Two case reports: EML4-ALK rearrangement large cell neuroendocrine carcinoma and literature review

Abstract

Anaplastic lymphoma kinase gene (ALK) rearrangement is present in only approximately 5% of non-small cell lung cancers (NSCLCs) and is scarce in LCNEC patients. The conventional first-line treatment options are chemotherapy combined with immunotherapy or chemotherapy followed by palliative radiotherapy. In this report, we present two cases of metastatic LCNEC with EML4-ALK fusion that were treated with ALK-TKI inhibitors and demonstrated a rapid therapeutic response. Both patients were nonsmoking women who declined cytotoxic chemotherapy, underwent Next-Generation Sequencing (NGS), and confirmed EML4-ALK fusion. They were treated with alectinib as first-line therapy, and the tumors showed significant shrinkage after two months, achieving a PR (defined as a more than 30% decrease in the sum of maximal dimensions). The PFS was 22 months and 32 months, respectively, until the last follow-up. A systematic review of all previously reported cases of LCNEC with ALK mutations identified only 21 cases. These cases were characterized by being female (71.4%), nonsmoking (85.7%), diagnosed at a relatively young age (median age 51.1), and stage IV (89.5%), with an overall response rate (ORR) of 90.5%. PFS and OS were significantly longer than those treated with conventional chemotherapy/immunotherapy. Based on the clinical characteristics and the effective therapeutic outcomes with ALK inhibitors in LCNEC patients with ALK fusion, we recommend routine ALK IHC (economical, affordable, and convenient, but with higher false positives) as a screening method in advanced LCNEC patients, particularly nonsmoking females or those who are not candidates for or unwilling to undergo cytotoxic chemotherapy. Further molecular profiling is necessary to confirm these potential beneficiaries. We suggest TKI inhibitors as the first-line treatment for metastatic LCNEC with ALK fusion. Additional studies on larger cohorts are required to assess the prevalence of ALK gene fusions and their sensitivity to various ALK inhibitors.

Keywords: ALK-TKI inhibitor; EML4-ALK rearrangement; alectinib; immunohistochemistry; large cell neuroendocrine carcinoma.

Figure 1

(A) CT enhancement scan shows a primary tumor in the left hilum with mediastinal and left hilar lymph node metastasis; (B) primary lung lesions were reduced significantly after two months; (C) CT scan demonstrating a dramatic shrinkage of the primary tumor after taking alectinib for 21 months; (D) HE staining at 100× magnification; (D) (a-d) Immunohistochemical stain revealed that CD56 (+), Syn (+), TTF-1 (+), and Ki-67 (+) (80%), ×100; (E) ECT showed the 6th thoracic vertebra and left localized iliac metastases; (F) distinctly decreased uptake of 99mTc-MDP in bone metastases after taking alectinib for 18 months.

Figure 2

(A) Primary tumor in the right upper lung field; (B) Primary lung lesions distinctly shrink in 2 months; (C) Primary tumor showed a further decrease and almost disappeared after taking alectinib for 32 months; (D) positive ALK protein expression by IHC staining using the anti-ALK antibody (clone D5F3) characterized by intense, diffuse cytoplasmic staining; (D) (a-e) a, HE staining at 100× magnification; (b-e) Immunohistochemical stain revealed that CD56 (+), Syn (+), TTF-1 (+), and Ki-67 (+) (90%), ×100; (E) ultrasonography (USG) of bilateral superficial cervical lymph nodes metastasis; (F) USG of bilateral superficial cervical lymph nodes shrank obviously after 20 months of therapy.

Figure 3

(A) Schematic of various ALK fusion variants in NSCLC, adapted from Ou et al. (29). (B) V proportion of 1387 EML4-ALK variants in EML4-ALK+ NSCLC, adapted from Zhang et al. (30). (C) Pie chart of ALK variants detected in LCNEC. The left graph shows the prevalence of fusion partners reported in our 19-case review, and the right diagram depicts the distribution of different EML4-ALK variants within the limited 9 cases.

Figure 4

A possible molecular testing algorithm for LCNEC patients. Given the physiological expression of ALK in neurocytes, we recommend performing ALK IHC to screen out potential candidates (yellow boxes), and for those with IHC ALK+ or with clinical features of nonsmoking history, young age, or female sex despite negative ALK, further molecular tests should be conducted to confirm ALK fusion to direct precision therapy. Furthermore, re-biopsy should be performed after first-line or second-line ALK-TKI resistance. The yellow boxes reveal the potential group benefit from ALK-TKIs. The red box and lines show patients who received traditional treatment. Green boxes and lines indicate the population that benefited from ALK-TKIs. ALK, anaplastic lymphoma kinase; TKI, tyrosine kinase inhibitor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; rt-PCR, real-time polymerase chain reaction; NGS, next-generation sequencing.