Triple reversal phenomenon in EGFR-mutant lung adenocarcinoma with prostate metastasis following hepatocellular carcinoma: a rare Case Report with diagnostic and therapeutic implications

Abstract

Background: Non-small cell lung cancer harboring EGFR mutations is responsive to targeted therapies such as Osimertinib. Although metastasis from lung cancer to the prostate is exceedingly rare, we present a rare case of prostatic metastasis from lung adenocarcinoma in a patient with a history of hepatocellular carcinoma (HCC) and no evidence of a primary lung lesion.

Case presentation: A 64-years-old male with chronic hepatitis B and a history of hepatocellular carcinoma (HCC) diagnosed in 2014 presented in 2023 with elevated carcinoembryonic antigen (CEA) levels. Initial imaging revealed isolated bone metastasis, initially presumed to be recurrent HCC. Given the long interval since diagnosis, a bone biopsy was performed, unexpectedly showing adenocarcinoma. Subsequent PET-CT identified a prostatic lesion without pulmonary abnormalities, leading to an initial diagnosis of metastatic prostate cancer. Prostate biopsy, however, revealed features consistent with lung adenocarcinoma. Molecular testing detected an EGFR exon 21 L858R mutation, confirming metastatic lung adenocarcinoma. The patient responded favorably to osimertinib therapy.

Conclusion: This case illustrates a rare instance of prostatic metastasis from EGFR-mutant lung adenocarcinoma and emphasizes the critical role of repeat biopsy, molecular profiling, and multidisciplinary evaluation in atypical metastatic presentations. The diagnostic process involved a "triple reversal" phenomenon, revising initial misdiagnoses of recurrent HCC and primary prostate cancer to metastatic NSCLC. Targeted therapy with osimertinib was effective, underscoring the importance of precision oncology in managing complex metastatic disease.

Keywords: EGFR mutation; case report; lung adenocarcinoma; multidisciplinary approach; prostate metastasis; targeted therapy; triple reversal phenomenon.

FIGURE 1

Imaging findings at baseline and post-operation. (A) Baseline liver imaging with abdominal MRI (T1 post-contrast, arterial phase). The arrow indicates mild liver cirrhosis and a 2 cm hypervascular mass in the right hepatic lobe (Segment VI). (B) Postoperative CT (Portal Venous Phase) showing surgical resection of liver segments V and VI.

FIGURE 2

Imaging findings of suspected bone metastases. (A) Non-contrast CT scan of Chest and Abdomen (Bone Window). The circled area highlights the osteoblastic lesions in the bilateral ribs and partial vertebrae (thoracic, lumbar, and sacral regions), which raise suspicion for metastatic disease. These high-density lesions are indicative of bone metastasis. (B) Whole-body Tc-99m Methylene Diphosphonate (MDP) Bone Scintigraphy. A bone scan demonstrates multiple foci of increased radiotracer uptake in the thoracic spine, bilateral ribs, and pelvic bones (arrow). These findings are highly suggestive of osseous metastases.

FIGURE 3

Immunohistochemical analysis of lumbar spine biopsy specimen. (A) Immunohistochemical staining for thyroid transcription factor-1 (TTF-1) shows strong nuclear positivity (TTF-1+, red arrows) in tumor cells, indicating a possible pulmonary origin (original magnification × 40; scale bar = 50 μm). (B) Immunohistochemical staining for Napsin A demonstrates cytoplasmic granular positivity (Napsin A+, red arrows) in the same tumor cells (original magnification × 40). TTF-1 and Napsin A are highly specific markers for lung adenocarcinoma, supporting the diagnosis of metastatic pulmonary adenocarcinoma involving the lumbar spine. All staining was performed using validated immunohistochemical protocols, and tissue sections were counterstained with hematoxylin. Positive and negative controls were included to confirm staining specificity.

FIGURE 4

Immunohistochemical staining results of prostate biopsy specimens. (A,B) Left prostate tissue from Core 1. (A) Immunohistochemical staining for prostate-specific antigen (PSA) shows strong cytoplasmic positivity (PSA⁺), confirming prostatic origin. Positive cells are indicated by red arrows (original magnification × 40). (B) P63 immunostaining reveals distinct nuclear positivity (P63⁺) in basal cells, a feature of benign prostatic glands. Positive nuclei are marked by red arrows (original magnification × 40; scale bar = 50 μm). (C,D) Right prostate tissue from biopsy Cores 2 and 4. (C) Thyroid transcription factor-1 (TTF-1) staining shows nuclear positivity (TTF-1⁺) in atypical glandular cells, suggestive of metastatic lung adenocarcinoma. Positive cells are indicated by red arrows (original magnification × 40; scale bar = 50 μm). (D) PSA staining is negative (PSA^–) in the same region, supporting a non-prostatic origin. Representative areas are marked with red arrows (original magnification × 40; scale bar = 50 μm). All sections were stained using standard immunohistochemistry protocols and counterstained with hematoxylin. Appropriate positive and negative controls were used.