Small intestinal metastasis in a lung adenocarcinoma patient with concurrent EML4-ALK V3 and TP53 mutations after distinct responses to tyrosine kinase inhibitors: A case report

Abstract

Background: Although anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have improved the survival rates of lung cancer patients with ALK fusion mutations, their effectiveness varies significantly across different subtypes. We report a case of small intestine metastasis in a lung adenocarcinoma patient with co-occurring echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variant 3 (V3) and tumor protein 53 (TP53) mutations after distinct responses to ALK-TKIs.

Case presentation: A 45-year-old woman was diagnosed with stage IV lung adenocarcinoma with brain metastasis. Next-generation sequencing revealed EML4-ALK V3 and TP53 co-mutations. After the initial treatment with ensartinib, the patient experienced intracranial disease progression. Radiation therapy (RT) was then administered. Despite good response to RT for the intracranial disease, the primary tumor enlarged. Thus, the patient was treated with oral ensartinib concurrent with chemotherapy, with a partial response in both the primary tumor and intracranial metastases. However, after three cycles of treatment, the patient discontinued chemotherapy because of acute kidney injury. Subsequent thoracic RT resulted in a partial response of the primary tumor; however, new brain and bone metastases were detected, prompting a switch to lorlatinib. The patient developed symptoms of intestinal obstruction 14 months after the initial diagnosis. Surgical intervention revealed a poorly differentiated metastatic lung adenocarcinoma of the upper jejunum. Genetic testing confirmed EML4-ALK V3 and TP53 co-mutations and high expression of programmed cell death-ligand 1. Despite pembrolizumab treatment, the patient's condition deteriorated, and she passed away.

Conclusion: We reported a rare case of small intestinal metastasis in a lung adenocarcinoma patient with concurrent EML4-ALK V3/TP53 mutations after distinct responses to ALK-TKIs in different lesions. Our findings revealed heterogeneity in ALK mutations and responses to ALK-TKIs, necessitating the close monitoring of genetic subtypes and associated mutations for tailored treatment strategies. Maintaining a heightened awareness of potential intestinal metastasis and vigilance in monitoring intestinal symptoms and abdominal metastases are pivotal for managing advanced lung adenocarcinoma.

Keywords: Anaplastic lymphoma kinase; Lorlatinib; Lung adenocarcinoma; Metastasis; Small intestine.

Fig. 1

Systemic treatment strategies: (A) Pre-treatment PET-CT revealing a hypermetabolic mass near the hilum of the right lower lung lobe, accompanied by enlarged right supraclavicular lymph nodes and distal lung atelectasis, measuring approximately 4.8 cm × 2.8 cm. Brain-enhanced MRI showing small metastases in the left frontal lobe cortex. (B) One-month follow-up after ensartinib treatment showed a reduction in the size of the soft tissue mass in the right lower lobe, measuring approximately 2.8 cm × 3.5 cm. Additionally, new brain metastases were observed, with the largest measuring about 1.3 cm. (C) Follow-up imaging on May 18, 2022, revealing an enlargement of the soft tissue mass in the right lower lobe, measuring approximately 5.6 cm × 5.6 cm, while a reduction in the intracranial tumor size is observed. (D) Follow-up imaging on August 1, 2022, indicating a reduction in the tumor in the right lower lobe of the lung, measuring approximately 3.8 cm × 3.6 cm. A significant reduction in brain metastatic tumor size is noted. (E) Follow-up imaging on December 27, 2022, revealing a continued reduction in the tumor in the right lower lobe of the lung and the development of a new metastatic tumor in the left temporal lobe, measuring approximately 1.8 cm × 1.2 cm. (F) PET-CT scan conducted on January 26, 2023, revealing a marked reduction in size and reduced metabolic activity of the malignant tumor in the right lung. Additionally, bone metastasis to the T12 vertebra and multiple small retroperitoneal lymph node metastases are observed. (G) Follow-up imaging on February 15, 2023, showing a reduction in the right lung lesion, measuring approximately 0.8 cm × 0.9 cm. Changes observed in the left temporal lobe tumor after radiation therapy. (H) Head MRI on April 4, 2023, indicating a new metastasis in the left parietal lobe, measuring approximately 2.7 cm × 1.5 cm. (I) Follow-up imaging on April 22, 2023, revealing stability in lung lesions, localized thickening of the small intestine wall in the upper left abdomen, and multiple enlarged lymph nodes in the retroperitoneum, suggestive of metastasis.

Fig. 2

Biopsy pathologic images of the right supraclavicular lymph node. (A) Hematoxylin and eosin (H&E) staining is positive (H&E × 200). Immunohistochemical (IHC) analysis showing positive staining for TTF-1 (B) and Napsin A (C) (IHC × 100).

Fig. 3

(A) Hematoxylin and eosin (H&E) staining revealing adenocarcinoma (H&E × 400). Immunohistochemical (IHC) analysis showing negative staining for CDX-2 (B) and positive staining for TTF-1 (C), p53 (D), and Ki-67 (E) (IHC × 100).