similarly, we have studied a patient with a mediastinal sarcoidosis, where the tumors did not accumulate [’‘Clmethionine (unpublished data). On the other hand, we found slight accumulation of [I ‘Clmethionine in another patient with a breast abscess ( 10). Hence, high uptake of [’'Clmethionine may reflect malignant transformation of the tissue, whereas slightly increased uptake may also be found in benign lesions, such as infections. However, further information regarding the uptake of [“Clmethionine in benign lesions is needed. Malignant tissue is metabolically more active than fibrous tissue, and there is evidence that PET imaging may be useful in differentiating viable tumor tissue from scar tissue after cancer treatment (9, 20). Such information may be particularly useful when a recurrent tumor is suspected. [’'C]Methionine may also provide a tool for the follow-up of cancer treatment. Early metabolical changes detected by PET have been found to correlate with the treatment response in lung and breast cancer (5, 8). The uptake of [’‘Clmethionine in hypophyseal adenomas has been shown to decrease in hours after effective treament, while the volume of the adenomas shrinks in weeks (2). The histological grade of squamous cell carcinoma did not correlate with the uptake of [“Clmethionine in this series of patients. The histological grade may be subjective, and there is some evidence that high uptake of [’‘Clmethionine may be associated with high proliferative activity in the tumor (10) or with survival (3). Malignant head and neck tumors can be effectively imaged with PET and [’‘Clmethionine. Positron emission tomography with[“C]methionine may help to delineate
PET in head and neck tumors 0 S. LESKINEN-KALLIO er a/.
a tumor not well defined by the conventional imaging methods, e.g., maxillary neoplasms, while the value of PET and [“Clmethionine in providing information regarding the clinical behavior and prognosis of cancer is not yet known. Only few benign head and neck tumors
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have been studied by PET, and it is not currently known if changes in [“Clmethionine uptake are useful in predieting response to radiotherapy. Similarly, the prognostic value of [“Clmethionine uptake in head and neck cancer needs to be evaluated.
REFERENCES 1. Begg, A. C.; Hofland, I.; Moonen, L.; Bartelink, H; Schraub, S.; Bontemps, P.; Le Fur, R.; Van Den Bogaert, W.; Caspers, R.; Van Glabbeke, M.; Horiot, J. C. The predictive value of cell kinetic measurements in a European trial of accelerated fractionation in advanced head and neck tumors: An interim report. Int. J. Radiat. Oncol. Biol. Phys. 19:14491453; 1990. 2. Bergstrom, M.; Muhr, C.; Lundberg, P. 0.; L&tgstrGm, B. PET as a tool in the clinical evaluation of pituitary adenomas. J. Nucl. Med. 32:610-615; 1991. 3. Fujiwara T. Reply to letter by Shih, W.-J.; Ryo, U. Y.; Dillon, M. L. J. Nucl. Med. 30:1421-1422; 1989. 4. Hoffman, R. M. Altered methionine metabolism, DNA methylation and oncogenic expression in carcinogenesis. Biochem. Biophys. Acta 738:49-87; 1984. 5. Huovinen, R.; Leskinen-Kallio, S.; Nagren, K.; Lehikoinen, P.; Ruotsalainen, U.; Teras, M. Carbon-l I-methionine and PET in evaluation of treatment response of breast cancer. Br. J. Cancer 67:787-791; 1993. 6. International Union Against Cancer: TNM. Classification of malignant tumours. Hermanek, P.; Sobin, L. H., eds. 4th edition. Berlin: Springer Verlag; 1987. 7. Kubota, K.; Matsuzawa, T.; Fujiwara T.; Ito, M.; Hatazawa, J.; Ishiwata, K.; Iwata, R.; Ido, T. Differential diagnosis of lung tumor with positron emission tomography: A prospective study. J. Nucl. Med. 3 1: 1927-1933; 1990. 8. Kubota, K.; Yamada, S.; Ishiwata, K.; Ito, M.; Fujiwara, T.; Fukuda, H.; Tada, M.; Ido, T. Evaluation of treatment response of lung cancer with positron emission tomography and L-[methyl-“Clmethionine: A preliminary study. Eur. J. Nucl. Med. 20:495-501; 1993. S.; Minn, H.; Joensuu, H. PET and 9. Leskinen-Kallio, [“Clmethionine in assessment of response in nonHodgkin lymphoma. [Letter] Lancet 336: 1188; 1990. S.; Nagren, K.; Lehikoinen, P.; Ruotsa10. Leskinen-Kallio, lainen, U.; Joensuu, H. Uptake of [“Clmethionine in breast cancer studied by PET. Br. J. Cancer 64: 112 I- 1124; 199 1. 11. Leskinen-Kallio, S.; Huovinen, R.; N&en, K.; Lehikoinen, P.; Ruotsalainen, U.; Teras, M.; Joensuu, H. Methods of [’'Clmethionine quantitation in cancer PET studies. J. Comput. Assist. Tomogr. 16:468-474; 1992.
12. Lindholm, P.; Leskinen-Kallio, S.; Minn, H.; Bergman, J.; Haaparanta, M.; Lehikoinen, P.; Nagren, K.; Ruotsalainen, U.; Terls, M.; Joensuu, H. Comparison of fluorine-l 8 fluorodeoxyglucose and [“Clmethionine in head and neck cancer. J. Nucl. Med. 34:171 l-1716; 1993. 13. Mosskin, M.; von Holst, H.; Bergstrom, M.; Collins, V. P.; Eriksson, L., Johnstrom, P.; Noren, G. Positron emission tomography with “C-methionine and computed tomography of intracranial tumours compared with histopathologic examination of multiple biopsies. Acta Radiol. 28:673-68 1; 1987. 14. Mosskin, M.; Ericson, K.; Hindmarsh, T.; von Holst, H.; Collins, V. P.; Bergstrom, M.; Eriksson, L.; Johnstrom, P. Positron emission tomography compared with magnetic resonance imaging and computed tomography in supratentorial gliomas using multiple stereotactic biopsies as reference. Acta Radio]. 30:225-232; 1989. 15. National Cancer Institute sponsored study on classification of nonHodgkin’s lymphomas. Summary and description of a working formulation for clinical usage. Cancer 49:2 1122135; 1982. 16. Photon treatment planning collaborative working group. State-of-the-art of external photon beam radiation treatment planning. Int. J. Radiat. Oncol. Biol. Phys. 21:9-23; 199 1. 17. Shamugaratnam, K.; Sobin, L. H. Histological typing of upper respiratory tract tumors. Geneva: WHO; 1978: 1433. 18. Shields, A. F.; Coonrood, D. V.; Quackenbush, R. C.; Crowley, J. J.; Cellular sources of thymidine nucleotides: Studies for PET. J. Nucl. Med. 28:1435-1440; 1987. 19. Spinks, T. J.; Jones, T.; Gilardi, M. C.; Heather, J. D. Physical performance of the latest generation of commercial positron scanner. IEEE Trans. Nucl. Sci. 35:721-725; 1988. 20. Strauss, L. G.; Clorius, J. H.; Schlag, P.; Lehner, B; Kimmig, B.; Engenhart, R.; Marin-Grez, M.; Helus, F.; Oberdorfer, F.; Schmidlin, P. Recurrence of colorectal tumors: PET evaluation. Radiology 170:329-332; 1989. 21. Strauss, L. G.; Conti, P. S. The application of PET in clinical oncology. J. Nucl. Med. 32:623-648; 1991.