Head and neck squamous cell carcinoma (HNSCC) is the eighth most common malignancy worldwide and refers to a group of malignancies involving the upper aerodigestive tract including the oral cavity, oropharynx, nasopharynx, hypo pharynx, and larynx. Advanced head and neck cancer require surgery with or without reconstructive procedure, significantly altering loco regional anatomy, while radiation treatment further adds to the distortion. Anatomic imaging, CECT and MRI, is therefore often inconclusive in suspected recurrent cancers. Functional imaging with fluorodeoxyglucose-positron emission tomography (FDG-PET) has been reported contributory in the evaluation of patients with SCC.[1] PET/CT has been described as accurate in evaluation of patients with suspected recurrent SCC of the head and neck, in whom anatomic imaging is inconclusive due to the loco regional distortions rendered by surgery and radiotherapy.[2] However, it is documented that tuberculosis and other chronic granulomatous infections result in high incidence of false positivity on FDG-PET. [3,4]  While numerous studies have documented high sensitivity and specificity rates, these studies emanate from centers located in countries with low prevalence of  chronic granulomatous infections. To the best of authors’ knowledge, no study has been reported in context of the Indian subcontinent which evaluates efficacy of FDG-PET in a region where  incidence of tuberculosis is high.

The purpose of this study was to analyze the ability of FDG-PET /CT in comparison to CECT Scan and Ultrasound in order to detect residual and/or recurrent disease after primary therapy in a large cohort of patients with squamous cell carcinoma of the head and neck.

Material and Method

This was a single center, prospective cohort study conducted between 2006-08.

Patients

Patients who were diagnosed cases of squamous cell carcinoma of the head and neck and had undergone prior therapy in form of surgery, radiation or both were eligible for the study. As per institutional protocol, these cases reported for regular three monthly follow up visits  to the Outpatients department and when they were suspected  to have  loco regional or distant recurrence based on clinical examination , they were enrolled for the study. A total of 63 patients with mean age 59.87 (range 39 -82 years) were enrolled in the study. The patients characteristics in terms of sex, sub-site distribution of the primary, the initial staging   and primary treatment received are as per Table 1.The patients underwent ultrasound of the neck followed by high definition contrast enhanced CT (CECT). This was followed by FDG-PET/CT. Recurrence was confirmed within 1 week of the final imaging studies by means of surgical resection and/or positive biopsy results. Patients with negative biopsy results (n = 4) were followed up clinically and with repeated biopsy for at least 6 months to confirm that there was no recurrence.

Table 1: Patient characteristics

CT examination of the head and neck was conducted after the administration of contrast material (dose, 150 cm³; Omnipaque [iohexol]; Nycomed, New York, NY). CT was performed by using a 9800 scanner (GE Medical Systems). After intravenous administration of 120 cm3 of contrast material, the axial images were obtained from the skull base to the thoracic inlet with a 5-mm section thickness. Images were displayed in both soft tissue and bone windows.

All PET/CT studies were conducted using a dedicated full ring Lutetium Ortho-silicate (LSO) crystal PET/CT scanner (Biograph 2, Siemens Medical Systems, Erlangen, Germany). Non-enhanced CT images were acquired at 130 KV and 90 mA (mean) with a section width of 5 mm. CT based attenuation correction was done for PET images and reconstruction done using iterative reconstruction algorithm. The PET/CT protocol included patient fasting for minimum six hours and confirmation of blood glucose levels below 140 mg/dl before intravenous injection of 370 MBq (10 mCi) of FDG. Whole body PET/CT scan (skull base to mid-thighs) was done one hour after FDG injection.

Image Interpretation

FDG PET and CT images were interpreted independently. CT images were interpreted without information of PET/CT findings or histopathologic confirmation. In the same manner, FDG PET images were interpreted by two radiologists who were experienced in PET imaging and not aware of  CT findings or final histopathologic confirmation. FDG PET images were interpreted from a direct digital display on a color-coded computer screen; black-and white hard-copy images of emission and transmission data were also available. Hardcopy CT images were interpreted and compared with previously CT images. A level of confidence in image interpretation was graded for both FDG-PET and CT images by using a five point system (0 = no recurrence, 1 = probably no recurrence, 2 = equivocal, 3 = probable recurrence, 4 = definite recurrence).

CT readers were asked to focus on the following findings: (a) presence of a focal mass or masses, (b) diffuse soft-tissue swelling, (c) asymmetric soft-tissue swelling,(d) presence of lymph node enlargement, and (e) interval increase in soft-tissue abnormalities in comparison with previous images.

FDG PET images were analyzed both qualitatively and quantitatively. General anatomic structures were identified by using emission and transmission scans. In visual interpretation, asymmetric and focally increased FDG uptake was considered to be suspicious for recurrence. The degree of focal FDG uptake was compared with physiologic FDG uptake in adjacent structures, such as the lymphoid tissue within the Waldeyer ring,the salivary glands, and the nasal turbinates. When focal uptake was detected, a region of interest (ROl) was placed at the area of increased FDG uptake and an SUV was calculated for total body mass as previously described. SUVs were compared for recurrence and non-recurrence by using a Student t test.

Data Collection & Analysis

Local/regional/or both recurrences reported by anatomical imaging ( USG and CT) as well as those  reported by functional  imaging( PET-CT) were correlated with histopathological diagnosis obtained by excision or biopsy, as case may be. Assuming histopathology as the bench mark, sensitivity, specificity, Positive predictive value(PPV) and negative predictive value (NPV) of USG , CT and PET were calculated. McNemars Chi square test was used to test significance amongst the imaging modalities.

Results

Out of the 63 cases , the whole-body 18F-FDG PET/CT results were positive for neck recurrence  in 37 patients and negative  in 26. CT Scan was positive in 38 cases and negative in 25 cases while Ultrasound reported 36 necks as positive with 27 negatives.Histology was obtained by  neck dissections in 41 cases , excision biopsy in 16 and by fine needle aspiration cytology in 6 cases. Amongst the 36 cases and 38 cases reported positive by USG and CT respectively, 24 each were proved histologically positive. Out of 37 cases reported positive by PET scan, 29 were histologically proven to be positive. These represented the true positive ( TP) USG , CT and PET failed to report  12, 12 and  2 cases respectively  which represent  false negative(FN) numbers for the  same. Hence calculated sensitivity for USG, CT and PET was 66.67 %, 66.67% and 93.55% respectively. (Table 2) 

Table 2. Comparison of USG, CT and PET in terms of true positive and false negative rates

USG and CT reported 27 and 25 necks as negative for recurrence, out of which 15 and 13 cases were actually negative on histology, while PET/CT reported 26 cases as negatives out of which 24 were actually histologically negative. These represent the true negatives (TN) cases. USG, CT and PET reported 12, 14 and  8 cases respectively as false positives (FP) ie  the imaging modality reported positive but histologically actually  negative. Detailed histopathological analysis of the PET –CT false positive showed tuberculosis in three out of eight cases, while three other cases had granulomatous lesion and two had non-specific inflammation, most likely radiation induced. Hence calculated specificity for USG, CT and PET was 55.56 % , 48.15 % and 75 % respectively (Table 3) The positive predictive value(PPV) for USG , CT and PET-CT was 66.67%, 63.16 % and 78.38 % while negative predictive value was 55.56 , 52 and 92.31 respectively ( Table 4 & 5).

With the confidence limits of 99% ( p- 0.01) , chi square test was applied to above values of sensitivity and specificity of CT and PET, PET was found superior to CT in terms of sensitivity and specificity , and the difference was statistically significant ( p<<0.01).

Table 3. Comparison of USG, CT and PET in terms of true negative and false positive rates

Table 4. Comparison of USG, CT and PET in terms of true positivity and false positivity rates

Table 5. Comparison of USG, CT and PET in terms of  true negativity and false negativity rates

Discussion

Squamous cell carcinoma of the upper aerodigestive tract has a high rate of involvement of local and regional lymph nodes and the primary site and involved or at-risk lymph nodes are generally treated with surgical resection, radiation therapy, or both.

Complete remission of primary site and/or nodal disease is achieved in 65% to 90% of patients with stage T2 to T4 disease, but control rates fall to 45% to 50% by 3 years. [5]

Recurrent carcinoma may develop either at the site of the original primary tumor or in the ipsilateral or contralateral cervical nodes. Distant metastasis as the sole manifestation of recurrent disease, without local recurrence at the primary site, occurs in only 3% to 8% of patients. [6]

Surgery and radiation therapy result in a variety of acute and chronic tissue changes, including edema, scarring and fibrosis, and necrosis, which obliterate and distort normal fascial planes on anatomic imaging studies which complicate the detection of recurrent disease by clinical examination or conventional anatomic imaging [7]. Biopsy may miss viable tumor if not properly directed and may cause significant complications in previously irradiated tissue. The timely diagnosis of residual or recurrent disease after primary therapy for squamous cell carcinoma of the head and neck is critical if salvage therapy is to be effective.

Positron emission tomography (PET) is an imaging technique that can map functional and metabolic activity before structural changes have taken place. PET scanning using [2- 18F]fluoro-2-deoxy-D-glucose (18FDG) can differentiate malignant from normal tissue based on enhanced glycolysis by tumour cells and can thus identify tumour in normal sized lymph nodes, differentiate sinus malignancy from secretions and fibrosis from tumour. Using FDG-PET, which depends on cellular activity and is not influenced by anatomical distortion is very helpful in these cases, although there are problems with false positives due to inflammation.[8]

The sensitivity and specificity of 18FFDG PET for detecting recurrent or residual disease has been reported as  approximately 88–100% and 75–100%, respectively, compared with 70–92% and 50–57% of CT and MRI. [3,9,10,11,12] In contrast, to high sensitivity and moderate specificity recorded in above studies , Rogers et al report relatively low sensitivity of 45%, specificity of 100%, positive predictive value of 100%, and a negative predictive value of 14% for PET/CT when correlated with histopathology.[13]

Our study shows FDG-PET to be significantly more sensitive than USG or CT in detecting neck recurrences in treated cases of head and neck squamous cell carcinomas( 93.55% vs 66.67% , p<0.01 ) .When seen in conjunction with a high negative predictive value of 92.31 % , this indicates that if PET-CT indicates negativity in a clinically suspected recurrence , then probably the patient does not have disease recurrence . This logically leads to the hypothesis that a negative FDG-PET result may obviate the need for additional unnecessary diagnostic and surgical procedures in such cases of indeterminate clinical or imaging findings in patients who have been previously treated for squamous cell carcinoma of the head and neck. This observation is in agreement with previous similar works.[14,15]PET-CT seems to have a rather low specificity (75%). This may be attributed to the fact that 18F-FDG is not a tumor-specific probe and its is well known to accumulate in non-neoplastic pathologic conditions, including infection whether acute or chronic, such as tuberculosis and granulomatous diseases (e.g. sarcoidosis). [4,16,17]Indeed, in our study 6/8 cases of the PET-CT false positive were attributable to granulomatous infection. It may be argued that a false-positive scan may be associated with the additional cost and potential morbidity of what proves to be an unnecessary biopsy if the clinician feels a biopsy is warranted but , conversely , a positive PET scan can direct the clinician to the site most likely to yield tumor when a biopsy is performed, and intervention can be accomplished early, when the likelihood of successful salvage therapy is greatest. 

In spite of low specificity (75%), our study indicates that FDG-PET still offers a definite advantage over conventional imaging in terms of specificity (p value<0.01). Similar low specificity (33-41%) in detecting residual disease after radiation or chemoradiation has been reported earlier by Yao et al [18] and Brkovich VS  et al [19], which the authors too have attributed to chronic granulomatous infections. Time-activity curves of malignant and benign lesions has been studied as a way to potentially differentiate inflammation from tumor ,but no major differences has been  detected [20]. It is unlikely that a nonspecific marker of metabolic activity such as FDG will be able to differentiate tumor from inflammation with complete accuracy. Hence, use of FDG-PET-CT in Indian scenario is likely to be continued to plagued by high degree of false positivity.

The PPV of PET-CT in detecting neck recurrences in our study was on the lower side (78.38%), which can again be attributed to the aforementioned factors for low specificity. The PPV was also not significantly different from that of conventional imaging (p value>0.05), which could either be due to inadequate sample size, or may point towards a true lack of advantage of PET-CT over conventional imaging in this respect.

Conclusion

FDG-PET is more sensitive than conventional imaging modalities in the detection of recurrent cancer in neck. In our scenario, FDG-PET-CT suffers in terms of specificity and positive predictive value for recurrent tumor because it is very sensitive to both tumor and inflammation. With high prevalence of tuberculosis and other chronic granulomatous infections, FDG-PET-CT results in high number of false positive cases. Nevertheless, it remains more specific than conventional modalities. On other hand ,a  negative FDG-PET-CT scan reliably excludes disease . The high negative predictive value suggests that a negative FDG-PET result may obviate unnecessary diagnostic and surgical procedures that ensue from indeterminate clinical or imaging findings in patients who have been previously treated for squamous cell carcinoma of the head and neck.

References:

1.     Goshen E, Yahalom R ,Talmi Y P,  Rotenberg G, Oksman Y, Zwas S T. The role of gamma-PET in the evaluation of patients with recurrent squamous cell cancer of the head and neck Int J Oral Maxillofac Surg. 2005 ;34:386-90.

2.     Goshen E, Davidson T, Yahalom R, Talmi YP, Zwas ST. PET/CT in the evaluation of patients with squamous cell cancer of the head and neck . Int J Oral Maxillofac Surg 2006 ; 35:332-36

3.     Güngör T , Nadal D , Hossle JP , Seger RA. Diagnostic and therapeutic impact of whole body positron emission tomography using fluorine-18-fluoro-2-deoxy-D-glucose in children with chronic granulomatous disease. Arch Dis Child 2001;85:341–45

4.     Bakheet SM, Powe J, Ezzat A, et al. F-18-FDG uptake in tuberculosis. Clin Nucl Med. 1998;23:739 –42.

5.     Fischbein NJ, AAssar OS, Caputo GR, et al. Clinical utility of positron emission tomography with 18F-fluorodeoxyglucose in detecting residual/recurrent squamous cell carcinoma of the head and neck. AJNR 1998;19:1189 –96

6.     Pigott K, Dische S, Saunders MI. Where exactly does failure occur after radiation in head and neck cancer? Radiother Oncol 1995;37:17–19

7.     Rankin SC . PET in face and neck tumours .Cancer Imaging. 2006; 6: S89–S95

8.     Kresnik E, Mikosch P, Gallowitsch HJ, et al. Evaluation of head and neck cancer with 18F-FDG PET: a comparison with conventional methods. Eur J Nucl Med. 2001;28:816–21

9.     Anzai Y, Carroll WR, Quint DJ, et al. Recurrence of head and neck cancer after surgery or irradiation: prospective comparison of 2-deoxy-2-[F-18]fluoro-D-glucose PET and MR imaging diagnoses. Radiology1996; 200:135 –41

10.   Wong WL, Chevretton EB, McGurk M, et al. A prospective study of PET-FDG imaging for the assessment of head and neck squamous cell carcinoma. Clin Otolaryngol 1997; 22:209 –14

11.   Farber LA, Benard F, Machtay M, et al. Detection of recurrent head and neck squamous cell carcinomas after radiation therapy with 2-18Ffluoro-2-deoxy-D-glucose positron emission tomography. Laryngoscope 1999;109:970 –75

12.   Goshen E, Davidson T ,Yahalom Y ,Talmi YP , Zwas ST. CT in the evaluation of patients with squamous cell cancer of the head and neck. International Journal of Oral and Maxillofacial Surgery 2006 ; 35: 332-6

13.   Rogers JW, Greven KM, McGuirt FW , et al .Can post–rt neck dissection be omitted for patients with head-and-neck cancer who have a negative pet scan after definitive radiation therapy? Int J Radiat Oncol Biol Phys 2004;58: 694-7.

14.   Abgral R, Querellou S, Potard G, Roux PYL, Duc-Pennec AL , Marianovski R , et al. Does 18F-FDG PET/CT Improve the Detection of Posttreatment Recurrence of Head and Neck Squamous Cell Carcinoma in Patients Negative for Disease on Clinical Follow-up? Journal of Nuclear Medicine 2009 ; 50: 24-29.

15.   Schechter NR, Gillenwater AM, Byers RM, Garden AS, Morrison WH, Nguyen LN Can positron emission tomography improve the quality of care for head-and-neck cancer patients? Int J Radiat Oncol Biol Phys. 2001 ;51:4-9

16.   Sumpe KD, Dazzi H, Schaffner A, von Schulthess GK. Infection imaging using whole-body FDG-PET. Eur J Nucl Med. 2000;27:822– 32.

17.   Yasuda S, Shothsu A, Ide M, et al. High fluorine-18-deoxyglucose uptake in sarcoidosis. Clin Nucl Med. 1996;21:983–84.

18.   Yao M, Smith RB, Graham MM, et al. The role of FDG PET in management of neck metastasis from head-and-neck cancer after definitive radiation treatment. Int J Radiat Oncol Biol Phys. 2005;63:991–99

19.   Brkovich VS, Miller FR, Karnad AB, Hussey DH, McGuff HS, Otto RA. The role of positron emission tomography scans in the management of the N-positive neck in head and neck squamous cell carcinoma after chemoradiotherapy. Laryngoscope. 2006;116:855–58

20.   Lapela M, Grenman R, Kurki T, et al. Head and neck cancer:detection of recurrence with PET and 2-[F-18] fluoro-2-deoxy-Dglucose.Radiology 1995;197:205–211