Neuroendocrine neoplasms of the lung: The latest updates

Abstract

Neuroendocrine neoplasms are a group of tumors with heterogenous malignancy that evolve from neuroendocrine cells, most frequently in the gastrointestinal tract and in the lung. The latest 2021 World Health Organization (WHO) classification of lung tumors defines neuroendocrine neoplasms of the lung as an independent group of tumors, including typical and atypical neuroendocrine tumors and small cell and large cell neuroendocrine carcinomas. Although the overall nomenclature is essentially unchanged from the fourth WHO classification, there are several clinically relevant updates. In this review article, we discuss the epidemiological, clinical, diagnostic, therapeutic and prognostic features of these fascinating neoplasms, including the latest insights, current challenges and future perspectives.

Key Words: Neuroendocrine lung cancer; Carcinoid; Small cell lung cancer; Large cell neuroendocrine lung cancer; Diagnosis; Management

Core Tip: Neuroendocrine neoplasms (NENs) arise from neuroendocrine cells and vary in malignancy, commonly affecting the gastrointestinal tract and lungs. The 2021 World Health Organization classification of lung tumors categorizes lung NENs into typical and atypical neuroendocrine tumors and high-grade small cell and large cell neuroendocrine carcinomas. While the classification remains largely unchanged, key clinical updates have been introduced. This review explores the epidemiology, diagnosis, treatment, and prognosis of lung NENs, highlighting emerging insights, and future directions.

INTRODUCTION

Lung neuroendocrine neoplasms (LNNs) represent a group of uncommon tumors with multiple grades of malignancy apparently deriving from Kulchitsky cells, which are argentaffin amine precursor uptake and decarboxylation cells of the bronchial epithelium[1]. In 2021, the latest World Health Organization (WHO) classification of lung tumors affirmed LNNs as an independent group of tumors with heterogeneous malignancy[2], as previously established in 2015[3], including low-graded typical carcinoid (TC), intermediate-graded atypical carcinoids (AC), high-graded small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), as presented in Table 1. The distinction is based on histopathological aspects, the Ki-67 index, mitotic rate, and presence of necrosis. TC is characterized by carcinoid histology, < 2 mitosis/2 mm², and lack of necrosis. AC has carcinoid histology but 2-10 mitosis/2 mm² or spotted necrosis. SCLC has characteristic small cells, scant cytoplasm, granular chromatin without nucleoli, and a high mitotic rate > 11/2 mm² (median 80) with extended necrosis. LCNEC has neuroendocrine morphology with palisades, trabecular cells and organoid clusters, a high mitotic rate > 11/2 mm² (median 70), and diffuse necrosis. The mitotic count is suggested as the major criterion for discriminating among low-, intermediate-, and high-grade neuroendocrine neoplasms[4]. On the other hand, cautions must be adopted about the Ki-67 rate, which should be applied only for separating TC and AC from high-grade neoplasms[5], due to lack of validated scoring rules in lung tumors: Ki-67 rate is usually below 5% for TC, 10%-20% for AC, over 30% for SCLC or LCNEC. It must be emphasized that low and intermediate graded tumors are biologically distinct entities from high-grade cancers, having distinct genomic profiles[6]. Some LNNs, mainly carcinoids, are thought to have common precursor lesions: Diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH), which is a generalized proliferation of lung neuroendocrine cells associated with tumor lets and obliterative bronchiolitis[7]. On immunohistochemical evaluation, LNNs are typically positive for chromogranin A, Synaptophysin and cluster of differentiation (CD) 56 (NCAM1)[8]. Insulinoma-associated protein 1 (INSM1) has recently been claimed as useful neuroendocrine marker[9]: It is a nuclear transcription factor, considered a pan-neuroendocrine factor. ASCL1 is another neuroendocrine transcription factor, with high specificity and low sensibility since it is expressed only in a subgroup of LNNs[10]. LNNs represent about 20% of lung primary neoplasia: Carcinoids account for 4% (TC: AC = 10:1), SCLC for 15%, LCNEC for 3%. Since 1907, when Oberndorfer described a carcinoid tumor for the first time[11], several relevant updates have been established on LNNs. In this review article, we discuss the latest epidemiological, histological, clinical, diagnostic, therapeutic and prognostic features of these neoplasms.

Table 1 Histologic, immunohistochemical and cytological features of lung neuroendocrine neoplasms.

	Typical carcinoid	Atypical carcinoid	Carcinoid with high mitotic/proliferation index	LCNEC	SCLC
Definition	Well-differentiated neuroendocrine morphology, no necrosis, mitotic index < 2 mitoses/2 mm2	Well-differentiated neuroendocrine morphology, necrosis (punctate) and/or mitotic index 2-10 mitoses/2 mm2	Well-differentiated morphology, mitotic index > 10 mitoses/2 mm2 and/or Ki-67 > 30%	High-grade NSCLC with neuroendocrine morphology, cytology (prominent nucleoli and/or moderate to abundant cytoplasm) and a mitotic count of > 10 mitoses/2 mm2	Small cells (usually less than the size of 3 resting lymphocytes) with scant cytoplasm, granular nuclear chromatin with absent or inconspicuous nucleoli and > 10 mitoses/2 mm2
Cytology
Cell size	Variable	Variable	Variable	Large	Small (less than 3 resting lymphocytes)
Nuclear chromatin	Finely granular texture (salt and pepper)	Finely granular texture (salt and pepper)	Finely granular texture (salt and pepper)	Coarse to vesicular	Finely granular texture, evenly distributed
Nucleoli	Occasional, small	Common, small	Common, small	Common, large	Absent or inconspicuous
Cytoplasm	Variable	Variable	Variable	Abundant	Scarce
Histology
Morphology	Organoid, trabecular, rosette formation, nested, insular	Organoid, trabecular, rosette formation, nested, insular	Organoid, trabecular, rosette formation, nested, insular	Organoid, trabecular, palisading	Sheet-like, diffuse
Mitotic count/2 mm2	0-1	2-10	> 10	> 10 (50-60)	> 10 (70-80)
Proliferation index (Ki-67)	< 10%	10%-25%	> 30%	25%-80%	70%-100%
Necrosis	Absent	Focal, punctate	Focal, punctate	Extensive	Geographic
IHC
Synpatophysin	+++	+++	+++	+++	+/-
CgA	+++	++	+	+	+/-
INSM1	+++	+++	+++	+++	+++
RB1	WT	WT	WT	WT/lost	Lost
P53	WT	WT	WT	Aberrant	Aberrant

LCNEC: Large cell neuroendocrine cancer; SCLC: Small cell lung cancer; NSCLC: Non-small cell lung cancer; IHC: Immunohistochemical; CgA: Chromogranin A; INSM1: Insulinoma-associated protein 1; WT: Wilms tumor. Adapted from[13]. Citation: Vocino Trucco G, Righi L, Volante M, Papotti M. Updates on lung neuroendocrine neoplasm classification. Histopathology 2024; 84: 67-85. Copyrights© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.

PRECURSOR LESIONS

DIPNECH could be defined as pulmonary disseminated proliferation of neuroendocrine cells, linked to fibrosis and small nodular aggregates < 0.5 cm (tumorlets) without mitoses or necrosis. It is more frequently diagnosed in women, and it is linked to obliterative bronchiolitis. DIPNECH is thought to be the preinvasive form of carcinoid tumors, since disseminated hyperplasia of neuroendocrine cells can be found in up to 25% of resected carcinoids, in the adjacent pulmonary parenchyma[12]. Instead, its relationship with high-grade LNNs appears to be just random, corroborating the hypothesis that carcinoids and high-grade cancers are different entities. Affected patients can either present with chronic cough and shortness of breath, suggestive for constrictive bronchiolitis, or being asymptomatic. In the latest WHO classification, terms clinical and pathologic DIPNECH are introduced, to further define this condition depending on the presence or not of associated clinical manifestations[13]. Pathologic evaluation of lung sample allows for definite diagnosis, nevertheless its appearance on high-resolution computed tomography (CT) scan could be pathognomonic: Multiple punctate nodules, airway thickening and mosaic attenuation[14]. Management of DIPNECH is unclear, but considering the potential evolution to carcinoids, most authors suggest annual CT scan follow-up.

CARCINOID TUMORS

Epidemiology

Lung carcinoids are a rare subset of lung tumors, accounting for about 2% of all lung tumors and 10%-20% of carcinoids found throughout the body[15]. Their incidence varies between 0.2 to 2 cases per 100000 individuals, and interestingly, their prevalence has been on the rise, showing an increase of up to 6% per year[16]. This increase is likely due to advancements in imaging and histological identification. Lung carcinoids are typically diagnosed in individuals aged 40 to 60, though they are the most common primary lung neoplasia in the first and second decades of life[17]. Most lung carcinoids are sporadic, with about 5% associated with multiple endocrine neoplasia type 1 (MEN1). Rarely, they occur in hereditary clusters known as familial pulmonary carcinoid tumors. Despite their slow-growing nature, lung carcinoids are not benign tumors. They are usually diagnosed at an early stage, with TC being more common than AC at a ratio of 10:1[18]. TCs rarely spread beyond the lungs, whereas ACs have a higher tendency to metastasize, particularly to the liver, bones, and brain.

Clinical presentation

Clinically, patients with lung carcinoids are often asymptomatic, with the tumors being discovered incidentally during chest imaging. When symptoms do occur, central carcinoids can cause cough, dyspnea, hemoptysis, and recurrent pulmonary infections[19]. In less than 10% of cases, symptoms may result from ectopic hormonal activity of the tumor, leading to syndromes such as the syndrome of inappropriate antidiuretic hormone secretion, Cushing syndrome due to adrenocorticotropic hormone hypersecretion, or carcinoid syndrome from serotonin hypersecretion, which causes skin flushing, diarrhea, dyspnea, and tachycardia[20].

Diagnostic workup

The diagnostic workup typically begins with a routine chest radiograph, followed by contrast-enhanced CT scans and 18F-fluorodeoxyglucose positron emission tomography (PET)-CT to define the primary lesion and exclude metastasis[21]. Promising imaging methods include single-photon emission computed tomography-CT with 99mTc-Tektrotyd tracer for somatostatin receptors and 68Ga-Edotreotide PET, which is more sensitive for low-grade carcinoids[22]. Flexible bronchoscopy may be performed to assess bronchial involvement and collect samples for histopathological diagnosis.

Morphology and immunohistochemistry

Morphologically, carcinoids display uniform round or plasmacytoid cells in a nesting or organoid pattern, with granular or speckled chromatin and thin or absent nucleoli[23]. Immunohistochemistry aids diagnosis, with carcinoids typically testing positive for chromogranin A, synaptophysin, cluster of differentiation (CD) 56, and INSM1[24]. Thyroid transcription factor-1 (TTF-1) can be positive in fewer than half of cases. Orthopedia homeobox protein (OTP) is particularly useful for distinguishing primary lung carcinoids from metastatic ones as it is almost exclusively expressed in pulmonary carcinoids[25].

Mitotic count and Ki67 rate

The mitotic count differentiates TCs from ACs: TCs have fewer than 2 mitoses/mm², while ACs have between 2 and 10 mitoses/mm². The role of the Ki67 rate is still debated, although it is considered a strong prognostic marker[26]. Generally, 10 mitoses/mm² and a Ki67 rate of 20%-30% are accepted thresholds for diagnosing carcinoids. Recently, cases of highly proliferative carcinoids with higher mitotic counts and Ki67 rates have been reported[27], classified as LCNEC with carcinoid morphology in the latest WHO classification[2]. The growing importance of Ki67 is evident in the latest WHO thoracic guidelines, which, while not requiring it for distinguishing typical from ACs, recommend its inclusion as a supplemental marker. Research confirms that, like mitotic counts, Ki67 is a strong prognostic indicator in carcinoids. Findings suggest that a Ki67 index above 5% in TCs and over 10% overall is linked to worse outcomes. Although classification relies on mitotic counts, Ki67 levels of 10% or higher are almost exclusively seen in ACs, warranting a careful mitotic recount in cases of discrepancy.

Treatment

Surgical resection remains the treatment of choice for both TCs and ACs, ensuring a 5-year survival rate of 90% for TCs and 70% for ACs[28]. Due to their low proliferative index, standard chemotherapeutics are generally ineffective[29]. For advanced or metastatic carcinoids, especially those associated with carcinoid syndrome, somatostatin analogues are the first line of therapy[30]. In cases of disease progression, peptide receptor radionuclide therapy or targeted therapy with everolimus may be beneficial[31]. In localized carcinoids, radical surgical excision should always be pursued when feasible[32]. Other loco-regional treatments, such as endobronchial resection, stereotactic radiotherapy, radiofrequency, or microwave ablations, are reserved for patients with undue surgical risk, those who refuse surgery, or as ancillary perioperative methods. High rates of local relapse have been reported after ablation, making anatomical lung resection and systematic lymphadenectomy the preferred approach in patients with adequate cardio-respiratory reserve. Given the indolent behavior of TCs, some authors advocate for sub-lobar resections without radical lymphadenectomy, particularly for TCs[33]. For stage I TCs, radical anatomical resection (R0) through lobectomy is recommended. However, sublobar resection may be acceptable in patients with peripheral TCs smaller than 2 cm. While anatomical resections are still preferred by some surgeons due to the propensity of TCs to metastasize to lymph nodes (LNs), segmentectomy has been suggested over wedge resection for better oncological outcomes. Approximately two-thirds of all carcinoid tumors arise in the major airways, with about 20% presenting as purely intraluminal endobronchial lesions. These tumors can be managed with bronchoplastic resections to preserve lung function without compromising oncological results[34]. Endoscopic techniques such as Nd-YAG laser, diathermy, and cryosurgery have been largely abandoned due to high recurrence rates and the risk of extraluminal spread[35]. Bronchoplastic and parenchyma-saving procedures are viable options for highly selected patients with typical endobronchial carcinoids. The prognostic impact of LN involvement has been well documented, particularly for ACs[36]. Radical lymphadenectomy is highly recommended for ACs, while for TCs, LN sampling may be sufficient due to the lower incidence of nodal metastases. Current guidelines recommend at least LN sampling or dissection during resection for NETs.

Future perspectives

While lung carcinoids have traditionally been considered a single pathological entity, recent multi-omic studies indicate they consist of three distinct biological subtypes[37]. These subtypes are defined by differences in gene expression, methylation, and mutation profiles. One subtype, characterized by MEN1 mutations and low OTP expression (Cluster B), is linked to poor prognosis, consistent with prior research on these markers[38]. Another small subset, termed “supra-carcinoids”, exhibits carcinoid-like morphology but shares molecular and clinical traits with neuroendocrine carcinomas, requiring further investigation[38]. While these findings offer insight into the biology and potential origins of lung carcinoids, their impact on diagnosis and clinical management remains uncertain.

Lung carcinoids, while rare, are a significant subset of lung tumors that require precise diagnostic and treatment strategies. Their slow-growing nature and indolent behavior do not preclude their potential for metastasis and recurrence. Surgical resection remains the cornerstone of treatment, with radical excision and systematic lymphadenectomy offering the best outcomes. Advances in imaging and histological techniques have improved the detection and management of these tumors, but ongoing research and clinical trials are essential to refine treatment protocols and improve patient survival rates.

SCLC

Epidemiology

SCLC is a highly aggressive form of lung cancer, representing more than 90% of small cell cancers in the body. It accounts for approximately 10%-15% of all lung cancers[39]. It is more prevalent among older adults, with the highest incidence occurring in individuals aged 65 years and older. Historically, SCLC has been more common in men than in women. However, this gap has been narrowing in recent years. The proportion of SCLC among newly diagnosed lung cancer cases dropped from 14.5% in 2000 to 11.8% in 2019. This decline occurred across all sex and racial groups but was more pronounced and began earlier in men than in women. As a result, the male-to-female ratio shifted from 1.14:1 in 2000 to 0.93:1 in 2019[40]. Smoking is the primary risk factor for SCLC[41]. Approximately 95% of cases are attributed to tobacco smoke, either through active smoking or exposure to secondhand smoke. The incidence of SCLC varies geographically, reflecting differences in smoking prevalence and exposure to environmental carcinogens[42]. Certain lung diseases, such as chronic obstructive pulmonary disease, are associated with an increased risk of developing SCLC[43]. There are some ethnic and racial disparities in the incidence of SCLC. For example, African American men have historically had higher rates of SCLC compared to other racial groups in the United States[44]. The overall incidence of SCLC has been declining over the past few decades, largely due to decreases in smoking rates and public health efforts aimed at tobacco control.

Defining features and diagnostic markers

Traditionally, SCLC has been a morphological diagnosis, but confirmatory immunohistochemistry has become more common to improve diagnostic accuracy[45]. The latest WHO classification recommends immunohistochemistry for excluding alternative diagnoses rather than as a requirement for SCLC diagnosis. SCLC is characterized by small cell size, typically smaller than three lymphocytes, with finely dispersed chromatin, scant cytoplasm, and fragile nuclei that exhibit molding. The presence of DNA streaming and encrustation of vessels (Azzopardi effect) are notable features[46]. Extensive necrosis and high mitotic and apoptotic rates are also common. While most SCLCs display a diffuse or sheet-like pattern, some may show a nested or organoid architecture. Concerning immunohistochemistry, CD56 is positive in most SCLC cases, though it can also be expressed in non-neuroendocrine neoplasms like hematolymphoid neoplasms[47]; Synaptophysin and chromogranin A are negative in up to 20% of SCLC cases; INSM1 is useful for diagnosing SCLC lacking other marker expressions but it is also present in non-neuroendocrine neoplasms such as sarcomas or adenoid cystic carcinomas[48]. Genomically, SCLC is relatively homogeneous, typically characterized by alterations in RB1 and TP53[49]. However, distinct subtypes exist based on global differences in gene expression and methylation profiles, primarily defined by master transcriptional regulators[50]: ASCL1 dominates in approximately 70% of SCLC cases, associated with the classic, chemosensitive type; NEUROD1 is linked with high levels of neuroendocrine marker expression; POU2F3 represents neuroendocrine-negative SCLC, accounting for about 10% of cases.

Treatment and prognosis

SCLC is typically treated with chemotherapy, with cisplatin and etoposide being the standard regimen[51]. Despite initial responsiveness, recurrence rates are high, up to 30%-50%. The prognosis for SCLC remains poor, with a 2-year survival rate of around 5% and median survival ranging from 15 to 20 months[52]. Surgery is considered only for early-stage SCLC (T1-2N0M0)[53]. Studies have shown 5-year survival rates of 50% for patients with stage I SCLC undergoing lobectomy. For non-metastatic SCLC, combined modality treatments, including chemotherapy and radiotherapy, can achieve 5-year survival rates of 25%-30%[54]. Prophylactic cranial irradiation is recommended for patients responding to initial treatment to reduce the risk of brain metastases[55]. Recent advancements include the addition of immune checkpoint inhibitors to first-line chemotherapy, improving progression-free and overall survival[56,57]. However, the response to T cell checkpoint blockade remains limited to about 15% of patients. Despite advances in treatment, SCLC continues to be associated with a poor prognosis due to its aggressive nature and high recurrence rates. There is a pressing need for novel therapeutic approaches and biomarkers to guide clinical decisions. Ongoing research into the molecular characteristics of SCLC and the development of targeted therapies hold promise for improving patient outcomes.

Future perspectives

Significant advances in SCLC research are shaping new investigative paths and offering hope for patients. Genetically engineered mouse models, patient-derived models, and primary tumor studies have deepened understanding of SCLC biology. Transcriptomic and proteomic analyses have identified potential tumor-specific vulnerabilities and mechanisms of therapy resistance[58]. Defining transcriptional drivers has helped classify SCLC subtypes, paving the way for targeted therapies[59]. Technological improvements in imaging and radiotherapy have enhanced survival for localized cases while reducing side effects. Immunotherapy has modestly improved survival in metastatic SCLC, marking progress but highlighting the need for more effective treatments[59]. Screening for early-stage SCLC remains a critical unmet need, as most cases are diagnosed at an advanced stage. SCLC exhibits significant heterogeneity, with studies identifying distinct subtypes that may originate from different lung epithelial cells. Epigenetic mutations play a role in transcriptional shifts, but their impact on prognosis and therapy response remains unclear. Tumor heterogeneity, including a mix of neuroendocrine and non-neuroendocrine cells, may influence metastasis, but its role in human SCLC is not well defined. While chemo-immunotherapy is now the first-line standard for metastatic disease, its benefits are limited to a small subset of patients[60]. Research is focusing on enhancing immune response through alternative checkpoint inhibitors, bispecific T-cell engagers, and DNA damage response inhibitors. Efforts are also underway to integrate immunotherapy into early-stage treatment alongside chemoradiotherapy. New biomarker-driven approaches, such as circulating tumor DNA analysis, could help identify patients needing additional therapy vs those likely to be cured with current treatments[61]. Despite progress, clinical advances in SCLC lag behind non-small cell lung cancers (NSCLC), and many questions remain. However, continued translation of laboratory discoveries into clinical trials is expected to drive meaningful improvements in patient outcomes.

SCLC is a highly aggressive and challenging form of lung cancer with distinct morphological and genomic characteristics. Advances in diagnostic techniques and treatment approaches have improved patient management, but the prognosis remains poor. Continued research into the molecular underpinnings of SCLC and the development of targeted therapies are crucial for improving outcomes for patients with this devastating disease.

LCNEC

Epidemiology

LCNEC is a rare but aggressive form of NSCLC that exhibits neuroendocrine differentiation, comprising approximately 3%-5% of all lung cancers[62]. It is less common than SCLC but more aggressive than typical NSCLC. LCNEC predominantly affects older adults, with a median age at diagnosis typically between 60 to 70 years. It shows a slight male predominance. Smoking is a significant risk factor for LCNEC. The majority of patients with LCNEC have a history of tobacco use[63]. There may be some geographic and ethnic variations in the incidence of LCNEC, but data specific to these variations are limited due to its rarity. Underlying lung diseases such as COPD may increase the risk of developing LCNEC.

Defining features and diagnostic criteria

LCNEC is defined by its unique blend of neuroendocrine morphology and non-small cell carcinoma cytologic features[64]. Key morphological characteristics include neuroendocrine architecture (organoid nesting with palisading, trabeculae, and rosettes), cytologic features (large cell size, prominent nucleoli, and abundant cytoplasm), high proliferation rate (greater than 10 mitoses per 2 mm², with median values often reaching around 70). The diagnosis of LCNEC requires the expression of at least one of the three standard neuroendocrine markers[65]: Synaptophysin, chromogranin A, or CD56. Newer markers such as INSM1 and ASCL1 show promise but their roles in diagnosing LCNEC remain to be fully clarified. Although not part of the WHO criteria for diagnosis, Ki67 is helpful in distinguishing LCNEC from carcinoids, particularly in biopsies with crush artifacts. Ki67 rates in LCNEC vary widely, typically between 70%-100%, but can overlap with highly proliferative carcinoids in the 20%-60% range[66].

Morphological spectrum

LCNEC exhibits a wide morphological spectrum, spanning two relatively distinct extremes: NSCLC-like LCNEC and SCLC-like LCNEC[67]. The formers have large cells, abundant cytoplasm, and prominent nucleoli, combined with neuroendocrine features like nesting and rosettes. These tumors often resemble NSCLC entities such as adenocarcinoma with solid or cribriform patterns, large cell carcinoma, and basaloid squamous cell carcinoma. Characterized by alterations typical of smoking-associated adenocarcinomas, such as mutations in STK11, KEAP1, and KRAS, and the absence of RB1 alterations[68]. These tumors are also associated with chemoresistance and aggressive behavior. The latter’s exhibit nuclear features similar to SCLC, such as small or intermediate cell size and coarsely granular chromatin, but with more prominent nucleoli or more abundant cytoplasm. The presence of visible intercellular membranes is a useful criterion to support the diagnosis of LCNEC, as SCLC typically lacks these due to scant cytoplasm[69]. Characterized by RB1 and TP53 alterations, similar to SCLC. These tumors often exhibit aggressive and treatment-resistant behavior. Diagnosing LCNEC can be challenging, particularly in small or poorly preserved biopsy specimens. However, recent trends in obtaining larger tissue volumes for molecular testing have made biopsy diagnosis more feasible. A semiquantitative scoring system has been proposed to aid diagnosis in biopsies, considering factors like neuroendocrine differentiation, necrosis, Ki67 rate, and neuroendocrine marker positivity[70].

Treatment and prognosis

LCNEC is associated with an extremely poor prognosis and high rates of brain metastases. The treatment approach to LCNEC has been uncertain, with both SCLC-type and NSCLC-type systemic therapies used in practice[71]. Recent studies suggest that molecular subtype, particularly the status of RB1, can influence treatment outcomes and prognosis. Surgery is the recommended treatment for early-stage, resectable LCNEC, achieving 5-year survival rates of 27%-67%[63]. However, a high incidence of recurrence, especially within the first 2 years, necessitates a multimodal approach, including adjuvant chemotherapy[72]. Lobar resection is preferred over sublobar resections for improved survival outcomes in stage I LCNEC. For advanced or metastatic LCNEC, the optimal systemic treatment remains debated. Platinum-based chemotherapy regimens used for SCLC (e.g., etoposide and cisplatin) are often recommended, although LCNEC generally shows lower chemosensitivity than SCLC[73]. Recent data suggest that RB1 expression could serve as a potential biomarker for selecting the appropriate treatment regimen[74]: RB1 loss indicates SCLC-type chemotherapy, while intact RB1 suggests NSCLC-type treatments. The role of immunotherapy and other targeted treatments in LCNEC remains under investigation[75-77].

Future perspectives

The diagnosis of LCNEC requires differentiation from NSCLC and SCLC, given its molecular overlap with both. This continuum can create diagnostic challenges, particularly in tumors with ambiguous features. Neuroendocrine marker expression alone is insufficient for diagnosing LCNEC, as some NSCLCs also express these markers. However, most LCNECs are positive for two or more standard neuroendocrine markers, whereas conventional NSCLC typically expresses only one, often focally[78]. Certain poorly differentiated tumors, such as SMARCA4-deficient undifferentiated tumors, can also express NE markers, complicating the distinction. Other immunohistochemical (IHC) markers provide limited help. Strong, diffuse Napsin A expression favors adenocarcinoma, but weak/focal expression occurs in about 15% of LCNECs[79]. A TTF-1-positive/Napsin A-negative profile should raise suspicion for neuroendocrine carcinoma, as most TTF-1-positive adenocarcinomas also strongly express Napsin A. The distinction between SCLC and LCNEC is primarily morphologic, based on cell size, nucleoli prominence, and cytoplasmic volume. SCLC typically lacks visible cell membranes and often presents with crush artifacts and extensive necrosis, making diagnosis difficult on small biopsies[80]. In such cases, high-quality hematoxylin-eosin stains and cytologic preparations can be helpful. A tumor with any identifiable SCLC morphology qualifies as combined SCLC-LCNEC rather than pure LCNEC. No definitive IHC markers exist for this distinction, but Napsin A expression supports LCNEC, as it is consistently negative in SCLC, though with low sensitivity. Dot-like keratin reactivity, commonly seen in SCLC, can also occur in LCNEC. Rb protein retention is more frequent in LCNEC than SCLC but lacks absolute specificity.

LCNEC is a highly aggressive and challenging form of lung cancer with distinct morphological and molecular characteristics. Advances in diagnostic techniques and molecular profiling have improved our understanding of LCNEC and its subtypes. However, the prognosis for LCNEC remains poor, highlighting the need for continued research into novel therapeutic approaches and biomarkers to guide clinical decisions. Multimodal treatment strategies, including surgery and systemic therapies tailored to molecular subtypes, offer the best hope for improving outcomes in this rare and aggressive malignancy.

CONCLUSION

Lung neuroendocrine tumors (LNETs) exhibit a range of common characteristics yet remain heterogeneous in terms of aggressiveness, progression, and prognosis. This diversity underscores the ongoing controversies surrounding their diagnosis and treatment across different subtypes. Recent molecular advancements hold promise for the development of novel diagnostic, prognostic, and predictive tools soon. These advancements may also pave the way for innovative treatment strategies tailored to the specific molecular profiles of LNETs. SCLC continues to pose significant challenges with high mortality rates. Current treatments have demonstrated limited efficacy, reflecting gaps in our understanding of the disease’s underlying mechanisms. LCNEC lacks specific therapeutic guidelines supported by prospective clinical trials. Despite efforts to optimize chemotherapy regimens, prognosis remains unfavorable, particularly in comparison to NSCLC. A multidisciplinary approach is imperative for accurate diagnosis and effective multimodal treatment planning in LNETs, aiming to improve patient outcomes through integrated care strategies. The urgent need for paradigm shifts in the management of LNETs underscores the importance of ongoing research and collaborative efforts to address current limitations and improve therapeutic outcomes for affected patients.