Surreal illustration of a liver with pathways leading to a hidden pancreas, symbolizing diagnostic challenges.

Unusual Liver Masses? How an Elevated AFP Level Can Signal More Than Just Liver Cancer

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Mira Elwood in Health & Wellness December 2025 • 5 min read.

"Navigating the complexities of tumor diagnosis when a routine blood test throws you a curveball. Learn how to interpret elevated alpha-fetoprotein levels in the presence of liver masses and the critical steps to take next."


Imagine facing a health scare that begins with vague symptoms like malaise and unexplained weight loss. Routine blood work reveals an elevated alpha-fetoprotein (AFP) level, a marker often associated with liver cancer. Now, picture the added complexity of discovering masses in your liver. The immediate assumption? Hepatocellular carcinoma (HCC), a primary liver cancer. But what if the real culprit is something far less common and initially overlooked?

This is the diagnostic dilemma faced by a 55-year-old man in a recent JAMA Clinical Challenge. His case highlights a crucial lesson for both medical professionals and patients: elevated AFP levels and liver masses don't always equate to HCC. Sometimes, a thorough investigation is needed to uncover the true source of the problem.

In this article, we'll delve into the details of this intriguing case, exploring the diagnostic process, the importance of advanced imaging techniques, and the critical role of biopsy in uncovering the unexpected diagnosis of a pancreatic neuroendocrine tumor (PNET). We'll also discuss how this case underscores the need for vigilance and a broad differential diagnosis when faced with seemingly straightforward medical presentations.

Decoding the Diagnostic Puzzle: When AFP Isn't Just Liver Cancer

Surreal illustration of a liver with pathways leading to a hidden pancreas, symbolizing diagnostic challenges.

Alpha-fetoprotein (AFP) is a protein produced by the liver and yolk sac during fetal development. Its levels typically drop significantly after birth, with only trace amounts detectable in healthy adults. However, elevated AFP levels can be a sign of certain medical conditions, most notably hepatocellular carcinoma (HCC), the most common type of liver cancer. Because of this strong association, doctors often rely on AFP levels as a key diagnostic marker for HCC, especially in patients with chronic liver disease.

However, AFP elevations aren't exclusive to HCC. Other conditions, such as non- cancerous liver diseases (like hepatitis and cirrhosis), germ cell tumors, and even certain gastrointestinal cancers, can also cause AFP levels to rise. This is where the diagnostic challenge begins. How do you differentiate between these possibilities, especially when liver masses are also present?

  • Comprehensive Medical History and Physical Exam: A thorough assessment helps identify potential risk factors for liver disease (alcohol use, hepatitis history) and other relevant medical conditions.
  • Advanced Imaging: Techniques like triple-phase CT scans and MRI can provide detailed information about the characteristics of liver masses, helping to distinguish between different types of tumors.
  • Biopsy: This is the gold standard for diagnosis. A tissue sample is taken from the liver mass and examined under a microscope to determine the type of cells present and confirm the diagnosis.
In the case presented in JAMA, the patient's initial CT scan revealed multiple liver masses and an alarmingly high AFP level (1252 ng/mL, far exceeding the normal upper limit of 9 ng/mL). Based on these findings alone, HCC seemed like the most likely diagnosis. However, further investigation revealed a crucial piece of the puzzle: a mass in the tail of the pancreas, which was only visible on a triple-phase CT scan. This led to an endoscopic ultrasound of the pancreas with fine-needle aspiration, which ultimately revealed the true diagnosis: a pancreatic neuroendocrine tumor (PNET) that had metastasized to the liver.

The Takeaway: Think Beyond the Obvious

This case underscores the importance of considering a broad differential diagnosis when evaluating patients with elevated AFP levels and liver masses. While HCC is a common culprit, it's crucial to remember that other conditions can mimic its presentation. Advanced imaging techniques, combined with biopsy, are essential for accurate diagnosis and appropriate treatment. For patients, this means being proactive in discussing all possible diagnoses with your doctor and understanding the rationale behind each diagnostic step. Don't hesitate to ask questions and advocate for thorough investigation, especially when faced with complex medical presentations.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

Everything You Need To Know

1

When liver masses and elevated AFP are present, is hepatocellular carcinoma (HCC) always the cause?

No, while hepatocellular carcinoma (HCC) is a common association with elevated alpha-fetoprotein (AFP) levels and liver masses, it is not the only possibility. Other conditions, such as pancreatic neuroendocrine tumors (PNETs), can also cause this presentation. A thorough investigation is necessary to uncover the true source of the problem, as illustrated by the case study in JAMA.

2

Besides HCC, what other conditions can cause elevated AFP levels when liver masses are present?

While hepatocellular carcinoma (HCC) is the most common cause, elevated alpha-fetoprotein (AFP) levels with liver masses can also be indicative of other conditions. These include non-cancerous liver diseases like hepatitis and cirrhosis, germ cell tumors, certain gastrointestinal cancers, and, as demonstrated in the JAMA case, pancreatic neuroendocrine tumors (PNETs) that have metastasized to the liver. It's crucial to consider these alternative diagnoses to ensure accurate treatment.

3

What specific imaging techniques are useful in differentiating between various types of liver masses when AFP is elevated?

Advanced imaging techniques such as triple-phase CT scans and MRI are essential in characterizing liver masses when alpha-fetoprotein (AFP) levels are elevated. Triple-phase CT scans provide detailed information about the blood supply to the liver masses, while MRI offers superior soft tissue contrast. These techniques help differentiate between hepatocellular carcinoma (HCC), metastases from other cancers like pancreatic neuroendocrine tumors (PNETs), and benign liver lesions, guiding further diagnostic and treatment decisions.

4

Why is a biopsy considered the 'gold standard' for diagnosing liver masses, especially when AFP levels are elevated?

A biopsy is considered the gold standard because it involves taking a tissue sample from the liver mass and examining it under a microscope. This allows pathologists to determine the exact type of cells present, distinguishing between hepatocellular carcinoma (HCC), metastatic tumors like pancreatic neuroendocrine tumors (PNETs), and other benign or malignant conditions. While elevated alpha-fetoprotein (AFP) levels and imaging can provide strong clues, a biopsy provides definitive confirmation, which is crucial for guiding appropriate treatment strategies.

5

What is the significance of considering a 'broad differential diagnosis' when evaluating a patient with elevated AFP and liver masses, and what does this entail?

Considering a broad differential diagnosis means that medical professionals should not immediately assume hepatocellular carcinoma (HCC) when encountering elevated alpha-fetoprotein (AFP) levels and liver masses. It involves actively considering and investigating other potential causes, such as pancreatic neuroendocrine tumors (PNETs), non-cancerous liver diseases, germ cell tumors, and gastrointestinal cancers. This approach includes a comprehensive medical history, physical examination, advanced imaging, and, if necessary, a biopsy to accurately identify the underlying condition and ensure the patient receives the most appropriate and effective treatment. Failing to consider alternative diagnoses can lead to misdiagnosis and delayed or inappropriate treatment, as highlighted by the JAMA case study.

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