Hepatic metastasis of pulmonary large cell neuroendocrine carcinoma: A case report and literature review

Abstract

Large cell neuroendocrine carcinoma of the lung is a rare and aggressive malignancy with a high propensity for metastasis. This carcinoma demonstrates a significantly higher propensity for hepatic metastasis compared with other non-small cell lung cancer subtypes, thereby exacerbating therapeutic complexity and worsening prognosis. A man in his early 60s was admitted to our institution with a hepatic space-occupying lesion. Hepatic segmentectomy was performed, and histopathological examination confirmed a neuroendocrine carcinoma. Following stabilization of vital signs, the patient underwent uniportal video-assisted thoracoscopic surgery for partial lobectomy of the right upper lung. Subsequent histopathological analysis confirmed the diagnosis of hepatic metastasis originating from pulmonary large cell neuroendocrine carcinoma. This case highlights that clinicians should maintain a high index of suspicion for large cell neuroendocrine carcinoma when encountering multifocal malignancies.

Introduction

Large cell neuroendocrine carcinoma (LCNEC) of the lung is a rare and aggressive malignancy, accounting for 1%–3% of all primary lung cancers, with a predilection for elderly male smokers. ¹ Defined by the World Health Organization as a high-grade neuroendocrine tumor, LCNEC is characterized by neuroendocrine morphology; high mitotic rates (>10 mitoses/mm²); necrosis; and immunohistochemical expression of synaptophysin, chromogranin A (CgA), or CD56.^2,3 Despite its rarity, hepatic metastasis occurs in approximately 15%–20% of advanced cases, contributing to a median survival of less than 8 months. ⁴ Globally, the incidence of LCNEC is rising, paralleling trends in smoking-related lung cancers, with an estimated annual mortality rate exceeding 60% even in early-stage disease. ⁵ Hepatic involvement is particularly associated with rapid disease progression and resistance to conventional therapies, underscoring the need for improved diagnostic and prognostic biomarkers. ⁶

Pathologically, LCNEC exhibits large polygonal cells with abundant cytoplasm, vesicular nuclei, and frequent necrosis, often overlapping morphologically with small cell lung cancer (SCLC) or non-SCLC (NSCLC). ⁷ Molecular subtyping has identified two distinct categories: SCLC-like (characterized by RB1/TP53 comutation) and NSCLC-like (with KRAS/STK11 alterations), which influence metastatic behavior.^8,9 Hematogenous dissemination to the liver, adrenal glands, and bones is common, driven by epithelial–mesenchymal transition and genomic instability linked to TP53 mutations.^10,11 The tumor microenvironment, marked by immune evasion via low programmed cell death ligand 1 (PD-L1) expression and stromal fibrosis, further facilitates metastatic colonization. ¹² These features highlight the aggressive biology of LCNEC and the urgent need for targeted therapeutic strategies tailored to its distinct molecular subtypes.

Case presentation

Patient information

A man in his early 60s with a history of coronary artery calcification and benign prostatic hyperplasia was admitted following the incidental detection of a hepatic mass during routine health screening and referred to Hangzhou First People’s Hospital (Affiliated of Westlake University School of Medicine) in mid-2024. The patient denied symptoms of abdominal pain, weight loss, or respiratory compromise.

Clinical findings

Results of the imaging studies were as follows: 1. Chest CT: a solitary 9 × 9-mm spiculated nodule was identified in the right upper lobe (Figure 1(a)). 2. Abdominal magnetic resonance imaging: a well-circumscribed, round lesion (46 × 36 × 32 mm) at the junction of hepatic segments VI and VII demonstrated arterial phase hyperenhancement with washout in portal and delayed phases, initially suggestive of hepatocellular carcinoma (Figure 1(b) and (c)). 3. 18F-fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET–CT): hypermetabolic activity was observed in the hepatic lesion, right hilar lymph nodes, and right upper lung nodule, consistent with metastatic malignancy. Chronic inflammatory changes were noted in the gastrointestinal tract. Results of the carcinoembryonic antigen (CEA) test revealed that the CEA level was 237.23 μg/L. Other tumor markers were within the normal range. Partial hepatectomy revealed a solitary 3.0 cm lesion in segment VI with clear resection margins (Figure 1(d)).

Diagnostic assessment

A hepatic segmentectomy was performed, and histopathological examination revealed nests of large polygonal cells with vesicular nuclei, prominent nucleoli, and extensive necrosis. Immunohistochemistry confirmed strong positivity for neuroendocrine markers (CD56+, synaptophysin+, and CgA+) and thyroid transcription factor-1 (TTF-1) (Figure 2(d) to (i)), with a Ki-67 proliferation index of 95%, supporting metastatic neuroendocrine carcinoma (NEC) of pulmonary origin (Figure 2(a) to (c)). Subsequent uniportal video-assisted thoracoscopic surgery (VATS) of the lung lesion demonstrated identical histology, confirming primary LCNEC with visceral pleural invasion.

Figure 1.

Imaging examinations and postoperative specimens. (a) Chest computed tomography scan showing a right upper lobe nodule (arrow). (b) Axial T2-weighted imaging demonstrates a heterogeneously hyperintense lesion (arrow) in segment VI of the liver. (c) Diffusion-weighted imaging at a high b-value (b = 1000 s/mm²) reveals marked hyperintensity (arrow) within the lesion, consistent with restricted diffusion and (d) tumor specimens after partial hepatectomy.

Figure 2.

Pathological and immunohistochemical results. (a) Pulmonary lesion: Combined morphology and immunohistochemistry, consistent with large cell neuroendocrine carcinoma. Tumor invasion into the visceral PL2 and thick-walled blood vessel is visible without lymphovascular invasion or perineural infiltration. (b) Hepatic metastasis: Poorly differentiated malignancy characterized by solid sheets of tumor cells with marked nuclear pleomorphism, high nuclear-to-cytoplasmic ratio, and extensive geographic necrosis. Immunohistochemical results; lung primary: diffuse positivity for (c) Syn, (d) chromogranin A, (e) CD5, and (f) thyroid transcription factor-1. Liver metastasis: Strong expression of (g) chromogranin A, (h) Syn, and (i) thyroid transcription factor-1 confirming neuroendocrine differentiation and pulmonary origin. PL: pleural layer.

Therapeutic intervention and outcomes

A multidisciplinary tumor board (MDT) comprising hepatobiliary surgeons, thoracic oncologists, and interventional radiologists recommended the prioritization of hepatic lesion management. The patient subsequently underwent laparoscopic anatomical liver resection (segments VI–VII). Postoperatively, the patient underwent transarterial chemoembolization (TACE) with etoposide (150 mg) and cisplatin (90 mg). Three weeks later, VATS resection of the lung lesion led to complete tumor removal. Molecular profiling revealed PD-L1 positivity and a pathogenic TP53 mutation. The patient subsequently received first-line therapy with serplulimab (300 mg, IV), cisplatin (35 mg/m²), and etoposide (100 mg/m²) within a 21-day cycle. The patient currently maintains stable clinical status. Surgical wound healing progressed uneventfully, and a plan for the second cycle of chemoimmunotherapy is pending. Until now, there has been no tumor recurrence and metastasis. The reporting of this study conforms to the Case Report (CARE) guidelines. ¹³

Discussion

In this case, the patient was admitted to the hospital because of a hepatic space-occupying lesion, and auxiliary examination indicated the possibility of liver and lung tumor lesions. The MDT evaluated the two lesions and found that the volume and shape of liver masses were more indicative of malignancy than those of lung lesions; thus, liver resection was performed first. Histopathological analysis of the hepatic resection specimen confirmed a poorly differentiated NEC; immunohistochemical profiling (synaptophysin+, CD56+, TTF-1+) strongly indicated metastasis from a pulmonary primary tumor. Notably, the primary lung lesion measured only 9 mm in diameter, whereas the hepatic metastasis exhibited rapid progression to a size of 46 × 36 × 32 mm. This is a striking discrepancy in tumor kinetics that is rarely reported in neuroendocrine malignancies. Although such rapid progression is uncommon in other NSCLC variants, it underscores the necessity for vigilant surveillance in LCNEC patients, even those with small primary lesions.

Hepatic metastasis in LCNEC of the lung is associated with aggressive disease progression and poor prognosis. Imaging plays a pivotal role in identifying metastatic lesions, with contrast-enhanced CT and PET–CT being the primary modalities. On CT, hepatic metastases typically present as hypoattenuating lesions with irregular margins, whereas PET–CT demonstrates intense FDG uptake (maximum standardized uptake value (SUV_max) > 9.0), reflecting high metabolic activity. ¹⁴ Notably, gallium-68 (⁶⁸Ga)-PET–CT demonstrates superior sensitivity in tumor localization compared with conventional imaging modalities. This technique significantly improves the detection ability of occult primary lesions and staging accuracy while maintaining diagnostic efficacy during somatostatin analog therapy.^15,16 In patients with suspected neuroendocrine tumors, ⁶⁸Ga-PET–CT should be strongly considered when clinically indicated. Furthermore, the presence of “camel hump signs” on ultrasound, indicative of staghorn-like calcifications, may further aid in differentiating LCNEC metastases from other hepatic malignancies. ¹⁷

Biomarkers such as neuron-specific enolase and CgA are elevated in 60%–80% of LCNEC cases, correlating with tumor burden and metastatic spread. ¹⁸ Ki-67 proliferation indices (>50%) are critical for distinguishing LCNEC from lower-grade neuroendocrine tumors and predicting metastatic potential. ¹⁹ Recent studies highlight the role of PD-L1 expression in metastatic LCNEC, with approximately 15%–20% of cases showing membranous positivity (≥1%), suggesting eligibility for immunotherapy. ²⁰ Molecular subtyping using next-generation sequencing further stratifies LCNEC into SCLC-like (RB1/TP53 mutations) and NSCLC-like (KRAS/STK11 alterations) subtypes, which may influence metastatic patterns and biomarker profiles.^21,22 Retrospective analyses suggest that SCLC-like LCNEC subtypes exhibit better chemotherapy responses compared with NSCLC-like subtypes, underscoring the importance of molecular profiling. ¹⁸

Prognostic factors include tumor stage, Ki-67 index, and molecular subtype. Patients with SCLC-like LCNEC and RB1/TP53 mutations demonstrate shorter median survival (8–12 months) compared with NSCLC-like subtypes (12–18 months). ²² Postoperative adjuvant chemotherapy may delay recurrence; however, its efficacy in metastatic conditions remains limited. ²³ Hepatic metastasis further reduces survival to 6–10 months, with elevated lactate dehydrogenase and neutrophil-to-lymphocyte ratio (NLR) serving as independent predictors of poor outcomes.^17,24 Systemic inflammatory markers hold significant prognostic value in stratifying outcomes in patients with pulmonary LCNEC. Readily accessible circulating biomarkers—NLR and platelet-to-lymphocyte ratio (PLR)—are established indicators of poor prognosis in advanced neuroendocrine neoplasms (NENs). In the context of cytokine pathways, elevated circulating interleukin (IL)-8 levels demonstrate a significant association with tumor progression in patients with advanced NEC. Furthermore, the expression of the tissue inflammation marker PD-L1 in tumor cells or tumor-infiltrating lymphocytes may serve as a negative prognostic biomarker in NENs. However, neither marker has been definitively validated, necessitating further studies to establish their clinical utility. The core inflammation network remains centered on dynamic monitoring of NLR/PLR and the IL-8/PD-L1 signaling axis. ²⁵

For the clinical management of patients with LCNEC, surgical resection is the preferred treatment for those with early-stage, resectable disease. Complete surgical resection remains the cornerstone of curative intent, with lobectomy and lymphadenectomy achieving 5-year survival rates of 30%–40% in stage I–IIIA disease.^16,20 The optimal systemic therapy for unresectable LCNEC presenting with locally advanced or metastatic disease remains undefined. Systemic therapy serves as a cornerstone in the management of advanced-stage LCNEC. For first-line treatment, platinum-based chemotherapy (cisplatin or carboplatin) combined with etoposide is the recommended regimen because of its association with significantly prolonged median progression-free survival compared with conventional regimens used for NSCLC, with response rates of 40%–50%.^1,13 No standard second-line therapy exists. Limited evidence regarding the use of immune checkpoint inhibitors (ICIs) following first-line progression suggests only modest efficacy. ²⁶ Patients with unresectable stage III LCNEC should receive multimodal therapy, including systemic chemotherapy and radiotherapy (RT), in accordance with current guidelines. ²⁷ Data concerning systemic therapeutic approaches for stage IV LCNEC are conflicting, and the gold-standard chemotherapy regimen for advanced or metastatic LCNEC remains contentious. ²⁸ Neither standard first- nor second-line systemic treatment regimens are currently established for LCNEC patients. Management strategies for LCNEC, particularly in the advanced setting, are not yet well-defined. ³ For patients with liver metastases, locoregional treatment options include the following: (a) surgical resection (which may encompass intraoperative thermoablation); (b) hepatic artery embolization techniques, including bland transarterial embolization, TACE, and transarterial radioembolization; (c) percutaneous thermoablation; and (d) RT. ²⁹ Patients with well-differentiated neuroendocrine tumors and unresectable, liver-dominant metastatic disease may benefit from hepatic artery embolization. ³⁰

Novel therapeutic strategies are urgently needed for metastatic LCNEC. ICIs, such as atezolizumab and nivolumab, have shown promise in PD-L1-positive cases, with case reports documenting partial responses.^14,20 The phase III KEYNOTE-604 trial demonstrated a 12-month overall survival benefit with pembrolizumab in high-grade neuroendocrine tumors, although LCNEC-specific data remain sparse. ¹

Targeted therapies are gaining popularity, particularly those for NSCLC-like subtypes. Sovantinib, a multi-kinase inhibitor, achieved disease control in a case of tonsillar LCNEC, suggesting potential cross-application in pulmonary variants. ²⁴ Anaplastic lymphoma kinase inhibitors (e.g. crizotinib) and rearranged during transfection inhibitors are being investigated for tumors that harbor actionable genetic mutations. ²² Additionally, delta-like ligand 3-targeted therapies, such as rovalpituzumab tesirine, are being evaluated in clinical trials for SCLC-like LCNEC. ²¹

Conclusion

The present case highlights the aggressive clinical behavior of pulmonary LCNEC, characterized by a small primary lung lesion with disproportionately rapid hepatic metastasis progression. The hepatic metastatic foci exhibited accelerated growth kinetics, surpassing the dimensions of the primary tumor—a phenomenon underscoring the tumor’s inherent metastatic potential and highly proliferative nature (Ki-67 index >80%). Clinicians should maintain a high index of suspicion for LCNEC when encountering multifocal malignancies, particularly in smokers presenting with discordant imaging findings or elevated neuroendocrine biomarkers. Early molecular profiling and multidisciplinary management are imperative to optimize therapeutic outcomes in this biologically aggressive entity.