First-line lorlatinib treatment in a 19-year-old patient with ALK-rearranged pulmonary large-cell neuroendocrine carcinoma: a case report and literature review

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive subtype of nonsmall cell lung cancer, typically occurring in elderly male smokers. Its occurrence in the adolescent population is exceptionally uncommon, with only a handful of cases reported in the literature. Even more rarely, LCNEC harbors ALK fusions, an unusual molecular alteration with important therapeutic relevance. We report a 19-year-old female patient who presented with bone pain and was found to have widespread skeletal and mediastinal lymph node involvement. Initial workup revealed elevated serum calcitonin and carcinoembryonic antigen (CEA) levels, and histopathology showed high-grade neuroendocrine carcinoma with immunoreactivity for chromogranin, synaptophysin, CD56, as well as calcitonin and CEA. Due to the neuroendocrine phenotype and calcitonin positivity, metastatic medullary thyroid carcinoma was initially suspected. However, thyroid fine needle aspiration from the suspicious thyroid nodule did not provide any evidence in this direction, and the RET mutation testing was also negative. Further molecular analysis revealed an EML4-ALK fusion and a TP53 mutation in tumor tissue. The patient was diagnosed with ALK-positive LCNEC and treated with lorlatinib and denosumab combination. A marked clinical and metabolic response was achieved within 3 months of treatment initiation. To our knowledge, this is the first reported case of ALK-rearranged pulmonary LCNEC in an adolescent patient treated with a tyrosine kinase inhibitor. This case underscores the extreme rarity of LCNEC in adolescents, highlighting that ALK rearrangements, although exceptionally rare in this histological subtype, can have significant therapeutic implications. It further emphasizes the importance of routine molecular profiling in atypical clinical scenarios and supports the utility of targeted therapies in rare tumor subsets.