Non-small cell lung cancer is a group of morphologically similar malignant neoplasms, including glandular, large cell and squamous cell lung cancer. Typical complaints of patients with persistent cough, shortness of breath, hemoptysis, hoarseness of voice, chest pain. Of the nonspecific symptoms, fever, weight loss, weakness are bothering. Pathology is diagnosed according to radiography/CT of the chest, fibrobronchoscopy, videothoracoscopy, histological picture. Treatment is carried out with the help of chemotherapy, immunotherapy, radiation therapy, lung resection (lobectomy/ bilobectomy, pneumonectomy).
C34 Malignant neoplasm of the bronchi and lung
Non-small cell lung cancer (NSCLC) accounts for up to 85% of all malignant neoplasms of this localization. The remaining 15% is accounted for by small cell carcinoma. The main histological types of NSCLC are adenocarcinoma, squamous cell and large cell carcinoma. In men, lung cancer is 2 times more common than in women. The average age at diagnosis is 65-70 years. Due to the fact that in 75% of cases, locally advanced (stage III) or metastatic NSCLC (stage IV) is diagnosed at the initial treatment, the problem of early diagnosis and selection of the optimal treatment algorithm is very acute in oncopulmonology.
Causes of non-small cell lung cancer
The carcinogenesis factors that cause lung cancer are the same for different types of the disease. In the etiology of non-small cell carcinoma, the predominant role is given to the inhalation of tobacco smoke and the effect of pollutants on the respiratory system:
- Smoking. Tobacco smoking remains the leading cause of lung cancer: in Europe, 90% of men and 80% of women are smokers. The risk of NSCLC increases in proportion to the length of smoking, the number of cigarettes smoked is less important. Passive smoking is disproportionately less harmful than active smoking, but its role should also not be underestimated.
- Harmful production factors. Occupational hazards have a significant impact on morbidity statistics. Among them are the effects of radon, arsenic, asbestos dust, cadmium, coal combustion products, paint vapors and solvents. At risk for the development of non-small cell lung cancer are mining workers, builders, stokers, welders, paint workers, artists, etc.
- Environmental pollution. The incidence of NSCLC is higher in cities than in rural areas, which underlines the importance of the state of the environment in its occurrence. Oncogenic risk factors are fuel combustion products, industrial emissions from chemical, metallurgical, oil refining, waste processing and other enterprises.
- Genetic predisposition. Patients with non-small cell lung cancer have an individual oncological predisposition. It may be associated with certain mutations in oncogenes and anti-oncogenes, polymorphism of genes whose expression products take part in the metabolism of carcinogenic substances.
Different morphological variants of NSCLC have their own gender and etiological features. Thus, squamous cell carcinoma of the lungs is more common in men and is mainly associated with smoking. Adenocarcinoma, on the contrary, is least associated with nicotine addiction ‒ women taking estrogens as HRT are more at risk of its development.
The following diseases are associated with the risk of developing non-small cell cancer:
- pneumoconiosis (asbestos);
- interstitial lung diseases;
- bronchial asthma.
The pathogenetic mechanisms of NSCLC are heterogeneous. In addition to the direct action of carcinogens on the respiratory tract, genetic damage plays an essential role in the initiation of the oncoprocess.
Carcinogenic agents influence the genetic apparatus of the cell by triggering inactivating mutations in suppressor genes and activating mutations in oncogenes. A significant factor in the pathogenesis of NSCLC associated with smoking is the polymorphism of genes of xenobiotic metabolism enzymes, in particular, cytochromes. To date, the association of an increased risk of non-small cell lung cancer with polymorphisms of the CYP1A1, GSTM1, hOGG1 genes, EGFR, BRAF mutations, etc. has been studied.
Of great importance in the development of tumor transformation is chronic inflammation caused by prolonged exposure to irritating substances, the addition of infection. The death of goblet-shaped and ciliated cells leads to a decrease in the barrier function of the epithelium. Direct contact of basal layer cells with carcinogens causes their damage. Against this background, the production of cytokines and growth factors that trigger cell proliferation increases.
Regeneration processes are disrupted, which is accompanied by basal cell hyperplasia and metaplasia, and later ‒ epithelial dysplasia. In the foci of dysplasia of the large bronchi (central lung cancer), small cell carcinoma and squamous cell carcinoma mainly develop. Peripheral cancer, in addition to the listed types, can be represented by adenocarcinoma, bronchioloalveolar cancer.
According to histological characteristics, there are 3 types of non-small cell lung cancer, which combine common features of biological development, clinical course and therapeutic tactics:
- adenocarcinoma – accounts for about 40% of lung cancer, develops from glandular cells that produce bronchial secretions;
- large-cell (low-grade) cancer is diagnosed in 10-15% of cases, more often represented by neuroendocrine carcinoma. Together with adenocarcinoma , it belongs to non – squamous cell carcinoma;
- squamous cell (epidermoid) carcinoma – is about 25-30%, originates from epithelial cells.
When staging NSCLC, the TNM classification from 2017 is used. The primary tumor is encoded by the Latin letter T (tumor):
- Tx – visually (radiologically, endoscopically) the tumor is not detected, however, atypical cells can be detected during cytological examination of bronchial secretions or sputum;
- T0 – no data for neoplasm;
- Tis – preinvasive carcinoma (cancer in situ);
- T1 is a tumor up to 3 cm in diameter with no signs of invasive growth;
- T2 is a tumor more than 3, but less than 7 cm in diameter, passing to the main bronchus or visceral pleura or causing atelectasis, pneumonitis;
- T3 is a tumor with a diameter of more than 7 cm, or sprouting the chest wall, diaphragm, diaphragmatic nerve, parietal pleura and pericardium;
- T4 – regardless of the size, the tumor invades the heart, main vessels, esophagus, trachea, recurrent nerve, vertebrae, or there is an additional node in another lobe of the same lung.
The presence of metastases in regional lymph nodes is indicated by the code N (nodus):
- Nx – assessment of regional lymph nodes is not possible;
- N0 – there are no metastases in the regional lymphatic basin;
- N1 –metastases in peribronchial, portal, pulmonary lymph nodes on the side of the primary tumor;
- N2 – metastases to mediastinal lymph nodes on the tumor side;
- N3 – metastases to mediastinal lymph nodes, portal, supraclavicular lymph nodes, including from the opposite side.
To designate distant metastatic foci, the code M (metastasis) is used:
- Mx – assessment of metastases is impossible;
- M0 – absence of distant metastases;
- M1 – distant metastases confirmed.
Non-small cell lung cancer symptoms
Early signs of non-small cell lung cancer are often not associated with the respiratory system. There is unmotivated weakness, lack of appetite, unexplained weight loss. It is often bothered by prolonged, uncupable subfebrility caused by cancer intoxication.
As NSCLC progresses, specific symptoms are added. There is a constant nagging cough – dry at first, as the bronchus is obstructed by a tumor – with the release of mucopurulent sputum. With hemoptysis, sputum acquires a “rusty” shade or the appearance of “raspberry jelly”. Recurrent endobronchitis and pneumonitis are often diagnosed. Breathing becomes difficult, there is a feeling of lack of air. Persistent pains in the chest, radiating into the shoulder, shoulder blade, abdomen, are bothering. If the recurrent nerve is affected, hoarseness of the voice may be noted.
In non‒small cell lung cancer, paraneoplastic syndromes may develop: hypercalcemia, “drumsticks” syndrome is typical for squamous cell type; gynecomastia is typical for large cell type; osteoarthropathy, dermatomyositis, black acanthosis, etc. for adenocarcinoma.
A feature of the course of non-small cell lung cancer is its high aggressiveness: rapid invasive growth, active metastasis. The spread of the tumor into the surrounding tissues may be accompanied by SVC syndrome, Gorner syndrome, paralysis of the diaphragm, compression of the brachial plexus. The formation of lung atelectasis, pneumothorax is possible.
With the invasion of the pleura, cancerous pleurisy develops, with the germination of the pericardium, an effusion is formed in the pericardial sac. Metastasis or germination of NSCLC into the esophagus leads to the formation of tracheoesophageal or bronchoesophageal fistulas. Arrosia of the bronchial arteries or branches of the pulmonary artery can contribute to massive pulmonary bleeding. Distant metastases of non-small cell carcinoma are detected in the liver, adrenal glands, kidneys, bones, spine, brain.
Diagnostics of non-small cell lung cancer
At the initial visit to a pulmonologist or oncologist, about a third of patients have signs of distant metastases, the same number have systemic tumor manifestations, and only 25-30% of patients have local symptoms of non-small cell lung cancer. The examination algorithm for suspected NSCLC includes:
- X-ray diagnostics. The primary routine methods are radiography and linear tomography of the lungs – with their help, you can identify the shadow of a tumor node, signs of hypoventilation or atelectasis of the corresponding area of the pulmonary field. Chest CT has a higher resolution, which helps to detect the initial stages of cancer with a tumor size of up to 3 cm.
- Bronchological examination. Fibrobronchoscopy is one of the mandatory diagnostic methods. It allows you to visualize the tumor at its central location, to judge the boundaries of its spread, to take diagnostic material: biopsies, smear prints, bronchial flushes. Promising methods are lung endosonography, fluorescence endoscopy.
- Clarifying diagnostics. To assess the local spread of non-small cell carcinoma, thoracoscopy, mediastinoscopy, PET-CT of the lungs can be indicated. The search for distant metastases may require ultrasound and chest CT, osteoscintigraphy, MRI of the brain with contrast. In preparation for surgery, it is necessary to assess the FVD, the state of the heart (ECG, EchoCG).
- Laboratory tests. Detailed clinical and biochemical blood tests are carried out, the study of PTH, blood calcium, and the coagulation system. An important aspect of confirming the diagnosis is sputum analysis for atypical cells, cytology of pleural punctate. For differential diagnosis and evaluation of treatment, the indicators of cancer markers are important: CYFRA 21-1, SCC, REA. To determine the activating mutations, a molecular genetic study is carried out.
Most manifestations of non-small cell lung cancer are nonspecific, occur in non-tumor pulmonary and extrapulmonary pathology. In this regard, as part of the diagnosis, it is necessary to exclude:
- tuberculosis of the lungs;
- pleurisy of inflammatory etiology;
- intercostal neuralgia;
- other volumetric processes in the lung: abscess, cyst, benign tumors.
Treatment of non-small cell lung cancer
The tactics of treatment of NSCLC is determined based on the stage of the tumor process, morphological diagnosis, functional reserves of the patient’s body. Depending on this, surgical, conservative treatment or a combination of methods is chosen.
Lobectomy, bilobectomy, and pulmonectomy are considered standard operations for non-small cell cancer. Lung resection can be supplemented by regional lymph dissection, removal of mediastinal fiber, resection of the trachea, esophagus, SVC, diaphragm. The radicality of the operation is confirmed by intraoperative histological examination. The nature of access (thoracoscopic, open) does not affect the results and prognosis.
With low cardiorespiratory indices, segmentectomy and atypical lung resection are performed, but these interventions are associated with a higher frequency of local relapses. With a high risk of complicated course (bleeding, abscessing, compression), palliative cytoreductive operations are performed.
It is used both at the preoperative stage (neoadjuvant therapy) and after surgery (adjuvant therapy). In inoperable non-small cell lung cancer, the presence of contraindications to surgery is the main method of therapy. Includes the following methods:
- Chemotherapy. Antitumor drug therapy can increase relapse-free survival after radical surgery, increase resectability in patients with advanced stages of the disease. In NSCLC, intravenous administration of platinum-containing chemotherapy drugs in various combinations is indicated. Intrapleural thermochemotherapy can be performed as an additional method.
- Radiation therapy. It includes irradiation of the primary tumor, regional lymph nodes, isolated metastases. It can be carried out in a radical and palliative mode, combined with PCT (chemoradiotherapy) for unresectable tumors. In recent years, along with remote, endobronchial LT has been used.
- Other methods of treatment. In patients with endobronchial NSCLC, endoscopic PDT and endobronchial stenting can be used to eliminate bronchial obstruction. If there is a threat of bleeding, embolization of the bronchial arteries is performed. In advanced forms, molecular-directed therapy with EGFR tyrosine kinase inhibitors (in the presence of appropriate mutations), immunotherapy with PD-1 inhibitors, combined immunochemotherapy is used.
- Symptomatic therapy. It is carried out at all stages in order to relieve the symptoms of NSCLC. It may include pleurocentesis for cancerous pleurisy, hemostatic therapy for hemoptysis, pain relief for pain syndrome, antibiotic therapy for pneumonia, etc.
Prognosis and prevention
The best response to treatment is achieved in patients with a small primary tumor without metastases. With radical removal, the relapse-free 5-year survival rate ranges from 70-85% at T1NOMO to 60% at T2NOMO. In the postoperative period, CT examination is performed every six months for the first 2 years, then annually. Inoperable stages of non-small cell lung cancer have an unsatisfactory prognosis.
To prevent NSCLC, the most significant risk factors should be excluded: smoking, contact with potential carcinogens. It is necessary to undergo an annual fluorographic examination, conduct an in-depth medical examination of workers with professional disabilities.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020 Jan;70(1):7-30. – link
- Funai K, Yokose T, Ishii G, Araki K, Yoshida J, Nishimura M, Nagai K, Nishiwaki Y, Ochiai A. Clinicopathologic characteristics of peripheral squamous cell carcinoma of the lung. Am J Surg Pathol. 2003 Jul;27(7):978-84. – link
- Clinical Lung Cancer Genome Project (CLCGP); Network Genomic Medicine (NGM) A genomics-based classification of human lung tumors. Sci Transl Med. 2013 Oct 30;5(209):209ra153. link
- Alberg AJ, Samet JM. Epidemiology of lung cancer. Chest. 2003 Jan;123(1 Suppl):21S-49S. – link
- Lorigan P, Radford J, Howell A, Thatcher N. Lung cancer after treatment for Hodgkin’s lymphoma: a systematic review. Lancet Oncol. 2005 Oct;6(10):773-9. – link