¹⁸F-FDG PET/CT in Lung Hepatoid Adenocarcinoma

A 39-year-old male with a smoking history presented with intermittent chest pain, a nonirritating cough, and shortness of breath. A chest X-ray revealed a pulmonary mass, and further systemic tumor marker testing showed a markedly elevated alpha-fetoprotein (AFP) level of 850 ng/mL (normal range <10 ng/mL). A subsequent Fluorine-18 fludeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) for staging purposes revealed a large, intensely hypermetabolic, heterogeneous mediastinal mass occupying the right hemithorax, with central areas of reduced FDG uptake consistent with necrosis, measuring approximately 156 mm × 153 mm × 162 mm, compressing both the trachea and major vascular structures, and associated with a significant pleural effusion on the right. No other abnormal FDG uptake was seen, particularly in the liver [Figures 1 and 2]. The pathological analysis of the biopsy reveals hepatoid carcinoma characterized by a solid pattern of large polygonal cells with abundant eosinophilic and clear cytoplasm. Immunohistochemical staining shows positivity for Hep Par 1 and cytoplasmic staining for Thyroid Transcriptor Factor 1 (TTF1) [Figure 3].

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Figure 1 Maximum intensity projection positron emission tomography (PET) image (a), coronal fused PET/computed tomography (CT) image (b), and sagittal fused PET/CT image (c) demonstrating a large, intensely hypermetabolic, heterogeneous lesion occupying the right hemithorax, with central area of reduced fludeoxyglucose uptake consistent with necrosis, and an associated large right-sided pleural effusion

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Figure 2 Axial fused positron emission tomography/computed tomography (PET/CT) images (a and b), axial CT image (c), and corresponding axial fused PET/CT image (d) of the thorax, showing a large mass invading the mediastinum, displacing the trachea, and compressing adjacent vascular structures

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Figure 3 (a) Microphotography showing hepatoid carcinoma, with solid pattern of large polyglonal cells with abundant eosinophilic and clear cytoplasm (H and E ×20). (b) Immunohistochemical stains: hepatoid adenocarcinoma. B1: Positive finding for Hep Par 1 stain and B2: Cytoplasmic staining for TTF1

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Hepatoid Adenocarcinoma (HAC) is a rare and highly aggressive extrahepatic malignancy, with morphological features similar to those of hepatocellular carcinoma (HCC). While HA most commonly originates in the stomach, it can develop in almost any extrahepatic organ, including the ovary, gallbladder, pancreas, and uterus.[1] However, HA of the lung (HAL) is an extremely rare form, accounting for only 2.3% of all HA cases.[2] This tumor predominantly affects middle-aged to elderly patients, with a clear male predominance and a significant history of chronic smoking. The clinical presentation and imaging findings of HAL are often nonspecific, mimicking those of common lung cancers, which leads to a diagnosis at advanced Stages (III-IV) and a generally poor prognosis.[13]

HAL is a highly aggressive neoplasm characterized by rapid local infiltration and early systemic dissemination. The tumor commonly metastasizes to regional lymph nodes, liver, bone, and brain. Pleural involvement with malignant effusion is frequently observed, consistent with advanced disease stage. Lymphatic spread predominates, while hematogenous dissemination, particularly hepatic metastases, can clinically and radiologically mimic HCC. This extensive metastatic potential contributes to the poor prognosis typically seen in HAL patients.[2]

AFP-producing lung cancers make up around 2% of all lung cancers, with HAL being the most common histological variant. Elevated AFP levels correlate with tumor burden, often decreasing significantly after effective treatment, though high AFP levels are no longer essential for HAL diagnosis.[4]

HAL is primarily diagnosed through histopathology and immunohistochemistry (IHC). The updated diagnostic criteria for HAL include tumors that demonstrate features of typical acinar or papillary adenocarcinoma, signet-ring cells, or neuroendocrine carcinoma, with hepatic differentiation markers even in the absence of AFP expression.[25] IHC is crucial for distinguishing HAL from metastatic HCC. According to Chen Z et al., all HAL cases described by Haninger et al., were positive for CK8, HEA 125, and MOC31, which were negative in HCC cases. While both HAL and HCC expressed CK18, HepPar1, and TTF-1, CK7 and CEA were positive in 60% of HAL cases but absent in HCC.[2] Although ¹⁸F-FDG PET/CT has limited sensitivity for well-differentiated HCC due to low and variable FDG uptake, this limitation does not apply to HAL. HAL generally demonstrates intense FDG avidity on PET/CT, reflecting its high-grade histology and aggressive biological behavior. ¹⁸F-FDG PET/CT plays a crucial role in the diagnosis, staging, and management of various cancers, including HAL.[6] It remains instrumental for detecting hypermetabolic tumor activity, thereby enabling accurate staging and assessment of disease extent. Furthermore, this imaging modality assists in differentiating HAL from other malignancies, such as metastatic HCC, by revealing distinct metabolic patterns.[67]