Overview
Definition
Lung nodule is an imaging finding that generally refers to a focal, rounded, hyperdense, solid or subsolid lung shadow ≤3 cm in diameter, which may be isolated or multiple, and is not accompanied by pulmonary atelectasis, hilar lymph node enlargement, or pleural effusion [1].
Pathologic biopsy is the gold standard for the diagnosis of benign or malignant lung nodules. Lung nodules in which tumor cells are found pathologically are called malignant lung nodules.
Malignant lung nodules are abnormal growths of tissue in the lungs that usually appear as one or more round-like nodules in the lungs. These nodules may be primary (originating in the lungs) or secondary (spread of tumor cells from other sites).
Classification
Malignant lung nodules are classified according to their size
Classification according to the density of malignant lung nodules
Classification according to the number of malignant pulmonary nodules
Classification according to histologic type
Incidence
The results of low-dose chest CT (LDCT) screening for community lung cancer risk groups conducted in China showed that the positive rate of lung nodules was as high as 22.9% (804/3512), of which the proportion of patients with malignant nodules amounted to 6.34% (51/804), and the detection rate of lung cancer was 1.5% (51/3,512).
The malignancy rate of tiny nodules <5 mm in diameter is <1%, the malignancy rate of nodules 5-9 mm in diameter is 2%-6%, the malignancy rate of nodules 8-20 mm in diameter is 18%, and the malignancy rate of nodules >20 mm in diameter is >50%.
Etiology
Malignant lung nodules are mainly seen in neoplastic diseases such as lung cancer. Age, gender, race, and smoking are high risk factors for malignant lung nodules.
Causes
Common pathologic types of malignant lung nodules include primary lung cancer, carcinoid tumor, and metastatic cancer.
Primary lung cancer
Malignant tumors that initially grow in the lungs and appear as lung nodules. Pathologic types include adenocarcinoma, large cell carcinoma, squamous carcinoma, and to a lesser extent, primary pulmonary sarcoma or primary extranodal lymphoma.
Metastatic cancer
A malignant tumor that has metastasized to the lungs from other parts of the body.
The most common metastatic cancers of the lung include malignant melanoma, sarcoma, bronchial cancer, colon cancer, breast cancer, kidney cancer, and testicular cancer. Most metastatic cancers do not usually present as episodic lung nodules and multiple lung nodules are often present.
Carcinoid tumor
A small, slow-growing malignant tumor, although carcinoid tumors are usually endobronchial and about 20% present as peripheral, well-defined lung nodules.
Risk Factors
Patient age, gender, race, smoking, family history, and past medical history are all risk factors for malignant lung nodules.
Age
The likelihood of malignant lung nodules increases with age. Lung cancer is rare in young people less than 35 years of age and rare in people less than 40 years of age, and the incidence of lung cancer steadily increases with each decade of age.
Gender
Boiselle et al. analyzed those with solid, non-solid, or sub-solid nodules and found that ground-glass nodules had the highest risk of malignancy in the female population.
The PanCan study also found that the risk of malignancy of lung nodules in the female population was 1.8 times higher than in the male population.
Family history
Patients with a family history of nodules and lung cancer are more likely to develop malignant lung nodules than those without a family history. A first-degree relative with lung cancer has a risk of developing cancer that is 1.5 to 1.8 times higher than normal.
Race
Overseas studies have found that the probability of malignant lung nodules varies among people of different races.
Past medical history
A history of cancer increases the likelihood of nodule malignancy. In addition, there is a close association between chronic obstructive pulmonary disease, pulmonary fibrosis and lung cancer.
Smoking/cigars/e-cigarettes
Smokers and former smokers have a much higher rate of malignant lung nodules than nonsmokers. The malignancy rate of lung nodules is significantly higher in active smokers, while passive smoking (history of secondhand smoke exposure) has a slightly lesser impact, but remains a risk factor for malignant lung nodules.
Environmental Factors
Symptoms
In the early stages, malignant lung nodules may have no obvious symptoms, which gradually appear and worsen as the tumor progresses.
Main symptoms
Cough
Cough is one of the most common symptoms.
There are different degrees of cough, mostly irritating dry cough or accompanied by a little white sticky sputum.
Some of them may also occur repeatedly with blood in sputum, or hemoptysis.
Chest pain and fever
Chest pain and chest tightness of varying degrees can sometimes occur. It is obvious when taking a deep breath, coughing or laughing.
If the lung nodule gradually increases in size and compresses the large bronchial tubes, it may manifest as chest tightness, shortness of breath, wheezing, dyspnea and breathlessness.
Some patients may have cancer fever.
Other symptoms
Hoarseness
Malignant lung nodules gradually increase in size and compress or invade the recurrent laryngeal nerve, which may lead to hoarseness.
Systemic symptoms
Weight loss due to loss of appetite and metabolic disorders.
Malignant pulmonary nodules may also cause an increase in body temperature and generalized fatigue, which may affect daily life.
Complications
Pleural effusion
Cancer cells in malignant pulmonary nodules may invade the pleura, causing chest pain and pleural effusion, further aggravating respiratory difficulties.
Pneumonia
When the lung nodules gradually increase in size, affecting the normal sputum discharge, the lungs may become infected, leading to pneumonia.
Metastasis
Cancer cells in malignant lung nodules may metastasize to other organs, such as liver, brain, bone, etc., leading to symptoms in the corresponding areas, such as wheezing, difficulty in swallowing, bone pain, intracranial metastasis.
Consultation
Department of Medicine
Thoracic Surgery, Respiratory Medicine
Oncology
If malignant lung nodules are clearly diagnosed but cannot be surgically removed, they can be treated in the Department of Oncology.
Preparation for medical treatment
Preparation for consultation: registration, preparation of documents, common problems
Tips for medical treatment
Patients and their family members should organize and bring along their past medical history, including their condition, diagnosis and treatment process.
Patients and their family members should bring relevant recent examination reports, such as X-rays, CT scans, blood tests, and so on.
Patients need to record the time of symptom onset, duration, and degree, etc., so that they can describe them in detail to the doctor.
Find out if there are cases of lung cancer or other cancers in the family so that the doctor can assess the genetic risk.
Preparation Checklist for Medical Visit
Symptom Checklist
Pay special attention to the time of symptoms, special manifestations, etc.
Medical History Checklist
Checklist
Test results in the last 6 months, which can be brought to the doctor’s office
Medication list
Medication in the last 3 months, if there is a medicine box or package, you can bring it to the doctor
Diagnosis
The diagnosis of malignant pulmonary nodules mainly relies on the history, clinical manifestations, examination, especially pathological findings.
Diagnosis is based on
Medical history
Clinical manifestations
There are symptoms such as chest pain, cough, blood in sputum or even hemoptysis, fever, emaciation, and fatigue.
Laboratory examination
Sputum cytology
The sputum coughed up by the patient is examined microscopically for the presence of abnormal cells.
This is a relatively simple test that can provide a diagnostic basis in the initial screening. However, the sensitivity and specificity of sputum cytology is limited and needs to be analyzed in conjunction with other test results.
Tumor marker test
Serum tumor markers such as CEA, NSE, CYFRA21-1 and SCC may be elevated in patients with malignant lung nodules, but their sensitivity and specificity are limited, and they are only used as auxiliary diagnostic means.
Imaging
Chest CT examination
Including ordinary lung CT, there are also three-dimensional lung CT reconstruction and lung-enhanced CT, which can provide information on the size, morphology and density of lung nodules, and is currently an important means of diagnosing malignant lung nodules. Thin-layer chest CT examination can better help the differential diagnosis. Enhanced CT scan can observe the enhancement of the nodule, which can help to distinguish benign and malignant.
Malignant lung nodules may show irregular margins, uneven density, burr sign, rough edges, lobulation sign, pleural depression sign, and dilated or twisted blood vessels on CT scan. Malignant nodules enhance >20 Heinz units.
PET-CT examination
This test is indicated for solid nodules >8 mm in diameter and helps to identify their benign or malignant nature. In patients with suspected malignant nodules, PET-CT can be used to evaluate metastasis and select the safest biopsy target.
PET-CT combines positron emission tomography (PET) and computed tomography (CT) to provide both structural and metabolic information.
Malignant lung nodules usually appear as hypermetabolic nodules on PET-CT, i.e., significant uptake of radioactive glucose (FDG), and SUV >2.5 is often used as a threshold to differentiate between lung nodules with a high probability of malignancy in most studies evaluating diagnostic performance.
PET-CT is unable to reliably characterize ground-glass nodules or the ground-glass component of some solid nodules compared with solid nodules, and PET has a lower sensitivity and specificity for detecting malignancy in ground-glass nodules.
Pathologic examination
Tissue specimens can be obtained for pathologic and genetic examination by CT-guided puncture biopsy or by bronchoscopy, mediastinoscopy, or thoracoscopy.
Detection of lung cancer-related gene mutations, such as EGFR, ALK, ROS1, etc., can help to develop individualized treatment plans, such as targeted therapy [3-4].
Non-surgical biopsy
Non-surgical biopsy can be performed by sampling the nodule via trans-airway (bronchoscopic technique) or trans-chest wall (transthoracic) puncture biopsy.
Indications: if the nodule has an intermediate probability of malignancy (5% to 65%) or if the probability of malignancy is high (>65%) but the patient is not a candidate for surgery or prefers a nonsurgical approach; for consideration of benign disease but requires treatment (e.g., mycobacteriosis); and occasionally for patients at low risk for malignancy who are very interested in establishing a diagnosis as soon as possible.
Bronchoscopic techniques (endobronchial ultrasound and conventional bronchoscopy) are usually preferred for larger central lesions, whereas trans-thoracic wall puncture biopsy is preferred for smaller peripheral lesions.
Surgical Biopsy
Surgical excisional biopsy is the gold standard for diagnosing lung nodules and can also cure certain malignant tumors.
Diagnostic wedge resection via televised thoracoscopic surgery is preferred in patients who are suitable for surgery, if the lung nodule has a high probability of malignancy (>65%), or if the probability of malignancy is intermediate but a non-surgical biopsy is not diagnostic or malignancy is suspected; for suspected benign conditions that require treatment, such as Mycobacterium avium infections; and for non-surgical biopsies which are not diagnostic or are used occasionally in patients in whom a definitive diagnosis is highly desirable.
During televised thoracoscopic surgery, the nodule to be resected is usually localized by visual observation, and is therefore best suited for lung nodules close to the pleural surface.
The diagnosis can usually be confirmed intraoperatively by wedge resection followed by frozen section analysis. If the diagnosis is consistent with non-small cell lung cancer, the procedure is best converted to lobectomy (or partial lung resection only if preservation of lung function is important) in combination with mediastinal lymph node sampling or clearance. For malignant lung nodules, diagnosis, staging and treatment can be accomplished in a single operation.
Note: Frozen section pathology is less reliable for lesions <1.1 cm in diameter and for certain specific pathologies, including low-grade or precancerous adenocarcinomas such as MIA, AIS, AAH, and carcinoid tumors. Therefore, if frozen section initially fails to detect cancer and the diagnosis of non-small cell lung cancer is subsequently confirmed by conventional histologic examination, a second surgery may be required.
Staging
The staging of malignant lung nodules helps to rationalize the treatment plan, correctly evaluate the efficacy of treatment, and judge the prognosis.
TNM staging
Currently, TNM staging of lung cancer is a staging system jointly developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC), which is mainly based on the three elements of T, N and M. The TNM staging system is based on the following three elements
T: represents the extent of primary tumor, mainly referring to the size of the primary tumor foci and the degree of extravasation.
N: represents regional lymph node metastasis, including the number of metastases and regional extent.
M: represents distant metastasis.
Special reminder: T, N, M will be followed by Arabic numerals, the larger the number, the more serious.
Overall staging
ⅡA stage
T2bN0M0
Phase IIB T1a~cN1M0, T2aN1M0, T2bN1M0, T3N0M0
Stage IIIB T1a～cN3M0, T2a～bN3M0, T3N2M0, T4N2M0
Stage IIIC T3N3M0, T4N3M0
Stage IIIC
T3N3M0, T4N3M0
Phase IVA any T, any N, M1a~b
Stage IVA
Any T, any N, M1a～b
Stage IVB any T, any N, M1c
Stage IVB
Any T, any N, M1c
Differential Diagnosis
Malignant lung nodules need to be differentiated from benign lung nodules and inflammatory lesion disease.
Benign tumors, inflammatory lesions
Similarities: both present as lung nodules on imaging and may also present with cough, sputum, and chest pain.
Points of difference:
Imaging: malignant lung nodules show gross edges and rapid growth of the lesion on CT or MRI, while benign lung nodules or inflammatory lesions may have smoother edges and slower growth.
Disease course: malignant lung nodules develop more rapidly and have a faster rate of symptom exacerbation, whereas chronic inflammatory lesions and benign tumors may have a longer course and a slower rate of symptom exacerbation.
Pathologic examination: Cancer cells are seen in the pathologic findings of malignant lung nodules, whereas benign nodules and inflammatory lesions are free of cancer cells.
Treatment
Aim of treatment: early intervention to improve prognosis and prolong survival.
For patients who are elderly and cannot tolerate surgery, such as those with poor cardiac or pulmonary function, other treatments, such as stereotactic radiotherapy, may be used.
Other treatments
Malignant nodules are often treated with a combination of the following methods, which can improve the therapeutic effect and prolong the patient’s survival.
Chemotherapy
Applicable to advanced non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and patients who cannot be operated.
Commonly used chemotherapeutic drugs: vincristine, cisplatin, carboplatin, paclitaxel, gemcitabine, docetaxel, pemetrexed and so on. The appropriate chemotherapy regimen is selected according to the patient’s specific condition.
Chemotherapy may lead to side effects, such as nausea, hair loss, leukopenia, etc. It is necessary to closely monitor the patient’s blood routine and liver and kidney functions, and give appropriate supportive treatment.
Radiation therapy
It is indicated for patients with locally advanced non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and those who cannot undergo surgery or chemotherapy.
Radiotherapy may cause skin redness and swelling, esophagitis, etc. Patients’ symptoms need to be closely monitored and appropriate symptomatic treatment should be given.
Targeted Therapy
Selection of drugs that target gene mutations or protein expression specific to tumor cells in order to inhibit tumor growth.
It is suitable for advanced non-small cell lung cancer (NSCLC) with specific gene mutations.
Targeted drugs such as gefitinib, erlotinib, afatinib, ositinib, and axitinib are used for EGFR-positive people.
ALK-positive people often use crizotinib, ceritinib, alectinib, loratinib and so on.
Crizotinib (domestic) and Entrectinib (foreign) are often used in ROS1-positive patients.
This approach helps the immune system recognize and attack cancer cells by stimulating or enhancing the patient’s own immune system.
It is suitable for patients with advanced non-small cell lung cancer (NSCLC), especially those who have already received chemotherapy but with poor efficacy.
Currently, the main application of immune checkpoint inhibitors are PD-1 inhibitors, such as pabolizumab, navulizumab, sindilizumab, tirilizumab, and karelizumab, as well as PD-L1 inhibitors, such as dulvarizumab, atilizumab, and sugilizumab.
Immunotherapy may lead to immune-related side effects, such as rash, liver function abnormalities, and pneumonia.
Traditional Chinese Medicine (TCM)
Therapeutic effects
Chinese medicine treatment can be used as an adjuvant treatment for lung cancer, which helps to reduce the adverse effects of radiotherapy, chemotherapy and immunotherapy.
It can help regulate the immune function and physical condition of patients, improve the quality of life of cancer, and play a role in improving the long-term survival rate of lung cancer patients.
Commonly used medicines
Individual Chinese medicine tablets are not usually used as therapeutic drugs.
Commonly used proprietary Chinese medicines include Kang Lai Te soft capsule, Compound Red Bean Pool capsule and so on.
Special reminder: secret prescriptions, biased prescriptions, folk remedies and other methods of treatment have no scientific basis, the indications and effectiveness are not clear, safety is difficult to guarantee, and are not recommended.
Prognosis
The prognosis of malignant lung nodules is relatively good if detected and treated at an early stage.
Cure
The lung cancer recurrence rate of stage I and II non-small cell lung cancer is about 30% about 5 years after surgery, while the recurrence rate or metastasis of stage III non-small cell lung cancer is about 60% about 5 years after surgery.
Generally speaking, patients with early staging, early and standardized treatment, and better personal physical fitness before the onset of disease have a relatively good prognosis.
Malignant lung nodules can cause symptoms such as shortness of breath, dyspnea, chest pain, and coughing up blood.
Daily Management
Dietary management
Maintain balanced nutrition, increase intake of fresh vegetables and fruits, and reduce high-fat, high-salt and high-sugar foods.
Eat more foods rich in protein, vitamins and minerals to enhance immunity.
Minimize alcohol intake.
Life Management
Avoid living or working in an environment full of dust, smoke and chemical irritants.
Avoid or reduce going out in smoggy weather. If you have to go out, you should wear an anti-haze mask.