The Spectrum of Histopathological Lesions Presenting as a Hepatic Nodule and Their Relationship With Serum Alpha-Fetoprotein Level

INTRODUCTION

The prevalence of hepatic lesions has increased significantly with advances in imaging modalities. Benign lesions typically arise in otherwise healthy livers and include focal nodular hyperplasia, hepatic adenoma, and hemangioma. Premalignant lesions comprise dysplastic foci and low- and high-grade nodules, whereas malignant lesions comprise hepatocellular carcinoma (HCC) and Cholangiocarcinoma. Metastatic involvement of the liver is more common than primary malignancy, with frequent primaries being colorectal, breast, lung, and pancreatic carcinomas.^[1-4] Precise diagnosis of precancerous or small lesions remains challenging, as imaging often fails to detect them due to poor vascularity.^[5,6]

Despite its limitations, including sampling error and the potential for needle tract tumour seeding, liver biopsy remains the diagnostic gold standard for confirming hepatic nodules.^[7,8] Both the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) recommend biopsy in nodules >2 cm when imaging is inconclusive or when findings from two modalities are discordant.^[7,8] Histological assessment not only confirms the diagnosis but also provides prognostic information that guides therapeutic planning.^[1-3]

Alpha-fetoprotein (AFP), a glycoprotein produced by the fetal liver and yolk sac, declines after birth but can reappear in specific hepatic pathologies.^[9,10] Although widely used in the diagnosis and surveillance of HCC, AFP levels can also be elevated in benign hepatic nodules and non-seminomatous germ cell tumours, limiting their specificity.^[9-11] Recent updates by major hepatology societies confirm that a threshold of 20 ng/mL remains widely used, but AFP’s sensitivity at this cutoff is only about 60-65%, with specificity around 80-90%.^[12] Moreover, many early or small tumours remain AFP-negative, and 30-40% of HCCs may never produce elevated AFP.^[13] Because of these limitations, there has been increasing interest in alternative or complementary serum biomarkers such as AFP-L3%, des-gamma-carboxy prothrombin (DCP/PIVKA-II), and others.^[14,15] Emerging data suggest that combined biomarker panels outperform AFP alone, particularly in early-stage HCC detection.^[16]

Nevertheless, in many resource-limited settings, access to advanced biomarker assays or regular high-quality imaging remains constrained. In such contexts, AFP remains in use due to its low cost, ready availability, and long-standing clinical familiarity. Therefore, this study aimed to evaluate the histopathological spectrum of hepatic nodules and correlate these findings with pre-procedural serum AFP levels.

MATERIAL AND METHODS

This cross-sectional study was conducted in the Department of Pathology at a tertiary hospital in South Karnataka. A total of 52 patients with radiologically detected liver masses who underwent liver biopsy and had available pre-procedural serum AFP levels were included. Patients with inadequate clinical records or insufficient biopsy material were excluded.

RESULTS

A total of 52 patients with radiologically detected liver mass lesions were included in the study. The cohort consisted of 36 males (69.2%) and 16 females (30.8%), with a male-to-female ratio of 2.3:1. The mean age at presentation was 59.3 years, with the highest proportion of cases occurring in the sixth decade of life (36.6%). Abdominal pain was the most frequent presenting symptom (46.2%), followed by abdominal distension, weight loss, and jaundice. Pallor was noted in 38.2% of patients. Imaging revealed single hepatic nodules in 32 cases (61.5%) and multiple nodules in 20 cases (38.5%), with the right hepatic lobe being most commonly involved.

Histopathological evaluation revealed that neoplastic lesions predominated (88.5%), while non-neoplastic lesions accounted for 11.5%. HCC was the most common diagnosis (50.0%), followed by metastatic adenocarcinoma (26.9%). Cholangiocarcinoma, epithelioid angiosarcoma, non-Hodgkin lymphoma, and sinusoidal hemangioma were less frequently encountered. Non-neoplastic lesions included cirrhosis with macro-regenerative nodules, focal nodular hyperplasia, hydatid cyst, and suppurative lesions. The complete distribution of lesions has been presented in Table 1.

Among the 26 HCC cases, well-differentiated tumours were most frequent (58%), followed by poorly differentiated tumours (23%) and moderately differentiated tumours (19%); 16 cases (61.5%) were unifocal, and 10 (38.5%) were multifocal. Among metastatic adenocarcinomas (n = 14), the colon and pancreas were the most common primary sites, with one case originating from the breast.

Serum AFP levels ranged from 0.76 to 61,775 ng/mL. Using the standard cutoff of 20 ng/mL, elevated AFP levels (>20 ng/mL) were observed in 42.4% of patients. A significant association was found between AFP level and final diagnosis: 73.1% of HCC cases showed elevated AFP, whereas only 14.3% of metastatic adenocarcinomas demonstrated high AFP values (χ² = 12.61, p = 0.001). These findings have been summarised in Table 2.

A scatter plot illustrating AFP distribution across broad diagnostic categories (neoplastic vs non-neoplastic) is shown in Figure 1. No significant correlation was identified between AFP levels and this categorization (Spearman’s Rho = 0.116, p = 0.412). Using the 20 ng/mL cutoff, AFP demonstrated a sensitivity of 73.08% and a specificity of 83.33% for detecting HCC. The positive predictive value was high (98.81%), whereas the negative predictive value was low (14.01%). The overall diagnostic accuracy of AFP for HCC was 73.59% [Table 3]. Detailed performance metrics are presented in Figure 1.

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Figure 1: Scatterplot demonstrating the distribution of serum AFP levels across neoplastic and non-neoplastic categories. A non-significant correlation was observed (Spearman’s Rho = 0.116, p = 0.412). AFP: Alpha-fetoprotein level, HCC: Hepatocellular carcinoma.

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DISCUSSION

Accurate histopathological diagnosis is crucial in patients with hepatic nodules, as the liver can be affected by a range of conditions, including neoplastic, non-neoplastic, metabolic, and vascular disorders. The correct interpretation of liver biopsies requires the integration of clinical, radiological, and pathological data. Serum AFP has historically been used as an initial biomarker in the diagnosis of suspected hepatic malignancy.^[4-7] However, its role in routine screening has declined, with current guidelines discouraging its use as a sole surveillance tool.^[5,8,9]

In the present study of 52 patients, a clear male predominance (69.2%) was observed, aligning with prior reports and consensus guidelines, which attribute this to genetic susceptibility, higher prevalence of chronic alcohol consumption, and hepatitis B/C infection in males.^{[10,11,17,18]} The peak incidence was noted in the sixth decade, consistent with global and Indian epidemiological data, which show that HCC incidence rises steadily with age and peaks in the 5^th-7^th decades.^[19-21] Clinically, abdominal pain was the most frequent presentation (46.2%), followed by distension, weight loss, jaundice, and fever. These symptoms mirror prior observations, with right upper quadrant pain and cachexia considered typical for HCC presentation.^[17,22,23]

Histopathology revealed predominantly neoplastic lesions (88.5%), with non-neoplastic lesions comprising only 11.5%. This trend of increasing neoplastic burden has been similarly reported in Indian studies.^[18,20] However, studies from Africa show higher rates of inflammatory and infectious lesions, reflecting regional differences in viral hepatitis prevalence and socioeconomic conditions.^[17,24] HCC was the most common malignant tumour (56.5%), followed by metastatic adenocarcinoma (30.4%). This pattern is consistent with global statistics, where HCC is the fourth leading cause of cancer-related mortality worldwide.^[25-27]

Among HCCs, 61.5% were unifocal and 38.5% multifocal, comparable to previous findings. Multifocal HCC is more common in patients with multiple risk factors (alcohol, HBV, HCV), emphasizing the need for surveillance imaging to detect early nodules.^[28,29] Metastatic adenocarcinoma commonly originated from the pancreas (50%) and colon (42.8%), with one breast primary. The high frequency of pancreatic and colorectal metastases parallels the liver’s rich dual blood supply and sinusoidal fenestrations that facilitate metastatic seeding.^[30,31] Cholangiocarcinoma accounted for 5.8%, in line with global incidence estimates,^[32] while rare tumours such as epithelioid angiosarcoma and non-hodgkin’s lymphoma were also identified.

Serum AFP demonstrated a strong diagnostic association in this study. Elevated AFP levels (>20 ng/mL) were present in 73.1% of HCC cases. Still, only 14.3% of metastatic adenocarcinomas were identified, reinforcing the value of AFP in differentiating primary hepatic malignancy from secondary deposits.^[23,27,33] All non-neoplastic lesions in our study demonstrated low AFP levels, consistent with the expected profile of benign hepatic pathology. Nevertheless, it is noteworthy that elevated AFP has occasionally been reported in certain benign conditions, including focal nodular hyperplasia and inflammatory pseudotumor.^[33-35] These reports highlight that although AFP elevation strongly suggests malignant hepatocellular transformation, it is not entirely specific, and benign conditions may occasionally demonstrate elevated levels.

The association between AFP and tumour differentiation remains variable in the published literature. Some studies have observed higher AFP production in well-differentiated tumours due to the maintenance of hepatocellular synthetic capacity. In contrast, others have linked elevated AFP to aggressive tumour biology.^[27,28] Recent analyses suggest that AFP levels are influenced by multiple factors, including tumour differentiation, lesion size, microvascular invasion, and surrounding hepatic microenvironment, rather than any single pathological attribute.^[13] In our cohort, AFP levels showed trends across differentiation categories, although without a statistically significant correlation.

The diagnostic performance of AFP, showing 73.08% sensitivity, 83.33% specificity, and 73.59% accuracy, is comparable with findings reported in previous studies [Table 3].^[27,33] Nevertheless, contemporary clinical guidelines emphasize that AFP alone has limited value for early HCC detection and should be used only as an adjunct in surveillance and diagnostic pathways.^[12] Additional biomarkers such as AFP-L3% & PIVKA-II have shown promise in improving diagnostic accuracy, especially for early-stage tumours.^[14] However, in many resource-limited settings, AFP remains widely used due to its accessibility and affordability.

AFP values in this study were available only in two predefined diagnostic categories (≤20 ng/mL and >20 ng/mL), reflecting institutional laboratory reporting practices. This format did not permit construction of a receiver operating characteristic (ROC) curve for data-driven cutoff estimation; however, the use of the widely accepted 20 ng/mL threshold remains consistent with established clinical practice and current evidence.^[12,14] This methodological constraint highlights the importance of future prospective studies that capture continuous biomarker data to enable more refined diagnostic modelling.

Despite limitations, including a modest sample size and single-centre design, this study provides meaningful regional insight into the spectrum of hepatic lesions and the diagnostic role of AFP. The findings underscore the need for a multimodal diagnostic approach and support continued use of AFP as an accessible adjunctive biomarker in settings where advanced diagnostics may not be readily available.

CONCLUSION

Liver nodules in adults are most often neoplastic, with HCC being the leading malignancy. AFP is a useful adjunct for differentiating HCC from metastases; normal levels do not rule out cancer, making biopsy the gold standard. In resource-limited settings, AFP remains a practical, cost-effective tool that supports comprehensive clinical, radiological, and histopathological evaluation.