1. Introduction

2. Mechanism and Application of PET-CT Scan

2.2. False positive and false negative PET/CT: Causes and Probabilities

2.2.1. Caveats in interpreting PET-CT in individuals with esophageal cancer in Table 2

Table 1. Caveats in the interpretation of PET-CT in patients with Esophageal cancer.

Table 1. Caveats in the interpretation of PET-CT in patients with Esophageal cancer.

Causes of False-Positive Findings	Casuses of False-Negative Findings
Infections/Inflammatroy lesions	Lesion dependent
Radiation-induced liver disease (RILD)	Small tumors (<8-10 mm)
Radiation pneumonitis	Low metabolic activity of the tumor
(Postobstructive) pneumonia/abscess	The presence of a treatment-induced decrease in tumor metabolism
Mycobacterial or fungal infection	Technique limitation
Granulomatous disorders (sarcoidosis, Wegener)	Hyperglycemia
Chronic nonspecific lymphadenitis	Paravenous FDG injection
(Rheumatoid) arthritis	Excessive time between injection and scanning
Occupational exposure (anthracosilicosis)	Low resolution or motion artifacts
Bronchiectasis
Organizing pneumonia
Reflux esophagitis
Iatrogenic causes
Invasive procedure (puncture, biopsy)
Talc pleurodesis
Radiation esophagitis and pneumonitis
Bone marrow expansion postchemotherapy
Colony-stimulating factors
Thymic hyperplasia postchemotherapy
Benign mass lesions
Salivary gland adenoma (Whartin)
Thyroid adenoma
Adrenal adenoma
Colorectal dysplastic polyps
Focal physiological FDG uptake
Gastrointestinal tract
Muscle activity
Brown fat
Unilateral vocal cord activity
Arherosclerotic plaques

2.2.3. Common non-malignant pathological conditions showing increased uptake of FDG before therapy

It has been estimated that benign non-physiological lesions with increased uptake of FDG are encountered in more than 25% of PET-CT studies performed in oncological patients [29,30,31]. Detection of malignant infiltration of lymph nodes is an important requirement in the accurate staging of most cancers, and FDG PET-CT can make a significant contribution to this process by demonstrating tumor involvement in non-pathologically enlarged nodes. However, there are numerous causes of false-positive nodal uptake of FDG. These include inflammatory causes, such as sarcoidosis or sarcoid-like reaction to malignancy, collagen-vascular diseases and anthracosis, and infective causes such as TB, infectious mononucleosis, acquired immunodeficiency syndrome (AIDS), and hepatitis C [32,33].

3. Current Treatment Protocol of Esophageal Cancer Involving True Liver Metastasis and False Liver Metastasis

3.1. Current Standard Procedure of Treatment for Esophageal Cancer in Figure 1

The typical duration between the completion of nCRT and esophagectomy can vary depending on the specific treatment protocol and the patient′s response to nCRT. Generally, a waiting period of about 4 to 8 weeks is considered to allow the patient to recover from the effects of chemoradiation and for any potential downsizing or downstaging of the tumor to occur. This period also allows for the assessment of the patient′s fitness for surgery and for any necessary preoperative planning.

Figure 1. Schematic figure of current gold standard procedure for esophageal cancer treatment with nCRT followed by esophagectomy.

Figure 1. Schematic figure of current gold standard procedure for esophageal cancer treatment with nCRT followed by esophagectomy.

NCRT for locally advanced esophageal cancer is accepted practice prior to surgical resection, as supported by the Chemoradiation for esophageal Cancer Followed by Surgery Study (CROSS) trial [34]. Restaging imaging is recommended to ensure that interval progression of disease or new metastases has not developed which would deem the patient unresectable [35]. In esophageal carcinoma, neo-adjuvant radiotherapy can be administered by three-dimensional (3D) conformal therapy or intensity-modulated therapy (IMRT). The application of IMRT results in a net increase of radiation dose to the primary tumor while limiting damage to surrounding tissue, when compared to conventional anterior–posterior opposing field radiotherapy [13]. At restaging with FDG-PET-CT after chemoradiotherapy, 8% of patients are found to have interval metastases [9,10]. However, inflammatory reactions may induce false-positive results on FDG-PET-CT [36,37]. Radiation-induced liver injury is described in 3–8% of patients who are reassessed with a PET-CT scan after neoadjuvant CRT. Although this phenomenon is relatively rare, awareness of its existence is important to prevent a false positive diagnosis of metastatic disease (Table 3) [14].

3.2. Reports of The Reference of True and False Metastasis for Restaging after nCRT

A retrospective analysis of 112 patients with distal esophageal cancer receiving nCRT and restaging PET-CT found new liver foci in 10/112 patients (9%). Nine of these were determined to have radiation-induced liver injury based on further imaging (n = 6) or biopsy (n = 2) and 1 patient had developed interval metastatic disease based on biopsy. Radiation-induced liver injury was solely seen in the caudate and left hepatic lobes [22]. Another retrospective study of 26 patients evaluated FDG uptake in the liver before and after nCRT for esophageal cancer. New focal FDG uptake in the left liver lobe after chemoradiation was seen in 2 patients (8%) with no increase of FDG in the right part of the liver. In one of these patients, biopsy confirmed radiation injury. On CT, atrophy and decreased attenuation of the irradiated left liver lobe were found in 58% of patients, without signs of liver metastases [13].

3.2.1. Case Reports Series and Cohort Study

The results of the present study indicate that (interval) metastases are detectable in more than 10% of esophageal cancer patients who receive nCRT. With a sensitivity and specificity of 73.9% and 91.3% respectively, PET-CT is an accurate tool to identify these cases. Currently an unequivocal restaging protocol is still absent, even though previous reports on this topic have shown incidence rates of interval metastases between 8%-17% [8,38,39,40,41]. Presently, two reports have addressed the use of PET-CT in detection of interval metastases as a primary topic. In a recent study by Blom et al. 4 cases of interval metastases were detected in a consecutive series of 50 neoadjuvantly treated patients (8%) [8]. Restaging PET-CT took place 6 weeks after completion of neoadjuvant therapy that consisted of 5-FU, cisplatinum and 50.4 Gy radiotherapy. A false-positive rate of 2% was reported in this cohort and in 1 out of 46 patients (2.2%) metastatic disease was observed intraoperatively [8]. In another study on restaging PET-CT the records of 85 patients treated either with induction chemotherapy followed by concurrent chemoradiotherapy or with concurrent chemoradiotherapy only were retrospectively reviewed [38]. In all patients who underwent a prenCRT PET-CT, the post-nCRT PET-CT identified metastatic disease in only 3.9% of patients. The PPV of the post-nCRT PET-CT for interval metastases was low at 15.6% (10/64). Regardless of the cause for this observation, post-nCRT PET-CT findings pertaining to the primary site did not seem to be related to the development of metastatic disease [21].

Findings in the current study demonstrate that 18F-FDG PET-CT restaging after nCRT detects interval metastases in 8% of esophageal cancer patients, with a patient-based sensitivity and specificity of 75% and 94%, respectively. The incidence of interval metastasis in the current study is consistent with the results of previous reports [8,9,10]. Yet, little is known about what patients are at risk for developing interval metastases, and the small number of patients in the previous mentioned studies precludes assessment of predictors for interval metastasis after neoadjuvant therapy [8,9,10,42]. the false positive rate of 6% during 18F-FDG PET-CT restaging was substantial, with the lungs and liver as the most frequent affected sites. This confirms previous findings in literature, with reported false positive rates ranging between 0% and 10% [8,43] and liver and lung as the most commonly affected sites [21,22]. Previous studies evaluating new FDG-avid hepatic lesions within the presumed radiation field of patients with esophageal cancer demonstrated that these lesions generally reflect radiation-induced liver disease rather than metastatic disease [13,14,22]. ¹⁸F-FDG PET-CT restaging detects true distant interval metastases in 8.3% of patients after chemoradiotherapy for esophageal cancer [11].

Table 4. Review of current case reports by Demey et al., 2017 [44].

Table 4. Review of current case reports by Demey et al., 2017 [44].

Table 4. Overview of current case reports.
Author (Year)	Age	TNM-pathology	Chemotherapy	Radiotherapy dose-Modality	Delay CRT to PET	PET	CT	MR	Biopsy	Liver Tests	Follow-up
Iyer et al.[2] (2007)	63	NA-adeno	NA	50.4 Gy - 3D conformal	6w	Nodular	Well-defined, low attenuation	-	Perop	AP↑	NA
Iyer et al.[2] (2007)	NA	NA-NA	NA	50.4 Gy - 3D conformal	6w	Nodular	Well-defined, low attenuation	-	NA	AP↑	NA
Nakahara et al.[3] (2008)	50	uT3N M2 1(bone) - NA	Docetaxel weekly (20mg/m2)	46 Gy + boost 14 Gy - AP-RT	4w	Wedge-shaped	Well-defined, low attenuation + band-likelesion (≈zoneof < 40Gy)	-	NA	AP↑	4months
DeLappe et al.[5] (2009)	61	uT3N M1 0 - NA	4 cycli (apirubicine þ oxaliplatin + capcetabine) + 3 cycli (docetaxel þ irinotecan) + concurrent 5-FU	50.4 Gy - IMRT	5w	Ill-defined nodular	Patchy defined, mixed attenuation, heterogeneous enhancement of left liver	-	CT-guided + perop	NA	NA
Wong et al.[6] (2012)	58	NA - NA	NA	50.4 Gy - AP-RT	6w	Nodular with linear distribution	Patchy-defined, low attenuation in segment 2 and 3	-	NA	Normal	NA
Rabe et al.[8] (2015)	53	uT3N M1 0 - squamous	5 cycli (carboplatin + paclitaxel)	50.4 Gy - 3D conformal	2w	Nodular	Well-defined, low attenation	Hyperintens T2-weighted	Perop	AP↑	12months
Current case (2015)	42	uT2N M1 0 - adeno	Concurrent Oxaliplatin + 5-FU	45 Gy - 3D conformal	4w	Nodular	Patchy-defined, low attenuationin segment 2	Hyperintens T2-weighted	Perop	Normal	18months

NA: data not available; adeno: adenocarcinoma; Gy: Gray; w: weeks; AP ": elevated alkaline phosphatase levels; AP-RT: conventional anterior–posterior radiotherapy; IMRT: intensity-modulated radiation therapy; 5-FU: 5-fluorouracil.

4. RILD Inducing False PET-CT

4.4. Incidence of RILD

In this systematic search of the reports, they found an incidence of RILI of 3%. Other retrospective reports found higher incidences (8%) of RILI when all scans were reassessed for focal uptake in the left liver lobe [13,22]. A possible explanation for the lower incidence in this study is that some cases of RILI may have been missed by our systematic search. The risk of RILD increases strongly with the mean liver dose and the irradiated liver volume. After a mean liver dose <31 Gy, RILD is unlikely [51,52]. In distal esophageal cancer, mean liver radiation doses are generally below 30 Gy. However, the radiation target volume often includes parts of the liver, which may receive doses up to 40–50 Gy. This can induce localized radiation induced injury in the liver without clinical symptoms [5,53,54]. In a study involving 205 patients undergoing nCRT, 6 cases with localized increased FDG uptake in the liver were identified post-nCRT. These cases were not associated with liver metastases. The incidence of RILD at the institute was 3%, and literature describes it as about 8% of patients at the time of restaging [14].

4.4.1. If Tumor Cell Type Pose Different Risk Factors for RILD: Squamous-Cell Carcinoma (SCC) and Adeno Carcinoma in Table 4

Distal esophageal cancers, including Squamous-Cell Carcinoma (SCC) and Adenocarcinoma, are associated with distinct risk factors. The table highlights alcohol consumption as a major risk factor for SCC. This suggests that patients with SCC might have a higher incidence of liver dysfunction compared to those with Adenocarcinoma, potentially increasing the likelihood of Radiation-Induced Liver Disease (RILD). However, this area remains underexplored in medical literature, indicating a need for additional research to understand these correlations better.

Table 4. Risk factors for esophageal cancer* from Enzinger et al., 2003 [55]).

Table 4. Risk factors for esophageal cancer* from Enzinger et al., 2003 [55]).

Risk Factor	Squamous-Cell Carcinoma	Adenocarcinoma
Tobacco use	+++	++
Alcohol use	+++	-
Barrett’s esophagus	-	++++
Weekly reflux symptoms	-	+++
Obesity	-	++
Poverty	++	-
Achalasia	+++	-
Caustic injury to the esophagus	++++	-
Nonepidermolytic palmoplantar keratoderma (tylosis)	++++	-
Plummer–Vinson syndrome	++++	-
History of head and neck cancer	++++	-
Frequent consumption of extremely hot beverages	+	-

*A single plus sign indicates an increase in the risk by a factor of less than two, two plus signs an increase by a factor of two to four, three plus signs an increase by a factor of more than four to eight, and four plus signs an increase by a factor of more than eight. The plus–minus sign indicates that conflicting results have been reported, and the dashes indicate that there is no proven risk.

4.4.2. Gender, age, race

While it is known that esophageal cancer predominantly affects males, the specific sensitivities of different genders, ages, and ethnicities to Radiation-Induced Liver Disease (RILD) remain unclarified in existing literature. Currently, there is a lack of detailed statistical analysis on these aspects, highlighting a significant area for future research attention.

4.7. Confirmation of RILD- Challenges in Characterizing RILD with Imaging

Differentiating RILD from metastatic disease using imaging techniques like PET/CT and MRI is fraught with challenges. Characteristic imaging features, though evolving, provide critical insights into the nature and extent of radiation-induced damage [45,53,59,60,61,62,63]. No specific information was found in the provided documents regarding Sono, CT, MRI, PET/CT liver sensitivity, or liver biopsy techniques.

4.7.1. Sono of Liver and Its Sensitivity

Ultrasonography has been a mainstay for anatomical imaging of the liver. With the introduction of new techniques like elastography and quantitative ultrasound parameters, the capability to assess liver tissue properties beyond echogenicity has been enhanced. This includes the measurement of acoustic parameters to characterize tissue microstructure, which is promising for monitoring the severity of hepatic steatosis in chronic liver diseases. These advancements in ultrasound technology are significant for improving the sensitivity and specificity of liver disease diagnosis, particularly in the context of RILD [64]. Sonography of the liver reveals a hypoechoic appearance over the caudate lobe (Figure 2A).

4.7.2. CT Scan and Its Sensitivity

Noninvasive imaging techniques for RILD characterization are evolving [59]. Post-radiotherapy CT scans of irradiated liver areas show reversible, distinct regions of reduced enhancement, possibly indicating increased water or fat [53,60,61]. Radiation-induced veno-occlusive disease can cause increased enhancement due to augmented arterial flow or delayed contrast clearance [62]. RILD may present as hypo or hyperattenuated non-anatomic areas [63], with CT typically showing sharp, straight margins matching the radiation portals [13]. In contrast, metastatic lesions appear more mass-like and rounded on CT [13]. The CT-graphic appearance of acute RH has been described as areas of low attenuation with sharp linear borders on noncontrast CT, which can occur in patients who receive more than 30–45 Gy [5,12,13,65]. Increased enhancement on contrast CT can be seen in the irradiated liver because increased arterial flow or delayed contrast clearance for radiation-induced veno-occlusive disease [12]. The contrast CT scan shows decreased enhancement in S1 of the liver (Figure 2B). Contrast-enhanced CT shows low attenuation due to edema at the irradiated area of the liver. Current advanced radiotherapy techniques using multiple beams from different angles have a less sharp dose gradient, with a relatively small volume of normal tissue close to the target volume receiving a relatively high dose, and a larger volume of surrounding tissue receiving lower doses. Liver injury is generally confined to the area irradiated to a high dose, resulting in focal areas of edema and lower attenuation on CT [66].

4.7.3. MRI and Its Sensitivity

MRI post-liver radiation reveals decreased T1 signal intensity, increased T2 intensity, and heightened proton spectroscopic imaging signals in irradiated lobes, suggesting increased water content [61]. MRI’s high resolution and soft tissue contrast are ideal for organ differentiation [67]. Clinical studies use MRI to track radiation damage in the liver [68], myocardium [69,70], and bone marrow [71,72]. The MR of the liver was performed five weeks after radiation therapy, and showed a hypointense signal on T1-weighted images and strongly hyperintense signal on T2-weighted images and facilitated diffusion at DWI-images. Additionally, we saw heterogeneous alterations on T2-weighted and DWI-images of the entire left liver lobe, which was attributed to mild RH of this entire left liver lobe and central acute RH in segment 2 [44]. MRI T1-weighted pictures of the liver reveal a low signal intensity over the caudate lobe (Figure 2C). MRI T2-weighted pictures of the liver indicate a strong signal intensity over the caudate lobe (Figure 2D). On magnetic resonance imaging (MRI), liver areas that received a high radiation dose generally have low signal intensity on T1-weighted images and high signal intensity on T2-weighted images, as a result of edema [37,66].

Figure 2. (A) Sonography of the liver reveals a hypoechoic appearance over the caudate lobe. (B) The contrast CT scan shows decreased enhancement in S1 of the liver. (C) MRI T1-weighted pictures of the liver reveal a low signal intensity over the caudate lobe. (D) MRI T2-weighted pictures of the liver indicate a strong signal intensity over the caudate lobe.

Figure 2. (A) Sonography of the liver reveals a hypoechoic appearance over the caudate lobe. (B) The contrast CT scan shows decreased enhancement in S1 of the liver. (C) MRI T1-weighted pictures of the liver reveal a low signal intensity over the caudate lobe. (D) MRI T2-weighted pictures of the liver indicate a strong signal intensity over the caudate lobe.

4.7.4. SUVmax value of PET/CT Serve as Indicator of RILD?

Current studies lack comparisons of PET-CT SUVmax between radiation injury and metastatic lesions, but RILD SUVmax ranges around 4~9/h, while metastatic lesions often exceed 10/h, indicating metastasis. New hepatic FDG foci during esophageal cancer neoadjuvant chemoradiation typically indicate radiation-induced liver disease, with increased FDG uptake by active leukocytes due to inflammation [45]. This suggests a low metastasis likelihood [22]. Foci location within the radiation field, typically the left and caudate lobes, is crucial [22]. Prior to nCRT, the esophageal tumor exhibits high FDG uptake (9.7×5.6 cm, SUVmax: 29.3/1h) (red circles). There are no active lesions in liver segment I before nCRT (red arrows) (Figure 3). Shows esophageal tumor reduction after six weeks of neo-adjuvant chemo-radiotherapy (2.1×1.6 cm, SUVmax: 7.7/1h, highlighted in yellow circles) (Figure 4). Six weeks following neo-adjuvant chemo-radiotherapy, a new FDG-avid lesion was found in liver segment I (3.5×1.5 cm, SUVmax: 4.2/1h, indicated by yellow arrows) (Figure 5).

4.7.5. Biopsy for Diagnosis of Liver- Options by Sono-guiding, CT-guiding, Open biopsy or Clinical Observation

4.7.5.1. Pathology of RILD

RILD is a veno-occlusive disease involving the central veins [49]. Radiation-induced endothelial damage results in platelet activation, fibrin deposition, congestion of vessels, hepatic stellate cell activation, and blood flow obstruction, causing loss of hepatocytes, fibrosis, and even necrosis [49].

4.7.5.2. Gross Appearance and Microscopy of RILD

The gross appearance and microscopic characteristics of RILD indicated significant pathological changes. The dark red, soft tissue, and blood infiltration in the caudate lobe suggest acute damage, likely due to the effects of radiation (Figure 6A-B). This is further supported by the microscopic findings of congestion with attenuated hepatic cords and spaces filled with erythrocytes (Figure 6C-D). These features typically point to a disruption in the normal liver architecture, indicating severe damage to the liver parenchyma, which could be attributed to the vascular and cellular effects of radiation exposure. This kind of damage often leads to impaired liver function due to the disruption of normal blood flow and cell death. The specific mention of the caudate lobe might also indicate a localized effect of radiation, which could be relevant for understanding the distribution and intensity of the radiation exposure.

5. Overview of Literature Review

6. Conclusions and Future Prospective

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