Detection of Primary Hepatocellular Carcinoma on ¹⁸F-Fluorodeoxyglucose Positron Emission Tomography-computed Tomography

INTRODUCTION

Hepatocellular carcinoma (HCC), sometimes referred to as hepatoma, is the predominant histopathological subtype of primary liver cancer originating from hepatocytes. Additionally, it ranks as the third most prevalent malignancy contributing to death associated with cancer on a global scale. Hepatocellular carcinoma is known to be the fifth most frequently diagnosed malignancy of the males while among females, it is ranked as the seventh most common malignancy.¹ Hepatocellular carcinoma often exhibits intrahepatic and extrahepatic metastasis due to the liver’s extensive dual blood supply. Cholangiocarcinoma and hepatocellular carcinoma are the principal categories of primary liver malignancies.^2,3 Hepatocellular carcinoma consistently represents a significant proportion, ranging from 70 to 80% of reported liver cancer incidences annually across the globe. Moreover, this malignancy is responsible for a staggering number of fatalities, resulting in over 600,000 deaths.^4,5 According to the data provided by Globocan, HCC is the eighth most frequent malignancy in Pakistan.⁶ Hepatocellular carcinoma prevalence varies between 3.7 and 16% per 100,000 individuals. In Pakistan, viral hepatitis is the most prevailing cause of HCC, which is strongly associated with the development of liver cirrhosis. Hepatitis C virus (HCV) is identified as the predominant etiological factor in 60–80% of HCC cases in local population.^7,8 HCC may be broadly classified into four grades determined by the degree of differentiation: grade I (well-differentiated), grade II (moderate differentiated), grade III (poor differentiated), and grade IV (undifferentiated). The measurement of serum alpha protein (AFP) levels is often used for the purpose of HCC detection. The AFP test, however, has a 25–72% reduced sensitivity for the identification of HCC.^9,10 Hepatocellular carcinoma does not require histological confirmation, in contrast to other solid tumors. An average subclinical lifespan of 3.2 years is observed in HCC.¹¹ During this particular period, imaging plays a pivotal role for noninvasive diagnosis of HCC. Imaging is also utilized for the management of HCC, evaluation of treatment efficacy, and differentiation between HCC and various benign nodules commonly observed in cirrhosis, benign lesions or pseudolesions, intrahepatic cholangiocarcinoma, and liver metastases.¹² Two distinct clinical scenarios are often present while making the diagnosis of HCC. Malignant tumors in individuals without chronic hepatic disease may exhibit substantial size and may exhibit vascular invasion, while also potentially lacking adherence to normal monitoring protocols. The noninvasive diagnosis of higher risk individuals can only be achieved by imaging techniques that include recognizable traits. The observed features on CT and MRI scans include arterial enhancement, followed by washout during the delayed or portal venous phase.¹³ The MRI and CT sensitivity is reported to be 100% for the detection of substantial lesions. However, for lesions ranging from 1 to 2 cm in size, the sensitivity declines to around 40–75% for CT and 45–80% for MRI.^14,15 Ultrasonographic identification of HCC is more challenging in individuals with chronic hepatic disease because cirrhotic liver showed the area with fatty infiltration and nodular re-growth. There are some restrictions in the pathological analysis of HCC that CT and MRI do not reveal. PET-CT using ¹⁸F-flourodeoxyglucose (FDG) radiotracer is noninvasive and effective nuclear medicine imaging modality that gives structural and functional information at cellular level for the detection of diversity of tumor including HCC. ¹⁸F-flourodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) evaluation is dependent on the metabolism of the tumor and it has the advantage of whole body examination. Hence, we can detect intrahepatic and extrahepatic metastasis in a single scan. By using FDG PET-CT, the diagnosis of HCC, histological HCC distinction, and therapy impact monitoring. The detection of primary HCC remains challenging because to the elevated levels of FDG activity seen in normal liver tissue (with an average mean of 1.55) and the liver’s substantial non-dietary glucose production rate of 2.0 mg/kg/min.⁹ This prospective study was conducted to detect sensitivity of primary HCC by using FDG PET-CT scan. Currently, there exist a scarcity of data regarding the utilization of FDG PET-CT for HCC detection. Additionally, application of FDG PET-CT in cancer diagnosis and staging is relatively uncommon because of limited availability, and thus restricted research has been published using this modality.

MATERIALS AND METHODS

RESULTS

The present research included the participation of 51 cases of primary HCC who underwent with ¹⁸F-FDG PET-CT scan. The distribution of patient gender was as follows: 10.6% of the patients were female (n = 11), while 78.4% were male (n = 40). The group varied between 32 till 70 years in age, with a mean of 51.8 ± 10.4 years (Table 1; Fig. 1). Within the cohort of patients, it was determined that 90.2% of individuals had liver lesions that were confirmed by CT scans, while 1% of cases were validated using MRI, and 7.8% were verified through histopathological examination.

DISCUSSION

The prevalence of HCC has been shown to be as high as 80% in the regions of South-East Asia and Africa. Current study population is situated in a geographical area characterized by intermediate prevalence rates of HCV and HBV.^17,18 Due to lack of awareness about the risk factors and limited screening for HCC which is around 8.2%, mostly, the individuals are identified when they exhibit symptoms due to advanced HCC; hence, they were not considered eligible for definitive treatment. Nevertheless, the existing data on HCC in local population is constrained, mostly consisting of observations from a solitary institution with a restricted number of participants, predominantly focusing on viral-related HCC. Moreover, there is a lack of relevant data about the frequency and prognostic variables associated with viral marker negative HCC in Pakistan.^19,20

Management of HCC can be done through a number of medical procedures that are available locally, including liver resection, loco regional therapy, transarterial chemoembolization, transarterial radioembolization, and immunotherapy. The overall survival of patients with HCC has improved over shorter duration due to these treatment options, but the risk of recurring illness persists.²¹

Specifically, the FDF PET-CT has been found to be an efficient imaging technique in the management and identification of HCC, especially in cases when hepatic resection and liver transplantation are being considered. FDG PET-CT is beneficial for multiple purposes, including the diagnostic work-up and decision of treatment of HCC, initial staging of the disease, and the assessment of therapeutic effectiveness.²²

However, there are no published data from Pakistan available evaluating the pattern of uptake and frequency of HCC detection on FDG PET-CT scan. The current study is an attempt to share the experience of a high reference institution regarding the diagnostic efficiency of FDG PET-CT among patients of HCC. The research was expected to identify the potential value of FDG PET-CT in local settings where the HCC incidence is rising in concordance with global pattern due to rising exposure to risk factors, an aging population, and lifestyle modifications, including alcohol consumption and metabolic liver disease.²³

Hepatocellular carcinoma in the early stages often do not exhibit any symptoms, and are mostly detected via routine monitoring. Diagnosing the condition upon manifestation of symptoms enhances the likelihood of encountering a more progressed stage of the disease. According to the findings of our research, it was observed that 84.3% of the patients exhibited infiltrative and poorly differentiated HCC. The findings of our study align with the research done by A Butt et al., who indicated that a significant proportion (62.8%) of Pakistani patients exhibited advanced or infiltrative HCC as a consequence of inadequate monitoring measures.¹⁹

Based on our research results, the average patient’s age was determined to be 51.8 years. These data suggest a higher incidence of HCC among older individuals, with males exhibiting the greatest prevalence. A research investigation conducted by A Bhatti et al. demonstrates consistent results, indicating an elevated male to female ratio and an increased incidence of HCC among individuals aged 55–80 years.¹⁷

It is vital to possess knowledge about the distinct imaging properties of HCC and other types of liver malignancies in order to effectively strategize for pre-study preparation. The routine application of FDG PET-CT however remains a subject of controversy for the diagnosis of HCC. In the present analysis, the sensitivity of FDG PET-CT scan was evaluated either through comparison with histopathology or by comparing with CT and MRI scans that detected HCC in these patients. Using an FDG PET-CT scan, the overall HCC was identified among 84.3% individuals. In 15.7% individuals with well-differentiated HCC, FDG PET-CT failed to detect the disease, it is seen that FDG PET-CT exhibits a sensitivity of 84.3% for the identification of HCC. This sensitivity value is comparable to the results reported by Kim et al., who demonstrated an 87.6% sensitivity in detecting HCC by PET-CT imaging.²⁴

In few previously published articles, the reported sensitivity of PET-CT for the identification of disease is as low as 55%.²⁵ The analysis done by Park et al. yielded the sensitivity of FDG PET-CT in diagnosing poorly differentiated disease which was 60.7%, whereas for highly differentiated HCC, it was 39.3%.²⁶

Current research’s detection rate is greater than that of the study by Abdelhalim H et al., which indicated a sensitivity of 76.5%.²² The augmented detection rate in the present research may be attributed to a larger cohort of patients diagnosed with poorly differentiated HCC, as well as variations in the sample size.

The amount of FDG that accumulates in HCC exhibits variability based on the tumor’s histological differentiation. Well-differentiated HCC has a poorer glucose metabolism compounded with relatively with poor FDG uptake. Conversely, HCC with poor histological differentiation has elevated FDG uptake and increased glucose metabolism. Since the physiological pattern of higher FDG activity in normal liver parenchyma and the fact that well-differentiated HCC exhibits FDG uptake analogous to that of normal hepatic cells, the PET-CT demonstrates relatively poor sensitivity in such cases. The findings of the current study also favors a limited sensitivity of FDG PET-CT in detecting well-differentiated HCC. These results align with the conclusions drawn by Trojan et al., who similarly reported that FDG PET-CT does not offer significant utility in identifying well-differentiated HCC.²⁷

The uptake of FDG serves as an accurate and reliable indicators for the existence of tumors. The use of SUV max allows for the quantitative assessment of both tumor histology and FDG absorption. According to the findings of many researchers, the SUV max of primary HCC varied from 1.9 to 14.²⁸Primary SUV max in the current study showed a similar pattern (mean 3.7 ± 2.8) varied from 1.9 to 16. Those diagnosed with positive HCC had significantly elevated SUV max levels in comparison to those diagnosed with negative HCC.

By unique virtue of combining the CT-based cross-sectional anatomical details with the metabolic map, the application of FDG PET-CT has expanded to include the evaluation of many malignant conditions. For HCC patients, the advantages include the assessment for candidature of local therapy, evaluation of response to such targeted therapies and detection of extrahepatic extent which is crucial prior to liver transplantation. In contrast to morphological imaging techniques, such as ultrasonography, CT, and MRI, FDG PET-CT determines the tumor viability as indicated by the degree of glucose metabolism and thus is independent of tumor morphology or lipiodol deposition. Previous published data yielded the finding that FDG PET-CT demonstrated better accuracy and sensitivity as compared with CECT in the detection of HCC recurrence subsequent to TACE. However, the presence of the beam hardening artifact caused by the high-attenuation lipiodol on CT scans may indeed impede the accurate identification of live tumors inside the lesion. Following TACE, the feeding arteries associated with the remaining tumor exhibit a notable reduction in thickness, which subsequently impacts the extent of tumor amplification. CECT may be able to conceal increased tumor activity because of the presence of highly dense lipidol.^29,30 The current analysis examined a cohort of four cases who had previously had TACE therapy, and it was found that the recurrence of tumors may reliably be detected using FDG PET-CT scans.

Based on this research, 75.4% of the patients had multifocal liver lesions that affected several liver segments. Segment VIII (25.5%) was most consistently impacted, whereas segments I and II had the lowest occurrences of afflicted segments, at 2.0 and 3.9% respectively. According to a study performed by Farahat et al., segments I and II were found to be the least affected segment, accounting for 6.7% of the total impact. Conversely, segment VIII was identified as the most significantly affected segment, representing 26.7% of the overall impact.³¹

The FDG PET-CT technique is considered the most pragmatic approach for detecting extrahepatic metastases. In the course of my research, it was determined via the use of FDG PET-CT that 23 people had extrahepatic metastases. The lungs and the abdominal lymph node are recognized as the two most prevalent locations for extrahepatic metastases. According to the published data, the FDG PET-CT whole body scan has found to exhibit better accuracy in comparison with other diagnostic modalities, such as X-rays, CT scans, and MRI in the identification of pulmonary sites, as well as intrathoracic and abdominal lymph nodes.³²

CONCLUSION

This study demonstrates that FDG PET-CT is a viable option for the detection of HCC in local settings. The PET-CT has demonstrated sensitivity comparable to internationally published research for detecting primary HCC in our population as well, mainly owing to greater capability for detecting high-grade HCC. However secondary to the reduced ability of FDG PET-CT scan to identify well-differentiated/low-grade HCC, the routine use of FDG PET-CT scan may not be considered for the evaluation of primary disease only.

ORCID

Kiran Arshad https://orcid.org/0009-0001-8517-1970

Sheikh Danial Hanan https://orcid.org/0000-0001-7500-4768

Muhammad Numair Younis https://orcid.org/0000-0002-3853-8805

Rimsha Badar https://orcid.org/0000-0002-8211-5682

Minahil Imran https://orcid.org/0009-0004-5938-5854

Nefal Numair https://orcid.org/0000-0002-1976-9325

Abubakar Imran https://orcid.org/0009-0009-6189-3336

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