Utility of [18F]FDG- PET/CT in Initial Staging and Management of Patients with Esophageal Carcinoma: A Tertiary Care Center Experience

Introduction

Esophageal cancer is the seventh most common cancer worldwide, and sixth among cancer-related deaths. In India, it is the 5^th most commonly diagnosed cancer with incidence of 4.5% of all cancer cases and accounts for 6.9% of cancer-related mortality.[1,2] Because of early dissemination, esophageal carcinoma is often diagnosed either during locally advanced or metastatic disease. Long-time survival depends on the stage at the time of diagnosis. Despite best care, it has a poor prognosis with overall 5-year survival ranging from 5% to 30%.[3,4]

Esophageal carcinoma requires a multimodality approach to treatment, surgery and radiotherapy are preferred modalities of treatment for initial stages, and chemotherapy is considered as treatment of choice for advanced stages.[5,6]

Due to the development of neoadjuvant chemotherapy and radiation therapy protocols, accurate initial staging of the disease is necessary to determine the mode of treatment and selection of patients who can potentially benefit from local treatment, while sparing those patients with metastatic disease from undergoing intensive multimodality local therapy.[7]

For staging of esophageal cancer, different imaging techniques are being used, these include endoscopic ultrasound (EUS), preferred for the evaluation of local invasion, and contrast-enhanced computed tomography (CECT) to detect nodal involvement.[5] The current study is planned to see the utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) in the initial staging and management of patients with esophageal carcinoma.

Materials and Methods

Histopathologically proven, treatment-naive 74 esophageal carcinoma patients (42 males; 32 females with mean age 59.4 ± 11.4 years; range of 35–86 years) referred to our tertiary care center from March 2020 to July 2023 were included in this prospective study after obtaining approval from the Institute’s Thesis Protocol Approval Committee (TPAC No: 542) and Institute’s Ethics Committee (IEC No: 1023) and written consent from the patient. All patients underwent contrast-enhanced CT of the chest and abdomen. Twenty-eight patients had scans performed outside our institution; the hardcopy images were available and of acceptable quality. The duration between CECT chest and abdomen and FDG PET/CT was <2 weeks. After overnight or at least 6 h fasting, in patients with blood glucose levels between 110 ± 39 mg/dL with a range of 74–180 mg/dL, 222–362 MBq (6–9.8 mCi) of ¹⁸F-FDG (obtained from M/s HCG, Chennai) was administered intravenously. Imaging was performed 60 min after ¹⁸F-FDG injection in a supine position with arms elevated over the head from skull to mid-thigh using Biograph-6, PET/CT scanner supplied by SIEMENS. For data acquisition, the CT component was operated at effective X-ray tube current, with Matrix size 256 × 256, effective current 320 mAs, 80–130 kVp, and Slice thickness – 3 mm. Immediately after the CT examination, the process continued with a full ring, dedicated PET System using a three-dimensional PET acquisition protocol, in seven-bed positions (2 min/bed position) head to mid-thigh of the same axial length. Both CT and PET scans were obtained in normal tidal breathing. PET, CT and fused PET/CT images was opened simultaneously and reviewed on SYNGO work station (SIEMENS) by Nuclear Medicine Physician and Radiologist. The interpretation of CECT and ¹⁸F-FDG PET/CT scans for the tumor was done by estimation of esophageal wall thickness (more than 5 mm), reference standard for lymph nodes with short axis diameter >10 mm with FDG uptake >(mediastinal blood pool [MBP]) and for distant metastases focal lesions with FDG uptake >MBP.

Results

Baseline characteristics of 74 patients (42 males and 32 females with mean age 59.4 ± 11.4; Range 35–86 years) who had ¹⁸F-FDG PET/CT and CECT chest and abdomen as initial workup in the study period are outlined in Table 1. Squamous cell carcinoma (SCC) represented 58/74 (78.4%) and adenocarcinoma (AC) represented 16/74 (21.6%) patients. SUV_max of primary tumor based on histopathological groups and nodal and distant metastases is outlined in Tables 2 and 3.

As per AJCC manual 8^th edition, any lymph node not in continuity in the esophagus is considered as nonregional lymph nodes and includes as sites of distant metastases (M1).[8] Distant nodal and organ metastases were seen in 30/74 (40.5%). Distant solid organ metastases were seen in 16/74 (21.6%) patients, including liver in 8/74 (10.8%), bone in 8/74 (10.8%), lung in 4/74 (5.4%), and brain in 1/74 (1.3%).

¹⁸F-FDG PET/CT identified otherwise occult and distant metastatic lesions and led to upstaging of disease in 10/74 (13.5%) patients, 7/74 (9.4%) from Stage IVA to IVB, one each from Stage II to Stage III, Stage II to IVB and one from Stage III to IVB [Tables 4 and 5].

Synchronous malignancy was detected incidentally in 3/74 (4.0%) patients, a small round cell tumor of the left thigh in 1/74 (1.3%), and invasive duct cell carcinoma in the right breast in 1/74 (1.3%) and carcinoma base of tongue in 1/74 (1.3%) patient.

¹⁸F-FDG PET/CT whole body survey detected additional skeletal lesions in 4/74 (5.4%) patients with distant organ involvement. These additional lesions were localized in the skull, pelvic bones, femur, and brain.

Discussion

Esophageal carcinoma is one of the common gastrointestinal malignancies and one of the leading causes of cancer-related mortality worldwide. Our study findings show the incidence of male-to-female ratio of 1.3:1, with the mean age of patients being 59.4 ± 11.4 years ranging between 35 and 86 years. Findings showed lesser male predominance as compared to the global data, but are consistent with the studies done in India.[1,9,10]

The current study findings are consistent with literature, with SCC involving 58/74 (78.4%) and AC in 16/74 (21.6%) patients with male preponderance among both subtypes and most common involvement is of middle third of esophagus in 31/74 (41.9) followed by lower third of esophagus in 20/74 (27%), upper esophagus in 17/74 (23%) and gastroesophageal junction in 6/74 (8.1%) patients.[111213]

Also, by the time of diagnosis, most of the patients has locally advanced disease with T4 lesion in 26/74 (35.1%) patients and T3 lesion in 32/74 (43.2%) patients.

The mean of SUV_max of primary tumor also increased (11.2 > 12.3 > 14.5; P = 0.09) as the disease progressed from localized tumor to nodal metastasis and to distant nodal and organ metastases. Similar findings were seen in studies conducted by Kato et al. in 2001 from Japan and Tan et al. from Malaysia, where progressively increased mean of SUV_max. The primary lesions were seen from localized tumors to nodal metastasis and to distant metastasis.[14,15] The variation in SUV_max also depends on the histological subtype of the primary lesion. Al-Taan et al. from the United Kingdom in 2014, reported that SCC shows higher SUV_max than AC.[16] Our study had a similar observation with the mean of SUV_max of SCC (15.2 ± 5.2) is greater than AC (10.6 ± 4.4) subtype with a significant P = 0.03. The SUV_max of primary tumor were different between different stages and a higher SUV_max was associated with a higher pathological T-stage similar to the study done by Huang et al.[17]

Along with local infiltration, due to late presentation, patients also tend to have nodal and distant organ involvement. About 20%–30% will have distant metastasis by the time of diagnosis.[18,19] In our study, regional lymph node involvement was seen in 28/74 (37.8%) and nonregional lymph nodes in 18/74 (24.3%) patients. Furthermore, distant organ involvement was seen in 16/74 (21.6%) patients. In a study done by Kumar et al. in 2011 from New Delhi, India, among 28 patients for staging (9/28) and restaging (19/28), 9/28 (32.1%) patients had regional lymph node metastases.[20] Gamal in 2019 also had similar findings in their study conducted among 19 patients, where 8/19 (42.1%) patients had lymph node metastases.[21]

Distant organ involvement frequently seen in esophageal carcinoma includes liver, lung, and bones.[18] Brain metastasis is rarely seen with reported rates ranging from 0.3% to 3.8%. Gamal reported organ metastases in liver, lung, and bone.[21] A study done by Xiao et al. reported brain metastasis in 66 (0.34%) of 19,225 patients with esophageal carcinoma.[22] In our study, distant organ metastases were seen in 16/74 (21.6%) patients. The most commonly involved organ in the present study is liver 8/74 (10.8%) patients. The distant organ involvement seen, in descending order include liver 8/74 (10.8%), bone 8/74 (10.8%), lung 4/74 (5.4%), and brain 1/74 (1.3%). Results were concordant with Kumar et al.’s study where, the organs involved were liver 5/28 (17.8%), lung 5/28 (17.8%), bone 2/28 (7.1%), and spleen 1/28 (3.5%).[20]

In literature, esophageal carcinoma patients reported advantage of PET/CT whole-body survey by localizing additional sites of metastases ranging from 15% to 40%. A study done by Purandare et al. in 2014 from Mumbai reported ¹⁸F-FDG PET/CT additionally detected metastatic sites in 25/156 (16.0%) patients over CECT findings.[23] Kumar et al.’s study showed whole-body ¹⁸F-FDG PET/CT detected distant nodal and organ metastases in 23/28 (82.1%) whereas CECT documented in 16/28 (57.1%) patients.[20] Similarly, Gamal study reported ¹⁸F-FDG PET/CT detected distant nodal and organ metastases in 17/19 (89.4%) while CECT identified in 11/19 (57.8%) patients.[21] In the present study, there is agreement between ¹⁸F-FDG PET/CT over CECT chest and abdomen in the evaluation of regional lymph nodes (28/74 (37.8%) versus 27/74 (36.4%); κ – 0.96), nonregional lymph nodes (18/74 (24.3%) v15/74 (20.2%), κ −0.74) and distant organ involvement (16/74 [21.6%] vs. 13/74 [17.5%], κ −0.87) [Table 4].

In one patient, ¹⁸F-FDG PET/CT detected left gastric lymph nodal involvement with low FDG uptake (SUV_max: 2.8) which was missed by CECT, later postoperative HPE confirmed metastases. In three patients, CECT identified regional lymph nodes with no evidence of distant nodal involvement, but ¹⁸F-FDG PET/CT indicated the involvement of supraclavicular and level II cervical lymph nodes (SUV_max: 7.9). Whole-body survey of ¹⁸F-FDG PET/CT detected nodal positivity at distant sites in the body (cervical, pelvic, and inguinal lymph nodes) which are not available with CECT, as it is a limited area imaging modality.

¹⁸F-FDG PET/CT whole-body survey detected an additional 4/74 (5.4) patients with distant organ involvement. These additional lesions were localized in skull, pelvic bones, femur, and brain. Skip lesions were also observed in 2/74 (2.7%) patients.

The presence of synchronous malignancy is a rarity and needs aggressive management. In 2010, Singh et al. from Haldwani, India reported a case of the synchronous esophagus and breast malignancy.[24] In 2015, Akiyama et al. from Japan reported a case of esophageal malignancy with synchronous invasive carcinoma right breast and left axillary lymph nodal involvement.[25] In our study, ¹⁸F-FDG PET/CT detected synchronous malignancies in 3/74 (4%) patients, these three includes, carcinoma breast, round cell sarcoma and carcinoma base of tongue respectively. Figure 1, shows a case of Ca GE junction with synchronous breast malignancy Histopathologically diagnosed as invasive duct cell carcinoma of right breast, and Figure 2, shows Ca cervical part of esophagus with synchronous round cell sarcoma of left femur mid region respectively. Figure 3, shows a case of carcinoma GE junction, skip lesions along with lung, liver and bone metastasis. A study done by Kumagai et al. in 2001 from Japan reported synchronous and metachronous malignancies of esophageal cancer can involve any part of the body such as head and neck, stomach, colon, lung, breast, urinary bladder, kidney, gall bladder, prostate, liver, and malignant lymphoma.[26]

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Figure 1 Image of a 72 year old female patient with Carcinoma gastroesophageal junction with nodal and liver metastases and synchronous breast malignancy: ¹⁸F-FDGPET/CT (a) MIP, (b) axial plain CT,(c) fused PET/CT images showing increased ¹⁸F-FDG uptake in gastroesophageal junction, coeliac axis lymph node (black arrows), right breast (red arrow), right axillary lymphadenopathy (d,e) (blue arrow) and hypodense lesion in liver(green arrow). HPE confirmed invasive duct cell cancer of right breast

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Figure 2 Image of 55 year old female patient with primary tumour of cervical oesophagus with synchronous small round cell tumour of thigh: ¹⁸F-FDGPET/CT (a) MIP, (b) axial plain CT and (c) fused PET/CT images showing focal increased ¹⁸F-FDG uptake IN cervical oesophagus with SUVmax 11.9 (black arrow). Sagittal (d) plain CT and (e) fused PET/CT images showing FDG uptake in lytic destructive lesion with soft tissue component involving diaphysis of left femur. HPE from left thigh confirms sarcoma

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Figure 3 Image of a 74 year old male patient of locally advanced carcinoma of esophagus GE junction with skip lesion, PET CT also localized lung and liver metastases: ¹⁸F-FDG PET/CT (a) PET, MIP image, (b) sagittal, plain CT and (c) sagittal, fused PET/CT images showing gastroesophageal junction lesion with increased ¹⁸F-FDG uptake involving lower thoracic oesophagus skip lesions, SUVmax 16.6 (black arrow) and in bilateral lung parenchymal and pleural based nodules and (green arrows)

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Overall, among 74 patients of esophageal carcinoma, ¹⁸F-FDG PET/CT identified otherwise occult and distant metastatic lesions and led to upstaging of disease in 10/74 (13.5%) patients, 7/74 (9.4%) from Stage IVA to IVB, one each from Stage II to Stage III, Stage II to IVB and one from Stage III to IVB. In our study 66/74 (89.1%) patients underwent chemoradiation, 2/74 (2.7%) patients underwent surgical treatment and ¹⁸F-FDG PET/CT contributed to change in treatment from neoadjuvant chemotherapy to intent of palliative management in 6/74 (8.1%) patients.

Although ¹⁸F FDG PET/CT and CECT chest and abdomen showed similar accuracy in the detection of regional lymph nodal metastases in staging of esophageal carcinoma, ¹⁸F FDG PET/CT ascertain its importance in routine evaluation for effective TNM staging by detecting occult and distant metastases, synchronous malignancies and helpful in determining treatment strategy.

Conclusion

¹⁸F-FDG PET/CT metabolic parameters help in identifying metastatic involvement in morphologically equivocal and clinically suspicious lesions in carcinoma esophagus patients. Being a whole-body imaging modality ¹⁸F-FDG PET/CT has inbuilt advantage to detect occult, distant metastases and synchronous malignancies for effective staging and improves plan of clinical management.