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### 3.2. Specific Genetic Alterations |
Each histological subtype of NSCLC displays a unique molecular signature that influences both tumor behavior and therapeutic response. Adenocarcinoma is frequently associated with activating mutations in EGFR, rearrangements in ALK and ROS1, and mutations in KRAS and BRAF. These alterations result in abnormal activatio... |
### 3.3. Mechanisms of Tumor Progression and Metastasis |
Profound remodeling of the tumor microenvironment through the gradual accumulation of genetic alterations leads to NSCLC progression, allowing tumor cells to grow abnormally, resist apoptosis, and acquire invasive properties. Epithelial–mesenchymal transition is the mechanism by which tumor cells become mesenchymal and... |
## 4. Pathological Features |
The pathological features of NSCLC constitute a fundamental component of diagnostic evaluation and play a decisive role in prognosis and therapeutic planning. A thorough pathological evaluation integrates macroscopic appearance, detailed microscopic examination, immunohistochemical profiling, and molecular characteriza... |
### 4.1. General Macroscopic and Microscopic Characteristics |
From a macroscopic perspective, NSCLC demonstrates considerable heterogeneity, influenced primarily by tumor histology and anatomical site of origin. Centrally located tumors usually arise from the larger bronchi and may obstruct the airway, while peripheral lesions typically develop within the distal lung parenchyma, ... |
### 4.2. Invasion Patterns and Pathological Staging Criteria (TNM) |
Assessment of tumor invasion into adjacent anatomical structures is a central component of the pathological evaluation of NSCLC. As the tumor grows, it may infiltrate the bronchial tree, compromise the pulmonary vasculature, or penetrate the visceral and parietal pleura. More advanced lesions may extend beyond the lung... |
### 4.3. Predictive and Prognostic Factors |
In addition to the parameters defined by the TNM classification, multiple additional pathological features significantly influence the course of NSCLC. Thus, blood and lymphatic vessel invasion stands out as one of the strongest predictors of an unfavorable prognosis, as this fact reflects an increased capacity for sys... |
## 5. Clinical Manifestations |
The clinical presentation of NSCLC includes multiple signs and symptoms, depending on the location, size, growth rate, and local or distant spread of the tumor. In the early stages, it does not produce obvious symptoms, allowing the disease to progress silently. Therefore, a significant percentage of cases are identifi... |
### 5.1. Respiratory Symptoms |
Respiratory manifestations are the most common clinical features of NSCLC and are often the initial reason for patient presentation. Cough is the dominant symptom and may present in various forms—persistent, dry, or productive—depending on the degree of bronchial irritation and airflow obstruction. In central tumors, c... |
### 5.2. General Symptoms |
In addition to respiratory manifestations, patients with NSCLC also present with general, nonspecific symptoms. Among these, unintentional weight loss is notable, serving as a clinical indicator of active metabolism and tumor progression. This weight loss often coincides with anorexia, alterations in nutrient absorptio... |
### 5.3. Paraneoplastic Syndromes |
Paraneoplastic syndromes are systemic disorders that arise from the ectopic production of hormones, cytokines, or growth factors by tumor cells. These syndromes, although relatively rare, can serve as early diagnostic indicators of NSCLC [47]. Hypercalcemia occurs primarily in association with squamous cell carcinoma, ... |
## 6. Paraclinical Evaluation |
Paraclinical assessment of NSCLC is an essential element in diagnosis, influencing both staging and selection of appropriate therapeutic strategies. This evaluation involves advanced imaging modalities, targeted invasive procedures for tissue acquisition, and increasingly modern molecular analyses. Imaging methods prov... |
### 6.1. Imaging |
Chest radiography remains one of the oldest and most widely used diagnostic tools in the evaluation of patients with suspected pulmonary disease, including those ultimately diagnosed with NSCLC. Although its diagnostic performance is limited compared with more advanced imaging modalities, it continues to serve as a pra... |
### 6.2. Histological and Cytological Diagnosis |
Diagnostic certainty in NSCLC is based on histological or cytological confirmation, which remains the gold standard for identifying the specific tumor subtype. Obtaining a sufficient volume of high-quality biological material is essential—not only for accurate morphological evaluation but also to allow immunohistochemi... |
### 6.3. Molecular and Immunohistochemical Analyses |
The integration of molecular and IHC analyses has become the cornerstone of contemporary NSCLC management, moving beyond morphology-based classification to a precision oncology framework. Histopathological evaluation, while essential, is now complemented by IHC markers and comprehensive genomic profiling to guide diagn... |
## 7. Treatment |
The treatment of NSCLC results from the integration of clinical, imaging, histological, and molecular information in a multidisciplinary context involving a pulmonologist, an oncologist, a pathologist, and a thoracic surgeon. Treatment selection is no longer stage-based alone, but is critically dependent on molecular a... |
### 7.1. Surgical Treatment |
Surgical resection remains the standard treatment with curative intent for early-stage (I–II) and selected stage IIIA NSCLC with limited and resectable nodal involvement. The primary goal is complete excision of the tumor with negative margins while preserving as much functional lung parenchyma as possible. Lobectomy i... |
### 7.2. Radiotherapy |
Radiotherapy plays a key role in the management of NSCLC as a curative, definitive or palliative treatment modality, depending on the stage of the disease, the characteristics of the tumor, and the operability of the patient. By minimizing radiation-induced toxicity to surrounding normal tissues, various radiation tech... |
### 7.3. Chemotherapy |
Chemotherapy continues to be a fundamental component of the therapeutic strategy for NSCLC, especially in patients with advanced disease and as adjuvant or neoadjuvant treatment in early stages, and remains indispensable in multiple clinical settings. Platinum-based doublet chemotherapy constitutes the basis of systemi... |
### 7.4. Targeted Therapy |
Targeted therapy represents one of the most significant advances in the management of NSCLC, reflecting a paradigm shift toward precision oncology based on the identification of oncogenic driver alterations. By selectively inhibiting molecular pathways essential for tumor growth and survival, targeted agents have demon... |
### 7.5. Immunotherapy |
Immunotherapy is notable for providing significant and sustained improvements in survival outcomes with immune checkpoint inhibitors. These agents inhibit key immune checkpoint pathways that tumors use to evade immune surveillance, and the most widely used inhibitors target programmed cell death protein 1 (PD-1) and it... |
### 7.6. Palliative Treatment |
In patients with advanced NSCLC or those with limited functional reserve who are not candidates for curative intent therapies, the main goals of treatment include symptom control, optimization of quality of life, and psychosocial support. Therefore, palliative care is an essential component of the complex management of... |
## 8. Prognosis |
The prognosis of this type of cancer is influenced by clinical, histological, molecular, and therapeutic factors, with the stage of the disease at diagnosis remaining the most important determinant of prognosis. Overall survival is significantly superior in early stages of the disease, where complete surgical resection... |
## 9. Conclusions |
The landscape of NSCLC has evolved far beyond traditional histopathological classification. While histology remains a fundamental component of diagnosis, it is no longer sufficient to guide optimal patient management in the era of precision oncology. Comprehensive molecular profiling has become the standard of care, en... |
## Abbreviations |
The following abbreviations are used in this manuscript: |
[TABLE] |
NSCLC | Non-small-cell lung cancer |
SCLC | Small-cell lung cancer |
EGFR | Epidermal growth factor receptor |
ALK | Anaplastic lymphoma kinase |
ROS1 | Proto-oncogene tyrosine-protein kinase ROS |
KRAS | Kristen rat sarcoma viral oncogene homolog |
PD-1 | Programmed cell death protein |
PD-L1 | Programmed death-ligand 1 |
PM2.5 | Fine particles with diameters less than 2.5 μm |
DNA | Deoxyribonucleic acid |
PI3K/AKT | Phosphatidylinositol 3-kinase/protein kinase B |
JAK/STAT | Janus kinases/signal transducer and activator of transcription proteins |
FGFR1 | Fibroblast growth factor receptor 1 |
TNM | Tumor-node-metastasis |
ACTH | Adrenocorticotropic hormone |
MRI | Magnetic resonance imaging |
CT | Computed tomography |
PET | Positron emission tomography |
EBUS-TBNA | Endobronchial ultrasound-guided transbronchial needle aspiration |
VATS | Video-assisted thoracoscopic surgery |
NGS | Next-generation sequencing |
ctDNA | Circulating tumor DNA |
TTF1 | Thyroid transcription factor 1 |
TKIs | Tyrosine kinase inhibitors |
TP53 | Tumor protein 53 |
TPS | Tumor proportion score |
## Author Contributions |
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