Hepatoid adenocarcinoma of the lung accompanied with multiple systemic metastases

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Hepatoid adenocarcinoma of the lung accompanied with multiple systemic metastases

Lung cancer is the leading cause of cancer death worldwide, but some rare subtypes are even more challenging to diagnose and treat. One such subtype is hepatoid adenocarcinoma of the lung (HAL)—a rare tumor that combines features of both lung cancer and liver cancer, often catching patients and doctors off guard. A recent case from researchers at Ruijin Hospital, Shanghai Jiaotong University, illustrates just how aggressive and confusing HAL can be.

The case involves a 63-year-old man with no significant medical history (including no hepatitis) who developed unexplained lumbar soreness and pain. He described a “skin tear” sensation, and his pain worsened every afternoon—only improving with ibuprofen. A month later, he noticed 6–7 small, movable subcutaneous nodules on his lower back, abdomen, and chest. The nodules were slightly raised (1–2 cm in diameter), tender to touch, but not red, swollen, or ulcerated.

Routine blood tests revealed clues: elevated white blood cells (11.07 × 10⁹/L) and platelets (436 × 10⁹/L), low hemoglobin (95 g/L), and abnormal liver enzymes (alanine aminotransferase: 68 U/L). Tumor markers were even more concerning: carcinoembryonic antigen (CEA) exceeded 100 ng/mL (normal <5 ng/mL), carbohydrate antigen (CA) 72-4 was over 300 U/mL (normal <6.9 U/mL), and cyfra21-1 (a lung cancer marker) was 31.8 ng/mL (normal <3.3 ng/mL).

Doctors removed several skin nodules under local anesthesia. A pathology review at Ruijin Hospital confirmed poorly differentiated adenocarcinoma—a fast-growing cancer. A positron emission tomography/computed tomography (PET/CT) scan then revealed the source: a soft-tissue mass in the left lung apex, a nodule in the right upper lobe near the pleura, and widespread metabolic activity indicating systemic metastases (enlarged lymph nodes, soft-tissue masses, and more subcutaneous nodules).

Sadly, the patient died of multiple organ failure due to distant metastases just 4 months after his initial diagnosis.

What Is Hepatoid Adenocarcinoma of the Lung?

HAL is a type of extrahepatic hepatoid adenocarcinoma (HAC)—a cancer that has both glandular (adenoid) and liver cell-like (hepatocyte) features. Most HAC cases occur in the digestive tract (stomach cancer accounts for 63% of cases, per a 2018 study by Zeng et al.). HAL, first described by Ishikura et al. in 1990, is unique because it originates in the lung but mimics hepatocellular carcinoma (HCC)—the most common type of liver cancer.

Originally, HAL was defined as an alpha-fetoprotein (AFP)-producing lung cancer (AFP is a protein usually high in liver cancer or pregnancy). But in 2014, Haninger et al. updated the diagnostic criteria to include “AFP-negative HAL,” recognizing that some cases don’t produce AFP. This is critical: doctors can’t rely solely on AFP tests to diagnose HAL—instead, the diagnosis depends on seeing HCC-like features in lung tissue under a microscope.

Treatment and Prognosis

Treatment for HAL depends on the clinical stage (how far the cancer has spread):

  • Early-stage (I–II): Radical surgery offers the best chance of long-term survival.
  • Advanced-stage (III–IV): Patients rarely qualify for surgery and typically receive chemotherapy or radiation.

Like other non-small cell lung cancers, the stage is the biggest predictor of survival. Advanced HAL often leads to multiple metastases (ribs, vertebrae, adrenal glands, brain, liver, tonsils) and poor outcomes—most patients with advanced disease live only months after diagnosis, as seen in this case. Only a small number achieve long-term disease-free survival.

Why This Case Matters

This case underscores the importance of early diagnosis for HAL—a rare tumor that most often affects elderly men with a long history of smoking, though exceptions (like this patient) exist. The 63-year-old man’s symptoms—back pain, skin nodules—were initially vague, but the rapid progression of his disease shows how quickly HAL can spread. For doctors, it’s a reminder to consider rare subtypes when standard tests don’t add up. For patients, it highlights the need to report persistent, unexplained symptoms to their healthcare provider immediately.

HAL remains poorly understood due to its rarity. More long-term, large-sample studies are needed to learn about its immune profiles, genetic changes, molecular pathology, and better treatment options.

This work was supported by grants from the Shanghai Famous Traditional Chinese Medicine Shen Xiaoheng Academic Experience Research Studio (No. SHGZS-2017011) and the Clinical Cooperation of Chinese and Western Medicine Pilot Project of Shanghai (No. ZY (2018-2020)-FWTX-1101). The authors declare no conflicts of interest. The patient’s family provided written consent for the publication of clinical details and images, with all efforts made to protect the patient’s identity.

References

  1. Zeng X, Zhang P, Xiao H, Wu X, Liu W, He J, et al. Clinicopathological features and prognosis of intestinal hepatoid adenocarcinoma: evaluation of a pooled case series. Oncotarget 2018;9:2715–2725. doi.org/10.18632/oncotarget.23595
  2. Ishikura H, Kanda M, Ito M, Nosaka K, Mizuno K. Hepatoid adenocarcinoma: a distinctive histological subtype of alpha-fetoprotein-producing lung carcinoma. Virchows Arch A Pathol Anat Histopathol 1990;417:73–80. doi.org/10.1007/bf01600112
  3. Haninger DM, Kloecker GH, Bousamra Ii M, Nowacki MR, Slone SP. Hepatoid adenocarcinoma of the lung: report of five cases and review of the literature. Mod Pathol 2014;27:535–542. doi.org/10.1038/modpathol.2013.170
  4. Kuan K, Khader SN, El Hussein S. Hepatoid adenocarcinoma of the lung. Diagn Cytopathol 2019;47:831–833. doi.org/10.1002/dc.24195
  5. Kashani A, Ellis JC, Kahn M, Jamil LH. Liver metastasis from hepatoid adenocarcinoma of the esophagus mimicking hepatocellular carcinoma. Gastroenterol Rep 2017;5:67–71. doi.org/10.1093/gastro/gov021

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