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Oral Oncology 51 (2015) 1047–1050 Contents lists available at ScienceDirect Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology Th...

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Oral Oncology 51 (2015) 1047–1050

Contents lists available at ScienceDirect

Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology

The incidence and sites of Nasopharyngeal carcinoma (NPC) metastases on FDG PET/CT scans Ammad Shanoon Al Tamimi a,⇑, Sumbul Zaheer b, David Chee Ng b, Saabry Osmany c a Department of Radiology/Nuclear Medicine and Molecular Imaging Division, Massachusetts General Hospital/Harvard Medical School, 55 Fruit Street, White 427, Boston, MA 02114, United States b Department of Nuclear Medicine and PET, Singapore General Hospital, Singapore c RadLink Diagnostic Imaging, Singapore

a r t i c l e

i n f o

Article history: Received 3 June 2015 Received in revised form 3 August 2015 Accepted 5 August 2015 Available online 24 August 2015 Keywords: Nasopharyngeal carcinoma FDG PET/CT Distant metastases Diaphragm

s u m m a r y Introduction: The only investigation to determine if a whole body FDG PET/CT scan is helpful in the evaluation of NPC is a study from Stanford. In this study, 26 patients with whole body PET/CT, were evaluated for lesions below adrenals and showed that 7.7% of distant metastases were below adrenals. Our study comparing distant metastases below diaphragm with Stanford study to evaluate the need for whole body PET/CT. Material and methods: Reports of NPC patients in Singapore General Hospital were reviewed. The lesions were analyzed for total number and number below diaphragm. The lesions below the diaphragm were further analyzed if they were solitary or involved multiple areas and if any additional lesions were above diaphragm. Results: 717 reports were included in final analysis. The number of FDG avid lesions in these reports was 709. Distant metastases represented 352 of the 709 lesions. The number of lesions below diaphragm was 152, of the lesions below diaphragm only 16 of lesions have no co-existing distant metastases above diaphragm. From these lesions, there were only 12 solitary lesions. The other 4 has concurrent metastases but all localized below diaphragm. Conclusion: Compared to Stanford study, number of reports is more representative in this study and the yield is much lower (7.7% versus 2.26%). From the results of our study we can consider limiting the scan area from vertex to below diaphragm. However, the symptoms and clinical presentation of the patient will further direct the requesting physician in the area to be imaged. Ó 2015 Elsevier Ltd. All rights reserved.

Introduction Nasopharyngeal carcinoma (NPC) is the most common head and neck malignancy in Singapore and the fifth most common malignancy overall. However it is a relatively rare head and neck tumor and estimated to occur in 10–30 persons per 100,000 people annually [1]. NPC is an epithelial neoplasm with World Health Organization (WHO) histological classifications of differentiated nonkeratinizing carcinoma (type II) and undifferentiated carcinoma (type III) [2]. The disease etiology is thought to be associated with the Epstein–Barr virus [3]. NPC is prevalent in China, Hong Kong, Singapore, Taiwan and in Chinese Americans [4]. The disease natural history, etiology and response to treatment in NPC is different from squamous cell carcinoma of the head and neck [2]. ⇑ Corresponding author. Tel.: +1 6176431966; fax: +1 6177266165. E-mail address: [email protected] (A.S. Al Tamimi). http://dx.doi.org/10.1016/j.oraloncology.2015.08.001 1368-8375/Ó 2015 Elsevier Ltd. All rights reserved.

Nasopharyngeal carcinoma is the head and neck tumor with the highest rate of lymph node and/or distant metastasis [5]. In reviews of large cohorts of Hong Kong patients by Sham et al. and Teo et al. [3], the common sites for distant metastasis were the skeleton, the thorax and the liver in descending order of frequency. In other studies distant metastases were detected in up to 11% of patients at initial diagnosis while the skeleton was involved in 70–80% of the patients who presented with distant metastasis [2] (see Fig. 1). The usual work up for NPC comprises of physical examination and nasopharyngeal scope assessment with biopsy sampling. CT or MRI of the head and neck are usually acquired for locoregional assessment. In addition chest radiographs, liver ultrasound and bone scintigraphy are performed for excluding distant metastasis [6]. Positron emission tomography (PET)/CT with F18 Fluorodeoxyglucose (FDG) is now routinely performed in many centers for the diagnosis, initial staging, follow-up and recurrence

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Fig. 1. Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) scan at the same trans-axial level (a–c) and Maximum intensity projection (MIP) of the FDG-PET/CT scans (d) show a solitary FDG-avid sclerotic lesion in the right posterior acetabular column.

of NPC. It is used also for evaluating local residual disease and treatment response. In the current practice FDG PET/CT is acquired from the vertex or base of the skull to the mid-thigh in almost all institutions. The only investigation to assess the utility of a ‘‘whole body” (defined as eyes to thighs in that study) PET/CT scan in the imaging evaluation of patients with NPC is a study from Stanford, USA [7]. In this retrospective study of 26 patients who had ‘‘whole body” FDG PET/CT scans, the lesions below the adrenal glands were tabulated. It was noted that 7.7% of distant metastases were below the adrenal glands in this clinical setting. The study concluded that ‘‘whole body” PET/CT is the appropriate protocol for evaluating patients with NPC. The aim of the current study is evaluating FDG PET/CT scans of NPC for the incidence and sites of distant metastases.

2003 and 2009 were analyzed individually. The data from all reports were analyzed for: 1. The indication of the study – (staging, treatment response, recurrence, follow-up). 2. Loco-regional nodal disease (ipsilateral, contralateral lymph nodes). 3. Distant metastasis. The distant metastases were localized to four body ‘‘regions”: chest, abdomen, pelvis and bones. The sites of the bony lesions were carefully noted.

Material and methods

The lesions were also analyzed for the total number of metastases and the number below the diaphragm (liver, retroperitoneal lymph nodes, spleen, adrenals, pancreas, pelvic lymph nodes, pelvic masses, lumbar spine, sacrum, pelvic bones and femur). The lesions below the diaphragm were further analyzed to see if they were solitary or involved multiple areas and for any additional lesions above the diaphragm.

The patients

18F-FDG PET/CT

FDG PET/CT scan reports of patients with histologically proven NPC imaged in the Department of Nuclear Medicine and PET, Singapore General Hospital, Singapore between 2003 and 2009 were reviewed using the Nuclear Medicine Information System (NuMIS). The study was approved by the Singhealth Centralized Institutional Review Board (CIRB). The scans were reported by qualified nuclear medicine physicians. Patients with additional malignancies were excluded. The reports of patients with more than one PET/CT scan between

The patients fasted for at least 6 h before the scan and received between 9 and 14 mCi (333 and 518 MBq) of 18-FDG according to body weight. An integrated PET/CT system (Biograph, Siemens, LSO crystals) was used for image acquisition. A low dose single slice CT with slice thickness of 5 mm, mAs range 200–400, KVp from 80 to 130 was acquired from the vertex of skull to mid-thigh followed by PET acquisition over the same area at 3 min per bed position. The CT data was used for attenuation correction and anatomical correlation. The PET data underwent iterative reconstruction (24 sub-

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sets, 3 iterations). Intravenous (IV) contrast was administered only when requested by the referring physician.

The determination of metastasis Metastasis was considered to be present if noted on the report. Equivocal lesions were considered negative though follow up reports within the targeted period were reviewed and were used to upgrade lesions later shown to be positive.

Table 2 The patient ethnic groups. Ethnic group

No of reports

Chinese Malay Indians Others

614 13 1 89

85.63% 1.81% 0.14% 12.41%

Total

717

100.00%

Table 3 The indication for the scan.

Results Patient demographics A total of 722 18F-FDG PET/CT reports on NPC patients imaged between 2003 and 2009 were reviewed. Five patients with additional concurrent primary malignancies were excluded and a total of 717 reports (628 patients) were included in the final analysis. Five hundred and fourteen (514) patients were male and 203 were female. The age distribution is described in Table 1 with the majority between 45 and 55 years of age. The ethnic groups of the patients are listed in Table 2. The noted indications for the FDG PET/CT studies are listed in Table 3. The total number of FDG avid lesions in these reports was 709. Of these, 357/709 (50.35%) were loco-regional nodal metastasis (retropharyngeal 115, cervical 226 and supraclavicular 16). The loco-regional nodal distribution is tabulated in Table 4. Distant metastases represented 352 (49.65%) of 709 lesions. One hundred and four (29.55%) of the 352 metastases were in the chest, 45 (12.78%) were in the abdomen, 11 (3.13%) were in the pelvis and 192 (54.55%) were in the bones. Of the chest lesions 27/104 (25.96%) were mediastinal lymph nodes, 21/104 (20.19%) were axillary lymph nodes, 16/104 (15.38%) were hilar lymph nodes, 39/104 (37.50%) were lung nodules/masses and 1/104 (0.97%) was a pleural lesion. On reviewing the abdominal lesions, 27/45 (60.00%) were liver parenchyma lesions, 12/45 (26.67%) were retroperitoneal lymph nodes, 4/45 (8.89%) were in the spleen parenchyma, 1/45 (2.22%) was an adrenal lesion and 1/45 (2.22%) was a pancreatic lesion. In the pelvis 10/11 (90.91%) were pelvic lymph nodes and 1/11 (9.09%) was a pelvic mass. Bone lesions were seen in the cervical spine (13/192, 6.77%), clavicles (7/192, 3.65%), ribs (23/192, 11.98%), sternum (8/192, 4.17%), scapulae (13/192, 6.77%), humerus (6/192, 3.13%), thoracic spine (26/192, 13.54%), lumbar spine (27/192, 14.06%), sacrum (28/192, 14.58%), pelvic bones (28/192, 14.58%) and femora (13/192, 6.77%). The distributions of distant metastases are summarized in Table 5. The total number of lesions below the diaphragm was 152/352, of which 96/152 (63%) were bone lesions (27 in the lumbar spine, 28 in the sacrum, 28 in the pelvic bones and 13 in the femur). The remaining lesions 56/152 (37%) were as follows: 27/152 (17.76%) were hepatic lesions, 12/152 (7.89%) were retroperitoneal lymph nodes, 4/152 (2.63%) were splenic lesions, 1/152 (0.66%) was in

Table 1 Age distribution of patients. Age

No of reports

>35 35–44 45–55 >55

41 181 291 204

5.72% 25.24% 40.59% 28.45%

Total

717

100.00%

Staging Response Recurrence Follow up

217 35 227 238

30.26% 4.88% 31.67% 33.19%

Total

717

100.00%

Table 4 The distribution of loco-regional nodes. Nodal station

Number

Retropharyngeal Cervical Supraclavicular

115 226 16

% of total loco-regional 32.21 63.31 4.48

Total

357

100.00

Table 5 The distribution of distant metastasis. Site

Number

% of Total

Total Subtotal above diaphragm Chest Mediastinal LN Axillary LN Hilar LN Pleura Lungs C-spine T-spine Ribs Sternum Scapula Humerus Clavicles Subtotal below diaphragm Abdomen Retroperitoneal LN Liver Spleen Adrenal Pancreas Pelvis Pelvic LN Pelvic mass Bones L-spine Sacrum Pelvic bones Femur

352 200 104 27 21 16 1 39 13 26 23 8 13 6 7 152 45 12 27 4 1 1 11 10 1 192 27 28 28 13

100.0 56.8 29.5 7.7 6.0 4.5 0.3 11.1 3.7 7.4 6.5 2.3 3.7 1.7 2.0 43.2 12.8 3.4 7.7 1.1 0.3 0.3 3.1 2.8 0.3 54.5 7.7 8.0 8.0 3.7

the adrenals, 1/152 (0.66%) was in the pancreas, 10/152 (6.58%) were pelvic lymph nodes and 1/152 (0.66%) was a pelvic mass. Of the lesions below the diaphragm; only 16/152 (10.53%) of lesions had no co-existing distant metastases above the diaphragm. Of these lesions there were 12/16 (75%) solitary lesions {5/12 (41.67%) in the liver, 5/12 (41.67%) in the pelvic bones, 1/12 (8.33%) in the sacrum and 1/12 (8.33%) in the retroperitoneal

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Table 6 The distribution of lesions below the diaphragm only. Lesions below the diaphragm Solitary Liver Pelvic bones Sacrum Retroperitoneal LN Multiple Retroperitoneal LN + pelvic LN + femur Retroperitoneal LN + pelvic LN + L-spine + iliac bone Liver + retroperitoneal LN

16 12 5 5 1 1 4 1 1 2

lymph node}. The other 4/16 (25%) metastases below the diaphragm had concurrent metastases below the diaphragm. The analysis of the lesions below the diaphragm without metastases above the diaphragm is summarized in Table 6. Discussion Nasopharyngeal carcinoma (NPC) is a malignant neoplasm of epidermoid origin seen mainly among specific ethnic groups [2]. It is a squamous cell carcinoma of the head and neck region and is very aggressive with a high incidence of loco-regional lymph node spread and distant metastasis at presentation. Despite the fact that NPC is radiosensitive and is potentially curable the 1 year mortality rate for NPC patients can reach 90% when distant metastasis is found at presentation [6]. As the presence of distant metastasis influences prognosis and treatment the accurate evaluation of distant metastases for patients with primary or recurrent NPC is essential. In most institutions, PET/CT scans are acquired from the vertex of skull to the mid-thigh but the radiation burden from the CT scan especially to the pelvic area is not negligible and the CT component of the radiation burden depends in part on the field of view. The radiation burden from the PET tracer is independent of the part of body being imaged. Radiologic imaging for evaluating head and neck malignancy is usually limited to the area from the vertex through the adrenal glands due to the low yield of finding metastasis below the level of adrenal glands [7]. Since most NPC patients are usually young and need more than one scan for staging and further assessment the radiation dose to the patient from the CT component should be seriously considered. For abdominal and pelvic scans the estimated median effective dose varied from 15 mSv for a routine non-contrast scan [8] though it would vary from center to center. From our study we can see that about half of the lesions are distant lesions. Of these distant lesions over half are in the bones and just over 43% are below the diaphragm. The current study showed that the total number of lesions that were only below diaphragm were 16 of 709 lesions which represents only 2.26% of all the lesions. The results also showed that 50% (6/12) of the solitary lesions below the diaphragm are bony metastasis. The usual work-up for NPC often includes bone scans to look for distant bone metastasis and as such these lesions may be detected on a bone

scan. In our study the indication for all patients with lesions below diaphragm was recurrence. The study has limitations as it is a retrospective study, it considered the number of scans not the number of patients and some patients had multiple scans. In addition, the distant metastases are not histologically proven and SUVmax measurements are not considered. The study was also limited to patients who could afford to have a FDG PET/CT scan. The study did not consider the ethnicity of the patients or other risk factors. A prospective study with a large number of patients would be helpful in correlating the metastases with the EBV titres and the treatment modality and this may be of great impact in patient management. Conclusion PET/CT confined to the region of the diaphragm and sparing the lower abdomen and pelvis is able to pick up most relevant distant metastases whilst reducing radiation exposure to the abdominal and pelvic organs particularly to the gonads in these patients, the majority of whom are in the reproductive age group. Careful patient selection may further reduce the likelihood of missing patients with distant metastases below the diaphragm. Patients with bulky loco-regional disease are the ones most likely to have distant metastases and hence may benefit from a ‘‘whole” body scan. Conflict of interest statement None declared. References [1] Yen Ruoh-Fang, Hong Ruey-Long, Tzen Kai-Yuan, Pan Mei-Hsiu, Chen Tony Hsiu-Hsi. Whole-body 18F-FDG PET in recurrent or metastatic nasopharyngeal carcinoma. J Nucl Med 2005;46:770–4. [2] Liu Feng-Yuan, Chang Joseph T, Wang Hung-Ming, Liao Chun-Ta, Kang ChungJan, Ng Shu-Kung, et al. [18F]Fluorodeoxyglucose positron emission tomography is more sensitive than skeletal scintigraphy for detecting bone metastasis in endemic nasopharyngeal carcinoma at initial staging. J Clin Oncol 2006;24:599–604. [3] Liu Feng-Yuan, Lin Chien-Yu, Chang Joseph T, Ng Shu-Hang, Chin Shy-Chyi, Wang Hung-Ming, et al. 18F-FDG PET can replace conventional work-up in primary M staging of nonkeratinizing nasopharyngeal carcinoma. J Nucl Med 2007;48:1614–9. [4] Ng Shu-Hang, Joseph Chang Tung-Chieh, Chan Sheng-Chieh, Ko Sheung-Fat, Wang Hung-Ming, Liao Chun-Ta, et al. Clinical usefulness of 18F-FDG PET in nasopharyngeal carcinoma patients with questionable MRI findings for recurrence. J Nucl Med 2004;45:1669–76. [5] Chang Joseph Tung-Chieh, Chan Sheng-Chieh, Yen Tzu-Chen, Liao Chun-Ta, Lin Chien-Yu, Lin Kun-Ju, et al. Nasopharyngeal carcinoma staging by (18)Ffluorodeoxyglucose positron emission tomography. Int J Radiat Oncol 2005;62:501–7. [6] Yen Tzu-Chen, Chang Joseph Tung-Chieh, Ng Shu-Hang, Chang Yu-Chen, Chan Sheng-Chieh, Lin Kun-Ju, et al. The value of 18F-FDG PET in the detection of stage M0 carcinoma of the nasopharynx. J Nucl Med 2005;46:405–10. [7] Iagaru Andrei, Mittra Erik S, Gambhir Sanjiv Sam. FDG-PET/CT in cancers of the head and neck: what is the definition of whole body scanning? Mol Imaging Biol 2011;13:362–7. [8] Smith-Bindman R, Lipson J, Marcus R, et al. Radiation dose associated with common computed tomography examinations and the associated lifetime attributable risk of cancer. Arch Intern Med 2009;169:2078–86.