PET Imaging Mini Symposium: Original Article
Incremental (?) role of positron emission tomography/ computed tomography in clinically unknown primary patients with neck metastasis Mohindra S, Bhattacharya A1, Goshal S2, Gupta B Department of Otolaryngology, Head and Neck Surgery, 1Departments of Nuclear Medicine, and 2Radiation and Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, India Correspondence to: Dr. Satyawati Mohindra, E‑mail: [email protected]
Abstract
OBJECTIVE: To study the incremental role of positron emission tomography (PET)/computed tomography (CT) in the detection of primary site in cases of occult primary with neck metastasis. STUDY DESIGN: A prospective study on 79 consecutive patients. SETTING: A tertiary care otolaryngology and head and neck surgery center. MATERIALS AND METHODS: This prospective study compares the results of PET/CT in 79 patients of occult
primary with neck metastasis with that of detailed comprehensive head and neck examination including imaging and panendoscopy. This study also attempts to define the incremental role of PET/CT in patients of occult primary. RESULTS: The sensitivity of PET/CT in identifying the primary tumor was 62.4%, the specificity was 64.7%, the positive predictive value was 69.7% and the negative predictive value was 93%. We had a false positive rate of 33.6% and a false negative rate of 2.6%. CONCLUSION: PET/CT is a sensitive investigation for detection of occult primary. However, it has a low specificity rate and a high false positivity rate. Due to a high false positive rate, multiple biopsies from suspicious sites should be taken rather than solely relying on PET/CT. PET/CT guided fine needle aspiration cytology should be utilized more frequently than we did in this study. Key Words: Carcinoma of unknown primary site, panendoscopy, positron emission tomography/computed tomography
Introduction Squamous cell carcinoma, metastatic to a cervical lymph node from an unknown primary tumor remains a controversial topic. The overall incidence of unknown primary tumors in the head and neck region ranges from 3% to 7% of all head and neck cancers.[1‑7] The traditional evaluation consists of a careful office examination, including fiber optic laryngoscopy/nasopharyngoscopy, detailed imaging (computed tomography (CT) and/or magnetic resonance imaging (MRI)), and panendoscopy, with directed biopsies of at‑risk sites and tonsillectomy.[1‑3] In the present study, we are presenting our findings of Positron emission tomography/computed tomography (PET/ CT) and their correlation with detailed comprehensive examination including panendoscopy and biopsy in diagnosing an occult primary tumor in 79 patients. Materials and Methods Patients with a diagnosis of an unknown primary tumor of the head and neck region were enrolled in this study. Ethics Committee approval for institutional research project was obtained from Post Graduate Institute of Medical Education and Research. Eligible subjects had results of fine‑needle aspiration cytology that proved metastatic carcinoma of the cervical lymph nodes. To rule out a primary occult tumor, all the patients underwent a comprehensive head and neck examination, including fiber optic laryngoscopy and nasopharyngoscopy. Routine imaging included CT and/or MRI with sections from the skull base to the mediastinum. All patients underwent a standard chest X‑ray (posteroanterior and lateral). Panendoscopy with directed biopsies of the tongue base and or nasopharynx was carried out in all patients. In addition, Access this article online Quick Response Code:
Website: www.indianjcancer.com DOI: 10.4103/0019-509X.138240 PMID: *******
142
any suspicious areas (e.g., nodular lesions, erythema or induration) underwent biopsy. In this protocol, all patients underwent total‑body PET CT before panendoscopy. The patients were instructed to fast for 8 h before PET. PET was performed after injection of 14.7 mCi (543.9 MBq) of fluorodeoxyglucose F 18. Oral contrast was also given. Whole‑body images were (base of the skull to mid‑thigh) acquired in 3‑D mode. Reconstruction of the acquired data was performed, so as to obtain fused PET‑CT images in transaxial, coronal and sagittal views. All patients then underwent panendoscopy with directed biopsies of the base of the tongue and nasopharynx and any other suspicious site based on the detailed comprehensive examination. Ipsilateral tonsillectomy was carried out in seven patients (suspected site on CT). The PET CT findings were used to guide the surgeon to perform multiple deep biopsies. The gold standard for comparison of the diagnostic modality (PET CT) remained the final histopathological report. Results Ours was a prospective study carried out in the Department of Otolaryngology between April 2009 and April 2012. Overall, 93 consecutive patients with an unknown primary carcinoma of the head and neck region were entered into this protocol. Two patients did not complete the panendoscopy secondary to diabetic hypoglycemia, and unfitness on account of general condition. Twelve patients showed a suspicious primary site on CT, which could be confirmed on panendoscopy and biopsy leaving 79 patients for analysis. Of the 79 patients, 71 (89.87%) were men and 8 (10.12%) were women. The mean age was 43.7 years (range: 13‑83 years). Results of the neck staging for the study group included N1 in 10 patients, N2a in 5 patients, N2b in 26 patients, N2c in 3 patients, and N3 in 35 patients. Contrast enhanced CT was performed in 51/79 patients from nasopharynx until the diaphragm. Out of 51, 16 patients showed a suspicious primary site but were negative on panendoscopy and biopsy. Rest of the 35 patients failed to Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2
Mohindra, et al.: Positron emission tomography/computed tomography in unknown primary
show a suspicious primary site. Two patients had brought an MRI with them carried from outside both were negative for any suspicious primary site. All 79 patients underwent panendoscopy under general anesthesia. Biopsy turned out to be positive in 28 patients (supraglottis 10 patients, nasopharynx 8, base of tongue 7 patients, thoracic esophagus 2 patients, and pyriform sinus in 1 patient). Biopsy was negative in 21 patients. In rest of the 30 patients there were no suspicious areas on close examination and palpation, which could be biopsied. In 58/79 patients, the occult primary tumor was detected by PET CT (13 in the palatine tonsils and vallecula, 11 at the base of the tongue, 9 each in the larynx and esophagus, 7 in the pyriform sinus, 5 in the nasopharynx, 3 in the parotid gland, and 1 each in the thyroid and lung). Panendoscopy and biopsy could document the tumor in 26 patients. Twenty three were negative on PET‑CT, 2 of these were positive on panendoscopy and biopsy (1 for supraglottis and 1 for pyriform sinus). PET CT guided FNAC was carried out in 6 patients, which was positive in two patient for adenocarcinoma and broncogenic carcinoma lung. Hence, overall 28 patients showed an evidence of a primary tumor. The relative figures for mild moderate and intense uptake have been shown in Table 1. Nearly, 65% of lesions with intense uptake were positive for the primary site. The figures for moderate and mild uptake have been 16.6‑21.4% respectively. On further break up in patients with N1 neck, PET/CT was positive in 6/8 patients and negative in 2/8. These results correlated well with panendoscopy and biopsy. In N2a, 4/5 patients were positive on PET/CT and all 4 were positive on panendoscopy. In N2b out of 32 patients, 22 were positive on PET/CT and 10 were negative. On panendoscopy only in 8/32 a primary could be located, and in 1 patient PET/CT guided FNAC showed a primary in the lung, rest 23 patients Table 1: Correlation between the amount of uptake and detection of primary site Amount of uptake on PET/CT
Total no. of patients
Mild
Panendoscopy and biopsy
14
Positive (%)
Negative (%)
3 (21.4)
11 (78.5)
Moderate
12
2 (16.6)
10 (83.3)
Intense
32
21 (65.6)
11 (34.3)
PET=Positron emission tomography; CT=Computed tomography
failed to show any primary on examination. In N2c, 2/3 patients were positive on PET/CT out of which one was negative and two positive on panendoscopy. In N3 patients, 24 patients out of 31 were PET/CT positive and the rest seven were negative. On panendoscopy, in only 7 patients a primary could be documented, another one was positive for bronchogenic carcinoma on PET/CT guided FNAC, rest 23 patients were negative on panendoscopy. The sensitivity of PET CT in identi fying the primary tumor was 62.4%, the specificity was 64.7%, the positive predictive value was 69.7%, and the negative predictive value was 93%. We had a false positive rate of 33.6% and a false negative rate of 2.6%. The sensitivity, specificity, the positive predictive value, the negative predictive value, false positive rate and false negative rate for N1, N2, and N3 stages of neck secondary have been shown in the Table 2. Discussion The diagnosis and management of an unknown primary carcinoma of the cervical region remains controversial. The goal of the diagnostic evaluation is to identify a small occult primary tumor that is not detectable on results of a careful office examination (including fiber optic examination). Despite more sophisticated imaging studies, including CT and MRI as many as 5% of all head and neck cancers will fall into the unknown primary category. Mendenhall et al.[5] have shown that more than 80% of the primary tumors, when found, will reside in the tonsils and base of the tongue. More recently, several authors have shown that the palatine tonsils can harbor the occult primary tumor in up to 30‑40% of cases, and in 10% of the cases the primary carcinoma can be located in the tonsil contralateral to the neck mass.[6,7] This has led to the recommendation to perform bilateral tonsillectomy in conjunction with the panendoscopy and biopsy of the base of the tongue and nasopharynx. None of the seven tonsillectomies, we performed revealed a tumor. Supraglottic larynx was the most common site of occult primary detected on panendoscopy and biopsy in our series. PET, in contrast to CT and MRI, is a nuclear medicine study that capitalizes on the fact that the neoplastic cells demonstrate preferential uptake of the glucose analogue. This uptake can guide the surgeon to regions for biopsy during the panendoscopy. However, a negative result should still be investigated further by means of panendoscopy with tonsillectomy and blind biopsies. [8] Recently, integrated
Table 2: Calculated values for neck staging Neck stage
No. of patients
Positive on panendoscopy
Positive on PET CT
Positive on PET CT FNAC
Sensitivity of PET CT %
Specificity of PET CT %
PPV of PET CT %
NPV of PET CT %
False positive rate %
False negative rate %
N1 N2a N2b N2c N3
8 5 32 3 31
5 4 9 2 9
6 4 22 2 24
1 1
83.3 100 36.3 100 29.1
50 100 39 100 34.6
8.3 100 36.3 100 29
100 100 90.0 100 75
33.3 0 44.44 0 73.9
0 0 5.8 0 7.6
Total
79
26
58
2
62.4
64.7
69.7
93
33.6
2.6
PET=Positron emission tomography; CT=Computed tomography
Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2
143
Mohindra, et al.: Positron emission tomography/computed tomography in unknown primary
PET/CT showed to be superior to PET in the detection of the primary site of clinically occult tumors in CUP syndrome. In one of the studies, integrated PET/CT had a significantly higher overall detection rate than dedicated PET alone (55.2% vs. 30.8%; P = 0.039) and positive prediction rate (93.3% vs. 46.1%; P = 0.01). [8] Our prospective data demonstrated a tumor detection rate of 73.4% (58/79 patients) on PET CT, and 35.4% (28/79) on panendoscopy. Previous retrospective reports in the literature suggest PET detection rates of 24‑27% for an occult head and neck primary carcinoma.[9,10] Our study, demonstrated a very high detection rate on PET CT, which could not be reproduced on panendoscopy [Figure 1]. Table 2 shows the various calculations for different stages of cervical lymphadenopathy. The majority of our patients fall in group N2b and N3 (32 and 31 patients respectively). In these groups, we have a false positive rate of 60.8% and 73.9% respectively. Such a high false positive rate has been documented only in one of the studies in the past.[11] These patients consisted of clinically large lymphadenopathies i.e., more than 3 and 6 cm in their greatest dimensions. The large size of neck masses probably led to distortion of normal anatomic structures and stasis or delayed clearance of oral contrast, which is given in these patients to demonstrate any mucosal irregularities. This pent up contrast could have been interpreted as an area of increased uptake on PET/CT. The low false positive rates in stages with smaller tumors (N1 (33.3%), N2a (0%) and N2c (0%) further supports this. Noticeable consistent finding, irrespective of neck node status in our study is the negative PET CT. Overall 23 patients failed to demonstrate any suspicious primary site on PET CT and in 20/23 no primary site could be demonstrated on detailed examination and panendoscopy and biopsy. Only in 2 patients a primary could be diagnosed (supraglottis and pyriform sinus in one patient each). False negative rate ranged from 0% to 7.6%.
a
b
c
d
Figure 1: Example of false positive positron emission tomography/ computed tomography (PET/CT). (a) Clinical photograph of the patient depicting a large neck metastasis on the left side. (b) CT scan neck, axial section showing a large heterogeneous neck swelling on the left side. Endolarynx and pyriform sinuses are looking normal. (c) PET/CT showing intense uptake in left pyriform sinus. (d) Endoscopic picture with normal endolarynx and pyriform sinuses
144
Even on follow‑up none of these patients showed an evidence of primary tumor until date. We have considered histopathology as the gold standard. This can be regarded as weakness in our study because we cannot be sure whether biopsy exactly represents the tissue, which showed uptake on PET/CT. we have found that FNAC after PET/CT localization was better (2/6 patients were positive). Once the robotic arm for PET/CT guided FNAC becomes available the results are likely to improve. Conclusion PET/CT is a sensitive investigation than even PET scan for detection of occult primary. However, it has a low specificity rate and a high false positivity rate. These problems can be obviated if the amount of uptake is taken into consideration while taking a biopsy from the lesions. Intensely positive lesions are rarely negative. With larger neck secondary PET/CT is more false positive and multiple biopsies from suspicious sites should be taken rather than solely relying on it. PET/CT guided FNAC should be utilized more frequently than we did in this study. References 1. van Veen SA, Balm AJ, Valdés Olmos RA, Hoefnagel CA, Hilgers FJ, Tan IB, et al. Occult primary tumors of the head and neck: Accuracy of thallium 201 single‑photon emission computed tomography and computed tomography and/or magnetic resonance imaging. Arch Otolaryngol Head Neck Surg 2001;127:406‑11. 2. Nguyen C, Shenouda G, Black MJ, Vuong T, Donath D, Yassa M. Metastatic squamous cell carcinoma to cervical lymph nodes from unknown primary mucosal sites. Head Neck 1994;16:58‑63. 3. Maulard C, Housset M, Brunel P, Huart J, Ucla L, Rozec C, et al. Postoperative radiation therapy for cervical lymph node metastases from an occult squamous cell carcinoma. Laryngoscope 1992;102:884‑90. 4. Harper CS, Mendenhall WM, Parsons JT, Stringer SP, Cassisi NJ, Million RR. Cancer in neck nodes with unknown primary site: Role of mucosal radiotherapy. Head Neck 1990;12:463‑9. 5. Mendenhall WM, Mancuso AA, Parsons JT, Stringer SP, Cassisi NJ. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Head Neck 1998;20:739‑44. 6. Koch WM, Bhatti N, Williams MF, Eisele DW. Oncologic rationale for bilateral tonsillectomy in head and neck squamous cell carcinoma of unknown primary source. Otolaryngol Head Neck Surg 2001;124:331‑3. 7. McQuone SJ, Eisele DW, Lee DJ, Westra WH, Koch WM. Occult tonsillar carcinoma in the unknown primary. Laryngoscope 1998;108:1605‑10. 8. Keller F, Psychogios G, Linke R, Lell M, Kuwert T, Iro H, et al. Carcinoma of unknown primary in the head and neck: Comparison between positron emission tomography (PET) and PET/CT. Head Neck 2011;33:1569‑75. 9. Jungehülsing M, Scheidhauer K, Damm M, Pietrzyk U, Eckel H, Schicha H, et al. 2 F ‑fluoro‑2‑deoxy‑D‑glucose positron emission tomography is a sensitive tool for the detection of occult primary cancer (carcinoma of unknown primary syndrome) with head and neck lymph node manifestation. Otolaryngol Head Neck Surg 2000;123:294‑301. 10. Johansen J, Eigtved A, Buchwald C, Theilgaard SA, Hansen HS. Implication of 18F‑fluoro‑2‑deoxy‑D‑glucose positron emission tomography on management of carcinoma of unknown primary in the head and neck: A Danish cohort study. Laryngoscope 2002;112:2009‑14. 11. Greven KM, Keyes JW Jr, Williams DW 3rd, McGuirt WF, Joyce WT 3rd. Occult primary tumors of the head and neck: Lack of benefit from positron emission tomography imaging with 2‑ F‑18 fluoro‑2‑deoxy‑D‑glucose. Cancer 1999;86:114‑8. How to site this article: Mohindra S, Bhattacharya A, Goshal S, Gupta B. Incremental (?) role of positron emission tomography/ computed tomography in clinically unknown primary patients with neck metastasis. Indian J Cancer 2014;51:142-4. Source of Support: Nil, Conflict of Interest: None declared.
Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2
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Incremental (?) role of positron emission tomography/ computed tomography in clinically unknown primary patients with neck metastasis Mohindra S, Bhattacharya A1, Goshal S2, Gupta B Department of Otolaryngology, Head and Neck Surgery, 1Departments of Nuclear Medicine, and 2Radiation and Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, India Correspondence to: Dr. Satyawati Mohindra, E‑mail: [email protected]
Abstract
OBJECTIVE: To study the incremental role of positron emission tomography (PET)/computed tomography (CT) in the detection of primary site in cases of occult primary with neck metastasis. STUDY DESIGN: A prospective study on 79 consecutive patients. SETTING: A tertiary care otolaryngology and head and neck surgery center. MATERIALS AND METHODS: This prospective study compares the results of PET/CT in 79 patients of occult
primary with neck metastasis with that of detailed comprehensive head and neck examination including imaging and panendoscopy. This study also attempts to define the incremental role of PET/CT in patients of occult primary. RESULTS: The sensitivity of PET/CT in identifying the primary tumor was 62.4%, the specificity was 64.7%, the positive predictive value was 69.7% and the negative predictive value was 93%. We had a false positive rate of 33.6% and a false negative rate of 2.6%. CONCLUSION: PET/CT is a sensitive investigation for detection of occult primary. However, it has a low specificity rate and a high false positivity rate. Due to a high false positive rate, multiple biopsies from suspicious sites should be taken rather than solely relying on PET/CT. PET/CT guided fine needle aspiration cytology should be utilized more frequently than we did in this study. Key Words: Carcinoma of unknown primary site, panendoscopy, positron emission tomography/computed tomography
Introduction Squamous cell carcinoma, metastatic to a cervical lymph node from an unknown primary tumor remains a controversial topic. The overall incidence of unknown primary tumors in the head and neck region ranges from 3% to 7% of all head and neck cancers.[1‑7] The traditional evaluation consists of a careful office examination, including fiber optic laryngoscopy/nasopharyngoscopy, detailed imaging (computed tomography (CT) and/or magnetic resonance imaging (MRI)), and panendoscopy, with directed biopsies of at‑risk sites and tonsillectomy.[1‑3] In the present study, we are presenting our findings of Positron emission tomography/computed tomography (PET/ CT) and their correlation with detailed comprehensive examination including panendoscopy and biopsy in diagnosing an occult primary tumor in 79 patients. Materials and Methods Patients with a diagnosis of an unknown primary tumor of the head and neck region were enrolled in this study. Ethics Committee approval for institutional research project was obtained from Post Graduate Institute of Medical Education and Research. Eligible subjects had results of fine‑needle aspiration cytology that proved metastatic carcinoma of the cervical lymph nodes. To rule out a primary occult tumor, all the patients underwent a comprehensive head and neck examination, including fiber optic laryngoscopy and nasopharyngoscopy. Routine imaging included CT and/or MRI with sections from the skull base to the mediastinum. All patients underwent a standard chest X‑ray (posteroanterior and lateral). Panendoscopy with directed biopsies of the tongue base and or nasopharynx was carried out in all patients. In addition, Access this article online Quick Response Code:
Website: www.indianjcancer.com DOI: 10.4103/0019-509X.138240 PMID: *******
142
any suspicious areas (e.g., nodular lesions, erythema or induration) underwent biopsy. In this protocol, all patients underwent total‑body PET CT before panendoscopy. The patients were instructed to fast for 8 h before PET. PET was performed after injection of 14.7 mCi (543.9 MBq) of fluorodeoxyglucose F 18. Oral contrast was also given. Whole‑body images were (base of the skull to mid‑thigh) acquired in 3‑D mode. Reconstruction of the acquired data was performed, so as to obtain fused PET‑CT images in transaxial, coronal and sagittal views. All patients then underwent panendoscopy with directed biopsies of the base of the tongue and nasopharynx and any other suspicious site based on the detailed comprehensive examination. Ipsilateral tonsillectomy was carried out in seven patients (suspected site on CT). The PET CT findings were used to guide the surgeon to perform multiple deep biopsies. The gold standard for comparison of the diagnostic modality (PET CT) remained the final histopathological report. Results Ours was a prospective study carried out in the Department of Otolaryngology between April 2009 and April 2012. Overall, 93 consecutive patients with an unknown primary carcinoma of the head and neck region were entered into this protocol. Two patients did not complete the panendoscopy secondary to diabetic hypoglycemia, and unfitness on account of general condition. Twelve patients showed a suspicious primary site on CT, which could be confirmed on panendoscopy and biopsy leaving 79 patients for analysis. Of the 79 patients, 71 (89.87%) were men and 8 (10.12%) were women. The mean age was 43.7 years (range: 13‑83 years). Results of the neck staging for the study group included N1 in 10 patients, N2a in 5 patients, N2b in 26 patients, N2c in 3 patients, and N3 in 35 patients. Contrast enhanced CT was performed in 51/79 patients from nasopharynx until the diaphragm. Out of 51, 16 patients showed a suspicious primary site but were negative on panendoscopy and biopsy. Rest of the 35 patients failed to Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2
Mohindra, et al.: Positron emission tomography/computed tomography in unknown primary
show a suspicious primary site. Two patients had brought an MRI with them carried from outside both were negative for any suspicious primary site. All 79 patients underwent panendoscopy under general anesthesia. Biopsy turned out to be positive in 28 patients (supraglottis 10 patients, nasopharynx 8, base of tongue 7 patients, thoracic esophagus 2 patients, and pyriform sinus in 1 patient). Biopsy was negative in 21 patients. In rest of the 30 patients there were no suspicious areas on close examination and palpation, which could be biopsied. In 58/79 patients, the occult primary tumor was detected by PET CT (13 in the palatine tonsils and vallecula, 11 at the base of the tongue, 9 each in the larynx and esophagus, 7 in the pyriform sinus, 5 in the nasopharynx, 3 in the parotid gland, and 1 each in the thyroid and lung). Panendoscopy and biopsy could document the tumor in 26 patients. Twenty three were negative on PET‑CT, 2 of these were positive on panendoscopy and biopsy (1 for supraglottis and 1 for pyriform sinus). PET CT guided FNAC was carried out in 6 patients, which was positive in two patient for adenocarcinoma and broncogenic carcinoma lung. Hence, overall 28 patients showed an evidence of a primary tumor. The relative figures for mild moderate and intense uptake have been shown in Table 1. Nearly, 65% of lesions with intense uptake were positive for the primary site. The figures for moderate and mild uptake have been 16.6‑21.4% respectively. On further break up in patients with N1 neck, PET/CT was positive in 6/8 patients and negative in 2/8. These results correlated well with panendoscopy and biopsy. In N2a, 4/5 patients were positive on PET/CT and all 4 were positive on panendoscopy. In N2b out of 32 patients, 22 were positive on PET/CT and 10 were negative. On panendoscopy only in 8/32 a primary could be located, and in 1 patient PET/CT guided FNAC showed a primary in the lung, rest 23 patients Table 1: Correlation between the amount of uptake and detection of primary site Amount of uptake on PET/CT
Total no. of patients
Mild
Panendoscopy and biopsy
14
Positive (%)
Negative (%)
3 (21.4)
11 (78.5)
Moderate
12
2 (16.6)
10 (83.3)
Intense
32
21 (65.6)
11 (34.3)
PET=Positron emission tomography; CT=Computed tomography
failed to show any primary on examination. In N2c, 2/3 patients were positive on PET/CT out of which one was negative and two positive on panendoscopy. In N3 patients, 24 patients out of 31 were PET/CT positive and the rest seven were negative. On panendoscopy, in only 7 patients a primary could be documented, another one was positive for bronchogenic carcinoma on PET/CT guided FNAC, rest 23 patients were negative on panendoscopy. The sensitivity of PET CT in identi fying the primary tumor was 62.4%, the specificity was 64.7%, the positive predictive value was 69.7%, and the negative predictive value was 93%. We had a false positive rate of 33.6% and a false negative rate of 2.6%. The sensitivity, specificity, the positive predictive value, the negative predictive value, false positive rate and false negative rate for N1, N2, and N3 stages of neck secondary have been shown in the Table 2. Discussion The diagnosis and management of an unknown primary carcinoma of the cervical region remains controversial. The goal of the diagnostic evaluation is to identify a small occult primary tumor that is not detectable on results of a careful office examination (including fiber optic examination). Despite more sophisticated imaging studies, including CT and MRI as many as 5% of all head and neck cancers will fall into the unknown primary category. Mendenhall et al.[5] have shown that more than 80% of the primary tumors, when found, will reside in the tonsils and base of the tongue. More recently, several authors have shown that the palatine tonsils can harbor the occult primary tumor in up to 30‑40% of cases, and in 10% of the cases the primary carcinoma can be located in the tonsil contralateral to the neck mass.[6,7] This has led to the recommendation to perform bilateral tonsillectomy in conjunction with the panendoscopy and biopsy of the base of the tongue and nasopharynx. None of the seven tonsillectomies, we performed revealed a tumor. Supraglottic larynx was the most common site of occult primary detected on panendoscopy and biopsy in our series. PET, in contrast to CT and MRI, is a nuclear medicine study that capitalizes on the fact that the neoplastic cells demonstrate preferential uptake of the glucose analogue. This uptake can guide the surgeon to regions for biopsy during the panendoscopy. However, a negative result should still be investigated further by means of panendoscopy with tonsillectomy and blind biopsies. [8] Recently, integrated
Table 2: Calculated values for neck staging Neck stage
No. of patients
Positive on panendoscopy
Positive on PET CT
Positive on PET CT FNAC
Sensitivity of PET CT %
Specificity of PET CT %
PPV of PET CT %
NPV of PET CT %
False positive rate %
False negative rate %
N1 N2a N2b N2c N3
8 5 32 3 31
5 4 9 2 9
6 4 22 2 24
1 1
83.3 100 36.3 100 29.1
50 100 39 100 34.6
8.3 100 36.3 100 29
100 100 90.0 100 75
33.3 0 44.44 0 73.9
0 0 5.8 0 7.6
Total
79
26
58
2
62.4
64.7
69.7
93
33.6
2.6
PET=Positron emission tomography; CT=Computed tomography
Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2
143
Mohindra, et al.: Positron emission tomography/computed tomography in unknown primary
PET/CT showed to be superior to PET in the detection of the primary site of clinically occult tumors in CUP syndrome. In one of the studies, integrated PET/CT had a significantly higher overall detection rate than dedicated PET alone (55.2% vs. 30.8%; P = 0.039) and positive prediction rate (93.3% vs. 46.1%; P = 0.01). [8] Our prospective data demonstrated a tumor detection rate of 73.4% (58/79 patients) on PET CT, and 35.4% (28/79) on panendoscopy. Previous retrospective reports in the literature suggest PET detection rates of 24‑27% for an occult head and neck primary carcinoma.[9,10] Our study, demonstrated a very high detection rate on PET CT, which could not be reproduced on panendoscopy [Figure 1]. Table 2 shows the various calculations for different stages of cervical lymphadenopathy. The majority of our patients fall in group N2b and N3 (32 and 31 patients respectively). In these groups, we have a false positive rate of 60.8% and 73.9% respectively. Such a high false positive rate has been documented only in one of the studies in the past.[11] These patients consisted of clinically large lymphadenopathies i.e., more than 3 and 6 cm in their greatest dimensions. The large size of neck masses probably led to distortion of normal anatomic structures and stasis or delayed clearance of oral contrast, which is given in these patients to demonstrate any mucosal irregularities. This pent up contrast could have been interpreted as an area of increased uptake on PET/CT. The low false positive rates in stages with smaller tumors (N1 (33.3%), N2a (0%) and N2c (0%) further supports this. Noticeable consistent finding, irrespective of neck node status in our study is the negative PET CT. Overall 23 patients failed to demonstrate any suspicious primary site on PET CT and in 20/23 no primary site could be demonstrated on detailed examination and panendoscopy and biopsy. Only in 2 patients a primary could be diagnosed (supraglottis and pyriform sinus in one patient each). False negative rate ranged from 0% to 7.6%.
a
b
c
d
Figure 1: Example of false positive positron emission tomography/ computed tomography (PET/CT). (a) Clinical photograph of the patient depicting a large neck metastasis on the left side. (b) CT scan neck, axial section showing a large heterogeneous neck swelling on the left side. Endolarynx and pyriform sinuses are looking normal. (c) PET/CT showing intense uptake in left pyriform sinus. (d) Endoscopic picture with normal endolarynx and pyriform sinuses
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Even on follow‑up none of these patients showed an evidence of primary tumor until date. We have considered histopathology as the gold standard. This can be regarded as weakness in our study because we cannot be sure whether biopsy exactly represents the tissue, which showed uptake on PET/CT. we have found that FNAC after PET/CT localization was better (2/6 patients were positive). Once the robotic arm for PET/CT guided FNAC becomes available the results are likely to improve. Conclusion PET/CT is a sensitive investigation than even PET scan for detection of occult primary. However, it has a low specificity rate and a high false positivity rate. These problems can be obviated if the amount of uptake is taken into consideration while taking a biopsy from the lesions. Intensely positive lesions are rarely negative. With larger neck secondary PET/CT is more false positive and multiple biopsies from suspicious sites should be taken rather than solely relying on it. PET/CT guided FNAC should be utilized more frequently than we did in this study. References 1. van Veen SA, Balm AJ, Valdés Olmos RA, Hoefnagel CA, Hilgers FJ, Tan IB, et al. Occult primary tumors of the head and neck: Accuracy of thallium 201 single‑photon emission computed tomography and computed tomography and/or magnetic resonance imaging. Arch Otolaryngol Head Neck Surg 2001;127:406‑11. 2. Nguyen C, Shenouda G, Black MJ, Vuong T, Donath D, Yassa M. Metastatic squamous cell carcinoma to cervical lymph nodes from unknown primary mucosal sites. Head Neck 1994;16:58‑63. 3. Maulard C, Housset M, Brunel P, Huart J, Ucla L, Rozec C, et al. Postoperative radiation therapy for cervical lymph node metastases from an occult squamous cell carcinoma. Laryngoscope 1992;102:884‑90. 4. Harper CS, Mendenhall WM, Parsons JT, Stringer SP, Cassisi NJ, Million RR. Cancer in neck nodes with unknown primary site: Role of mucosal radiotherapy. Head Neck 1990;12:463‑9. 5. Mendenhall WM, Mancuso AA, Parsons JT, Stringer SP, Cassisi NJ. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Head Neck 1998;20:739‑44. 6. Koch WM, Bhatti N, Williams MF, Eisele DW. Oncologic rationale for bilateral tonsillectomy in head and neck squamous cell carcinoma of unknown primary source. Otolaryngol Head Neck Surg 2001;124:331‑3. 7. McQuone SJ, Eisele DW, Lee DJ, Westra WH, Koch WM. Occult tonsillar carcinoma in the unknown primary. Laryngoscope 1998;108:1605‑10. 8. Keller F, Psychogios G, Linke R, Lell M, Kuwert T, Iro H, et al. Carcinoma of unknown primary in the head and neck: Comparison between positron emission tomography (PET) and PET/CT. Head Neck 2011;33:1569‑75. 9. Jungehülsing M, Scheidhauer K, Damm M, Pietrzyk U, Eckel H, Schicha H, et al. 2 F ‑fluoro‑2‑deoxy‑D‑glucose positron emission tomography is a sensitive tool for the detection of occult primary cancer (carcinoma of unknown primary syndrome) with head and neck lymph node manifestation. Otolaryngol Head Neck Surg 2000;123:294‑301. 10. Johansen J, Eigtved A, Buchwald C, Theilgaard SA, Hansen HS. Implication of 18F‑fluoro‑2‑deoxy‑D‑glucose positron emission tomography on management of carcinoma of unknown primary in the head and neck: A Danish cohort study. Laryngoscope 2002;112:2009‑14. 11. Greven KM, Keyes JW Jr, Williams DW 3rd, McGuirt WF, Joyce WT 3rd. Occult primary tumors of the head and neck: Lack of benefit from positron emission tomography imaging with 2‑ F‑18 fluoro‑2‑deoxy‑D‑glucose. Cancer 1999;86:114‑8. How to site this article: Mohindra S, Bhattacharya A, Goshal S, Gupta B. Incremental (?) role of positron emission tomography/ computed tomography in clinically unknown primary patients with neck metastasis. Indian J Cancer 2014;51:142-4. Source of Support: Nil, Conflict of Interest: None declared.
Indian Journal of Cancer | April–June 2014 | Volume 51 | Issue 2
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