Large cell carcinoma of the lung

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Overview of Lung Cancer

It is a relatively rare subtype of lung cancer, the cancer cells are large and lack of specificity in the early stage, there may be cough, blood in sputum or hemoptysis, wheezing, chest pain, etc. The cause of the disease is unknown, and it is closely related to heavy smoking Surgery is the first choice of treatment for large cell carcinoma of the lung, and most of them adopt the combination of comprehensive treatment and personalized treatment

Definition

  • Lung large cell carcinoma is a tissue subtype of non-small cell lung cancer.
  • Lung large cell carcinoma is essentially a poorly differentiated carcinoma without the differentiating features of adenocarcinoma, squamous carcinoma, or small cell carcinoma and is a diagnosis of exclusion.
  • Lung large cell carcinoma is an aggressive tumor that can be explosive, develop rapidly, metastasize early, and have a poor prognosis.

    • This term refers to large cell carcinoma newly defined in the 2015 WHO lung cancer classification, i.e., a kind of undifferentiated non-small cell lung cancer that needs to be assisted with immunohistochemistry for differential diagnosis on the basis of lack of differentiated structural features of adenocarcinoma or squamous carcinoma cells.

    Staging

    Lung large cell carcinoma is less studied at present, and some studies show that the incidence of lung large cell carcinoma with known driver gene alterations in the tests performed is about 18.2%.

    Therefore, lung large cell carcinoma can also be further typed according to the status of the driver gene, which can help in treatment planning and prognosis evaluation.

    Molecular typing

    Important genes related to cancer development are called driver genes, and currently the main driver genes studied in lung cancer include EGFR, ALK, ROS1, BRAF, NTRK, MET, RET, KRAS, and HER-2.

    Targeted therapy against driver gene variants has gradually become the main treatment method for lung cancer, and has achieved remarkable efficacy.

    Common molecular typing
  • EGFR-positive lung large cell carcinoma: This type can generally be treated with molecularly targeted drugs such as EGFR-TKIs (tyrosinase inhibitors), including gefitinib, erlotinib, ectinib, afatinib, daclatinib, and ositinib.
  • ALK-positive lung large cell carcinoma: molecularly targeted drugs such as alectinib, crizotinib and ceritinib are generally available for this type.
  • ROS1-positive lung large cell carcinoma: this type can be treated with molecular targeted drugs such as crizotinib.
    • Other molecular typing

    With the major breakthroughs in clinical research on rare driver gene targets, in addition to the above common molecular phenotypes, some rare molecular phenotypes have been gradually proposed, such as BRAF, NTRK, MET, RET, KRAS, HER-2 and other genes.

  • Patients with advanced lung large cell carcinoma with MET14 exon skipping mutation who cannot tolerate chemotherapy can use cevotinib.
  • Patients with BRAF V600 mutation-positive advanced lung large cell carcinoma may use dabrafenib in combination with trametinib.

    • Staging by site of occurrence

    According to the site of occurrence of lung large cell carcinoma, it can be divided into the following two types.

  • Central type lung large cell carcinoma: the tumor occurs in the bronchus above the opening of segmental bronchus, which is less common. It has more clinical symptoms and the accuracy of fiberoptic bronchoscopy and sputum cytology is higher, but the difficulty of surgery is often greater than that of peripheral type.
  • Peripheral large cell carcinoma of the lung: the tumor occurs in the bronchus below the opening of the segmental bronchus, i.e. from the subsegmental bronchus to the alveoli.

    • Morbidity

    Large cell carcinoma of the lung lacks authoritative epidemiologic data because it is relatively rare. Current studies are based on a small number of samples, and their results vary somewhat, so the following data are for scientific reference only.

  • Lung large cell carcinoma is relatively rare, and its incidence accounts for about 3% to 9% of non-small cell lung cancer.
  • It is generally more common in males than females, especially in male heavy smokers.
  • Lung large cell carcinoma is mostly peripheral lung cancer, and most of them are giant lesions.

    • Focus

    About diagnosis

    The diagnosis of large cell carcinoma of the lung is mainly made by histopathological examination. It is not suitable to use this diagnosis for small biopsy specimens, intraoperative frozen specimens, and requires surgical resection of the entire tumor of the specimen or adequate sampling before a definitive diagnosis can be made.

    Since there may be driver genes in lung large cell carcinoma, patients with conditions are also recommended to undergo gene mutation testing, which helps to understand the molecular typing of their driver genes, so as to prepare for the subsequent targeted therapy.

    About treatment and prognosis

    The treatment of lung large cell carcinoma needs to be decided according to the patient’s physical condition, molecular typing, the extent of invasion and developmental tendency and other factors, and generally adopts a multidisciplinary integrated treatment model.

    At present, there is no diagnosis and treatment guideline for large cell lung cancer, and the relevant diagnosis and treatment guideline for non-small cell lung cancer is generally referred to in clinical work.

    Stage I and II large cell lung cancer patients
  • Radical surgical resection is the main treatment method, and some patients need postoperative adjuvant chemotherapy or targeted therapy. For patients who cannot undergo surgery, radical radiotherapy ± chemotherapy can be chosen as the treatment plan.
  • Stages Ⅰ and Ⅱ belong to the early stage, after active standardized treatment, most of the patients may obtain a normal natural life expectancy.
    • Patients with stage III and stage IV lung large cell carcinoma
  • Stage III lung large cell carcinoma belongs to the locally advanced stage, some patients still have the opportunity of surgical treatment, and after surgery, supplemented with comprehensive treatment such as chemotherapy, radiotherapy, targeted therapy, etc., they can still obtain better therapeutic effect, further prolong the survival period of patients and improve the quality of life.
  • Stage III inoperable patients, as well as stage IV patients, through targeted therapy, radiotherapy and immunotherapy and other integrated treatment, may also be able to obtain a long survival and improve the quality of life, it is recommended to actively accept standardized treatment.

    • Causes

    Causes

    The etiology of lung large cell carcinoma is not different from that of lung cancer, which is not completely clear so far. From the perspective of lung cancer, it may be related to the following factors.

    Smoking and passive smoking

  • Smoking is the most common cause of lung cancer. About 85% of lung cancer patients have a history of smoking, and studies have shown that the risk of lung cancer is increased by more than 10 times in people with a long history of smoking.
  • The longer you smoke and the more you smoke, the higher the incidence and mortality rate of lung cancer.

    • History of Chronic Obstructive Pulmonary Disease (COPD)

    Studies have shown that the risk of lung cancer in people with Chronic Obstructive Pulmonary Disease (COPD) is 1.57 times higher than in people without COPD.

    Occupational Exposure

    A variety of specific occupational exposures can increase the risk of lung cancer, including asbestos, radon, beryllium, chromium, cadmium, nickel, silica, soot and coal smoke.

    Family history and genetic susceptibility to lung cancer

  • Family aggregation exists among lung cancer patients. These findings suggest that genetic factors may play an important role in populations and/or individuals susceptible to environmental carcinogens.
  • It is currently believed that genetic polymorphisms may be genetic susceptibility factors for lung cancer, with metabolic enzyme genes and DNA damage repair gene polymorphisms being two of the more studied aspects.

    • Others

  • Other factors associated with the development of lung cancer include nutrition and diet, physical exercise, immune status, estrogen levels, infections (human immunodeficiency virus, human papillomavirus), chronic inflammation of the lungs, and economic and cultural levels.
  • However, the association between the above factors and lung cancer is still controversial and there is no recognized authoritative evidence.

    • Symptoms

  • Symptoms of large cell carcinoma of the lung are not significantly different from those of other types of lung cancer, and it is not possible to determine the specific type of lung cancer by symptoms.
  • Early stage of the disease usually has no obvious symptoms, and symptoms appear only after the disease has developed to a certain stage, and the symptoms are related to the site of tumor, size, type, whether it invades or oppresses the neighboring organs, and whether it has metastasis or not.

    • Special reminder: Lung large cell carcinoma is a type of lung cancer that can only be confirmed by histopathological examination, and it is generally difficult to be identified by symptoms, so the following are the symptoms that often appear in lung cancer patients.

    Primary symptoms

    Primary symptoms refer to the symptoms caused by the local growth of the primary tumor itself.

    Cough and sputum

  • Cough is the most common symptom when lung cancer patients visit the doctor, and more than half of the patients have cough symptoms when they visit the doctor.
  • Most of them have irritating dry cough with no sputum or a little white mucus sputum.

    • Hemoptysis

  • About 40% of lung cancer patients will have hemoptysis symptoms.
  • It is usually manifested as blood in sputum, hemoptysis is rare.
  • Hemoptysis is the most suggestive symptom of lung cancer.

    • Dyspnea

  • About 10% of lung cancer patients have dyspnea as the first symptom.
  • It manifests as chest tightness, shortness of breath, and some patients may have chest pain.

    • Fever

  • It can be caused by necrosis of tumor tissue or secondary pneumonia (such as obstructive pneumonia).
  • Fever is characterized by delayed and repeated, sometimes good and sometimes bad, difficult to cure.
  • Intermittent moderate or low fever is common, and high fever may be present when combined with infection.

    • Weight loss, malaise

    The tumor may cause consumption, loss of appetite, etc., leading to malaise with weight loss.

    Wheezing

  • It is a harsh sound made when inhaling.
  • If the tumor is located in the large airways, especially in the main bronchial tubes, it can often cause symptoms of restrictive stridor.

    • Extrinsic symptoms

    Extrinsic symptoms are symptoms caused by the primary tumor invading neighboring organs and structures.

    Superior vena cava obstruction syndrome

  • About 10% of lung cancer patients consult the doctor with this as the first symptom.
  • The main manifestations are edema of the head and neck or even both upper limbs, aneurysm of the veins in the neck and upper chest (the veins are in the shape of cords and are clearly visible), capillary dilatation and so on.

    • Horner’s syndrome

    Depression of the eyeball on the side where lung cancer occurs, drooping of the upper eyelid, small fissure of the eye, narrowing of the pupil, and absence of facial sweating.

    Hoarseness

  • Involvement of the recurrent laryngeal nerve causes hoarseness.
  • Some lung cancer patients consult the doctor with this as the first symptom.

    • Difficulty in swallowing

    It is mostly caused by direct invasion of tumor or lymph node metastasis compressing esophagus.

    Pleural effusion

  • Invasion of pleura can cause pleural effusion (hydrothorax), which is often a large amount of bloody effusion.
  • At first, patients gradually feel chest tightness, which may be accompanied by chest pain. As the amount of fluid increases, chest pain decreases or disappears, but dyspnea increases.

    • Distant metastatic symptoms

    Metastatic symptoms refer to the symptoms caused by distant metastasis of the tumor. The most common is brain metastasis, followed by bone metastasis, liver metastasis and so on.

    Intracranial metastasis (brain metastasis)

    Early stage may be asymptomatic, sometimes accompanied by mental status changes and visual disturbances.

    Frequent central nervous system symptoms:

  • Headache, vomiting, dizziness.
  • Diplopia (two images when both eyes look at the same object at the same time).
  • Ataxia (e.g., clumsy movements, unsteady walking).
  • Hemiparesis (impaired movement of the upper and lower limbs on one side).
  • Seizures, etc.

    • Bone metastases

  • Commonly found in the ribs, spine, pelvis and long bones.
  • They may be asymptomatic in the early stages, with localized pain and pressure in the later stages.
  • If spinal metastasis compresses or invades the spinal cord, it may lead to urinary and fecal incontinence or paraplegia.

    • Liver metastasis

  • Hepatomegaly and pain in the liver area may occur.
  • It may be accompanied by loss of appetite, nausea, emaciation, and elevation of liver enzymes such as aspartate aminotransferase (AST) or bilirubin.

    • Adrenal metastasis

  • May present with symptoms of Addison’s disease, with loss of appetite, diarrhea, deepening of skin color, loss of axillary hair, and low blood pressure.

    • Lymph node metastasis

  • Often metastasize first to hilar lymph nodes along the lymphatic reflux pathway, followed by mediastinal and supraclavicular lymph nodes.
  • The enlarged superficial lymph nodes are usually hard and can be fused into a mass, and are not accompanied by pressure pain.

    • Others

  • Lung cancer may metastasize to many parts of the body leading to different clinical signs, such as subcutaneous nodules, skin ulcers and abdominal pain.
  • Malignant stasis, also known as malignant fluid, is seen in some advanced cancer patients. It is characterized by extreme emaciation, weakness, general exhaustion and other symptoms.

    • Paraneoplastic syndrome

    A small number of lung cancer patients may present some rare symptoms and signs not caused by direct invasion or metastasis of tumor, but a series of manifestations caused by ectopic endocrine, bone and joint metabolic abnormalities, neuromuscular conduction disorder, etc., which is called paraneoplastic syndrome or paraneoplastic syndrome.

    Hypertrophic pulmonary osteoarthropathy

  • It is mostly seen in patients with lung large cell carcinoma.
  • The main manifestations are pain in large joints, pestle-like fingers/toes (abnormal manifestation of hyperplasia and hypertrophy at the ends of fingers or toes, which are enlarged in the shape of a pestle).
  • This manifestation may occur in the early stage of lung cancer or appear before the local symptoms of lung cancer, and may even be the only symptom of lung cancer in the consultation.

    • Cushing’s syndrome

  • Ectopic secretion of adrenocorticotropic hormone can cause Cushing’s syndrome.
  • Patients usually present with muscle weakness, weight loss, hypertension, hirsutism, and osteoporosis.

    • Dermatomyositis and Polymyositis

  • Dermatomyositis and polymyositis are 2 different forms of inflammatory myopathies, both of which clinically present with muscle weakness.
  • These inflammatory myopathies can be the first symptom of lung cancer or can appear later in the course of lung cancer.

    • Hypercalcemia

  • Hypercalcemia in patients with lung cancer may be due to bone metastases and, in a few cases, to tumor-secreted parathyroid hormone-related proteins, osteotriol, or other cytokines, including osteoclast activating factor.
  • Symptoms of hypercalcemia include anorexia, nausea, vomiting, constipation, lethargy, polyuria, irritable thirst, and dehydration.
  • Blurred consciousness and coma as well as renal failure and renal calcinosis are late manifestations.

    • Male breast development

    The main manifestation is bilateral or unilateral breast development.

    Consultation

    Access to medical care for large cell carcinoma of the lung is not significantly different from other types of lung cancer.

    Department of Medicine

    Thoracic Surgery

    Please consult the Department of Thoracic Surgery if nodules or space-occupying lesions are found in the lungs on chest imaging (X-ray, chest CT, etc.) during a routine physical examination or other tests.

    Medical Oncology

    Patients diagnosed with large cell carcinoma of the lung may choose to undergo drug treatment, such as chemotherapy, targeted therapy and immunotherapy, in the Department of Medical Oncology.

    Respiratory Medicine

    Please consult the Department of Respiratory Medicine when symptoms such as cough, blood in sputum or hemoptysis, wheezing and chest pain occur.

    Preparation for medical treatment

    How to prepare for your visit: registration, preparation of documents, frequently asked questions

    Tips for your visit to the doctor

    Chest X-ray or CT examination may be required. Please avoid wearing metal clothing such as shirts with buttons, blouses with sequins, and dresses with zipper openings.

    Preparation Checklist

    Symptom Checklist

    Pay particular attention to the time of onset of symptoms, special manifestations, etc.

  • Is there coughing and sputum, and for how long?
  • Is there blood in the sputum?
  • Is there chest tightness and shortness of breath, and for how long?
  • Is there fatigue with unexplained weight loss?
    • List of medical history
  • Do you smoke, for how long and how many cigarettes per day?
  • Is there a family history of lung cancer or other malignant tumors?
  • Are there any other diseases, such as tuberculosis?
  • Any drug or food allergies?
    • Checklist

    Test results in the last six months, which can be brought to the doctor’s office

  • Specialized tests: lung biopsy pathology report, chest X-ray or CT report, tumor markers.
  • Laboratory tests: blood routine, urine routine, stool routine, blood biochemistry tests.
  • Other tests: magnetic resonance imaging (MRI), PET-CT.

    • Diagnosis

    The diagnosis of lung large cell carcinoma can be divided into qualitative diagnosis and staging diagnosis.

  • Qualitative diagnosis: generally, it is necessary to obtain histological specimens and then carry out histomorphological examination and immunohistochemical examination, which are the necessary means to confirm the diagnosis.
  • Staging diagnosis: with the help of CT, ultrasound, magnetic resonance, bone scanning, PET-CT and other imaging examinations, the clinical stage of the patient can be comprehensively evaluated, so as to preliminarily judge the severity of the patient’s condition and provide the basis for the formulation of subsequent treatment plan.

    • Pathologic examination

    Pathological examination is the “gold standard” to determine the diagnosis of lung large cell carcinoma, while molecular biology examination is helpful to determine the molecular staging of lung large cell carcinoma.

    Histologic examination

    Morphology (routine HE staining) and histomorphology can clarify small cell lung cancer and non-small cell lung cancer.

    Non-small cell lung cancer requires further clarification of lung adenocarcinoma, lung squamous carcinoma, adenosquamous carcinoma, and lung large cell carcinoma, and needs to be diagnosed with the aid of immunohistochemical examination.

    Immunohistochemical labeling is an important adjunctive diagnostic method for large cell lung cancer. For poorly histologically differentiated cancers, the diagnosis of large cell carcinoma of the lung is generally considered only when the immunohistochemical markers for adenocarcinoma and squamous carcinoma are negative.

    Commonly used diagnostic markers for lung adenocarcinoma are TTF1, Napsin A and CK7.

    Commonly used immunohistochemical markers for squamous carcinoma include p40, p63, CK5/6, Desmocollin-3, Sox2 and so on.

    [Special reminder] In the pathology report, the expression (positive) of a certain immunohistochemical index is usually represented by “+”, and the more “+”, the higher the degree of expression, which may be more helpful in supporting the diagnosis, and there can be up to 3 “+”. “.

  • When the pathologist suspects that the tumor involves the lung membranes, special staining of elastic fibers may be necessary to aid in the diagnosis.

    • Molecular Biology Tests

    Gene mutation testing can determine the molecular typing of the driver genes of lung large cell carcinoma and provide a basis for decision-making for subsequent treatment plan development.

    Domestic guidelines recommend the following molecular tests for non-small cell lung cancer (NSCLC), and lung large cell carcinoma, which is a type of NSCLC, is generally applicable as well [1].

  • For patients with stage II-IIIA NSCLC, tumor tissue EGFR mutation testing is performed.
  • For patients with advanced NSCLC, tumor tissue testing for EGFR mutations, ALK, ROS1 and RET fusion genes, and C-MET exon 14 jump mutations should be routinely performed along with diagnosis.
  • Detection of KRAS, BRAF, HER2 and other gene mutations, NTRK1/2/3 and NRG1/2 and other fusion genes, etc. can be performed when available.

    • Imaging examination

    Commonly used imaging methods for lung large cell carcinoma include chest X-ray, computed tomography (CT), ultrasound, magnetic resonance imaging (MRI), bone imaging (also known as bone scanning), positron emission tomography (PET) and so on.

    Imaging tests can accurately stage the tumor so that precise treatment can be given.

    X-ray examination

    Frontal and lateral chest radiographs, which cannot provide details such as the extent of tumor invasion and lymph node enlargement, are often used as a general physical examination.

    CT examination

  • This is the most commonly used imaging examination method for diagnosis, clinical staging and follow-up observation of lung large cell carcinoma.
  • CT of chest and abdomen can accurately determine the invasion range of primary tumor, mediastinal lymph node metastasis, and whether there is any tumor metastasis in important abdominal organs (e.g. adrenal glands, liver, retroperitoneal lymph nodes, etc.).
  • In the absence of contraindications, doctors may recommend enhanced scanning for better diagnosis.

    • MRI

  • Commonly used to assess the efficacy of chemotherapy and targeted drugs.
  • In special cases, it can be used to determine the invasion of the chest wall or mediastinum, and to show the relationship between suprapulmonary sulcus tumors and brachial plexus nerves and blood vessels.
  • Enhanced MRI of the brain can be used as routine examination before surgery or primary staging of lung large cell carcinoma.

    • PET-CT examination

    Whole-body PET-CT examination can further improve the accuracy of staging diagnosis of lung large cell carcinoma. However, it is relatively expensive.

    Bone Scan

  • Whole-body bone imaging is a routine test to exclude bone metastasis with high sensitivity but low specificity.
  • When suspected bone metastases are found in whole-body bone imaging, it is generally recommended to add MRI examination for clear diagnosis.

    • Ultrasonography

  • Ultrasonography of bilateral cervical and supraclavicular lymph nodes can make up for the insufficiency of physical examination and CT examination in determining lymph node metastasis in this region.
  • Puncture biopsy of lymph nodes suspected of metastasis can be performed, and further pathologic diagnosis can be made.

    • Laboratory examination

    Generally, there is no specific laboratory test for lung large cell carcinoma, similar to other types of lung cancer, mainly used for preliminary auxiliary diagnosis and differential diagnosis.

    [Reminder] For more laboratory tests, please refer to the section on diagnosis of lung cancer.

    Staging

    The staging of lung large cell carcinoma follows the staging criteria of lung cancer, and the staging of lung large cell carcinoma is helpful in formulating treatment plans, evaluating the efficacy and judging 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 the primary tumor, mainly referring to the size of the primary tumor foci and the degree of extravasation.
  • N: represents the situation of regional lymph node metastasis, including the number of metastases and regional extent.
  • M: represents the situation of distant metastasis, which mainly means that cancer cells are also present in other organs.

    • Special reminder: TNM will be followed by Arabic numerals, the larger the number, the more serious it is.

    Overall Staging

    According to different TNM staging, the total overall staging (prognostic grouping) of the patient is finally determined, which is indicated by the Roman letters I, II, III and IV.

    Overall staging TNM stagingStage 0 TisN0M0Stage 0TisN0M0Stage IA1 T1aN0M0ⅠA1 stageT1aN0M0ⅠA2 period T1bN0M0ⅠA2 periodT1bN0M0ⅠA3 stage T1cN0M0ⅠA3 periodT1cN0M0

    ⅠB stage T2aN0M0

    ⅠB stage

    T2aN0M0

  • ⅡA stage T2bN0M0
  • ⅡA stage

    • T2bN0M0

    IIB stage T1a~cN1M0T2aN1M0T2bN1M0T3N0M0

  • Phase IIB
  • T1a～cN1M0T2aN1M0T2bN1M0T3N0M0

    • Phase IIIA T1a～cN2M0T2a～bN2M0T3N1M0T4N0M0T4N1M0

    全部分期
  • Stage IIIA

    • T1a～cN2M0T2a～bN2M0T3N1M0T4N0M0T4N1M0

  • Phase IIIB T1a～cN3M0T2a～bN3M0T3N2M0T4N2M0
  • Stage IIIB
  • T1a～cN3M0T2a～bN3M0T3N2M0T4N2M0

    • Stage IIICT3N3M0T4N3M0

    Stage IIIC

    T3N3M0T4N3M0

    Phase IVAAny T, any N, M1a～b

    Stage IVA

  • Any T, any N, M1a～b
  • Phase IVB Any T, any N, M1c

    • Stage IVB

    Any T, any N, M1c

    Differential Diagnosis

    Large cell carcinoma of the lung is the final diagnosis after pathologic confirmation, but it may sometimes be confused with other lung diseases before the diagnosis is confirmed, and a differential is needed.

  • Differentiation of other subtypes of lung cancer
  • Similarities: In pathological examination, when lung large cell carcinoma is poorly differentiated, the histologic features are similar to those of lung low-differentiated squamous carcinoma or adenocarcinoma or sarcomatoid carcinoma.

    • Differences: Some poorly differentiated large cell carcinomas need to be distinguished from poorly differentiated squamous carcinomas, adenocarcinomas and sarcomatoid carcinomas with the help of immunohistochemistry.

    Differentiation between primary and metastatic

    Even though they are all poorly differentiated carcinomas, they may be metastatic poorly differentiated carcinomas or undifferentiated carcinomas that have metastasized to the lungs from esophageal carcinoma, thyroid carcinoma, prostate carcinoma, gastrointestinal adenocarcinoma, and so on.

    Similarity: All tumors in the lungs show the pattern of poorly differentiated carcinoma.

    Difference: primary lung cancer and metastatic cancer need to be identified by combining immunohistochemical indexes such as TTF1, NapsinA, TG, PSA, PAP and villin.

    Treatment

    Purpose of treatment
  • Through the planned application of surgery, radiotherapy, chemotherapy, molecular targeted therapy and immunotherapy, with a view to maximizing the survival time of patients, increasing the survival rate, controlling tumor progression and improving the quality of life of patients.
  • Treatment principles
    • The treatment of lung large cell carcinoma generally adopts the principle of combining multidisciplinary comprehensive treatment (MDT) with individualized treatment.

    According to the patient’s physical condition, pathological and histological type and molecular typing of the tumor, the extent of invasion and the tendency of development, the mode of multidisciplinary comprehensive treatment is adopted.

    Stage I

    Stage I lung large cell carcinoma, which can be divided into stage IA and stage IB, is preferred to be resected by radical surgery, and if patients are not suitable for surgery, radiotherapy can be chosen.

    Patients suitable for surgery

    Surgical treatment

  • There are mainly the following surgical treatment options, which need to be determined according to the specific conditions of patients.
  • Anatomic lobectomy + hilar mediastinal lymph node dissection.

    • Anatomic lobectomy + hilar mediastinal lymph node dissection with minimally invasive techniques (thoracoscopic, robot-assisted).

    Reoperation is recommended for stage I patients with positive margins, and postoperative combined radiotherapy is recommended for patients who cannot undergo reoperation for any reason.

    Postoperative treatment

    For incomplete surgical resection, such as stage I patients with positive margins, reoperation is generally recommended, and for patients who cannot be reopened for any reason, postoperative combined radiotherapy is recommended.

    If complete surgical resection is performed, the following follow-up treatment options are available depending on the specific situation:

    Stage IA: Patients with completely resected stage IA lung large cell carcinoma are not recommended to routinely apply postoperative adjuvant chemotherapy, radiotherapy and targeted drug therapy.

  • Stage IB: Patients with completely resected stage IB lung large cell carcinoma may need to apply postoperative adjuvant chemotherapy due to poor differentiation.
  • Patients who are not suitable for surgery
    • For patients with severe medical comorbidities, advanced age, refusal of surgery and other contraindications to surgery, stereotactic radiotherapy (SBRT/ASBR) can be performed.
  • Stage II
  • For stage II lung large cell carcinoma, radical surgical resection is preferred, if patients are not suitable for surgery, radical radiotherapy can be chosen.
  • Patients suitable for surgery
  • The choice of operation is the same as stage I. However, reoperation is recommended for stage II patients with positive margins, and postoperative radiochemotherapy is recommended for patients who cannot undergo reoperation for any reason.
  • Adjuvant chemotherapy
    • For patients with completely resected stage II large cell lung cancer, 4 cycles of postoperative adjuvant chemotherapy with platinum-containing two-drug regimen is recommended.

    The starting time of adjuvant chemotherapy is recommended to be when the patient’s physical condition is basically back to normal after surgery, usually 4 to 6 weeks after surgery, and the latest recommendation is not more than 3 months after surgery.

    Adjuvant targeted therapy

    For patients with stage II lung large cell carcinoma who are tested positive for EGFR after surgery, adjuvant chemotherapy with ocitinib or ectinib can be considered.

    Adjuvant immunotherapy

    Patients with stage II lung large cell carcinoma who test negative for driver genes after surgery, such as positive PD-L1 expression (≥1%) can be treated with adjuvant therapy with atirizumab after platinum-based chemotherapy.

    Patients who are not suitable for surgery

  • For patients with severe medical comorbidities, advanced age, refusal of surgery and other contraindications to surgery, there are several main treatment options, which need to be tailored to the patient’s specific situation.
  • Radiation therapy followed by chemotherapy with a platinum-containing two-drug regimen.
  • Synchronized radiotherapy: three-dimensional conformal radiotherapy or conformal intensity-modulated radiotherapy + chemotherapy.
    • Stage III
  • Stage III lung large cell carcinoma, including stages IIIA, IIIB and IIIC, is divided into two categories, resectable and unresectable, according to whether the tumor has the possibility of surgical resection.
  • Treatment of patients with resectable category
  • The resectable category of stage III refers to some stage IIIA and IIIC patients. Depending on the regional lymph node (N), they are further categorized into N0 to 1 and N2 cases.
  • The case of N0～1
  • For patients with T3 to 4N1 or T4N0 in stage III, the following treatment options are available:
  • Surgery + adjuvant chemotherapy.
  • Neoadjuvant therapy ± radiotherapy + surgery.
  • In the case of N2
  • The following treatment options are available for patients with a single group of enlarged mediastinal lymph nodes and <3 cm in diameter in stage N2, or two groups of enlarged mediastinal lymph nodes without fusion and expected to be completely resected:

    • Surgical resection + adjuvant chemotherapy ± postoperative radiotherapy.

    Neoadjuvant chemotherapy ± radiotherapy + surgery ± adjuvant chemotherapy ± postoperative radiotherapy.

    For patients with N2 multisite lymph node metastasis who also anticipate the possibility of complete resection, the following treatment options are available:

    Neoadjuvant chemotherapy ± radiotherapy + surgery ± adjuvant chemotherapy ± postoperative radiotherapy.

    Targeted therapy

    Patients with stage III large cell carcinoma of the lung, after radical surgery, can be treated with adjuvant therapy with oxitinib or ectinib after surgery if the pathologic test is positive for EGFR mutation.

    Immunotherapy

    Patients with stage III lung large cell carcinoma, after radical surgery, if the driver gene is negative. If PD-L1 expression is positive (≥1%) adjuvant treatment with atirizumab may be administered after platinum-based chemotherapy.

    Treatment of patients in the unresectable category

  • Definition.
  • Unresectable stages IIIA, IIIB, and IIIC are defined as having the following imaging or lymph node pathology evidence.

    • Multiple ipsilateral mediastinal lymph node metastases into a large mass or multiple metastases (IIIA: T1-2N2 or IIIB: T3-4N2).

    Contralateral hilar and mediastinal lymph nodes, or ipsilateral and contralateral diagonal or supraclavicular lymph node metastases (IIIB: T1-2N3; IIIC: T3-4N3).

    The lesion invades the heart, aorta, and esophagus (IIIA: T4N0-1).

  • Treatment regimen
  • Radical simultaneous radiotherapy
  • If the patient is in good health, such as a PS score of 0 to 1, the recommended treatment of choice is radical synchronized radiotherapy.
    • If there is no disease progression after simultaneous chemoradiotherapy, the addition of maintenance therapy with divalizumab may be considered.

    Synchronized chemotherapy regimen: etoposide + cisplatin; vincristine + cisplatin; pemetrexed + cisplatin or carboplatin; paclitaxel analog + cisplatin or carboplatin

  • Sequential radiotherapy
  • If the patient cannot tolerate synchronized radiotherapy, sequential radiotherapy is better than radiotherapy alone.
    • Sequential chemotherapy: vincristine + cisplatin; paclitaxel + cisplatin or carboplatin; pemetrexed + cisplatin or carboplatin.

    It is recommended to perform chemotherapy for 2 to 4 cycles for evaluation before radiotherapy.

    If the patient is in poor physical condition, such as PS 0 to 2 points, radiotherapy alone (three-dimensional conformal radiotherapy) or sequential radiotherapy + chemotherapy can be considered.

    Stage IV
    Before starting treatment for stage IV lung large cell carcinoma patients, tumor tissues should be obtained for gene mutation testing, such as EGFR, ALK and ROS1, etc. The corresponding treatment strategy should be decided according to the above driver gene status.Driver gene negativeFor patients with negative driver genes, platinum-containing two-drug regimens are the standard first-line chemotherapy regimen, and can be combined with anti-vascular therapy such as bevacizumab or vascular endothelial inhibitory protein on top of chemotherapy.Platinum-containing two-drug chemotherapy based on immune checkpoint inhibitors in combination with pemetrexed is recommended for patients with suitable conditions.Immunologic agents

    Commonly used immune checkpoint inhibitors include pembrolizumab, karelizumab, sindilizumab, tirilizumab, atelizumab, and sugilizumab.

    PD-L1 Assay

    PD-L1 expression testing is generally required when using immune checkpoint inhibitors.

    For patients with positive PD-L1 expression (≥1%), pembrolizumab, for example, may be used as a single agent, but the benefit is more pronounced in patients with high PD-L1 expression (≥50%).

    For patients with high PD-L1 expression (≥ 50%), atelizumab can be used as a single agent.

  • Driver gene positivity
  • EGFR sensitive gene mutation
    • For more information, please refer to the entry EGFR mutant lung cancer.

    EGFR-TKIs are recommended, and ositinib, gefitinib, erlotinib, ectinib, afatinib, and amitinib are available.

    For patients with non-classical mutations such as G719X, L861Q, and S768I, afatinib is first recommended.

    Ⅰ期

    For patients with EGFR-sensitive gene mutations detected during the course of first-line chemotherapy already initiated, it is recommended to switch to EGFR-TKIs after completing conventional chemotherapy (including maintenance therapy), or to start targeted therapy after interrupting chemotherapy.

    ALK fusion gene positive

    For more information, please refer to the term ALK fusion lung cancer.

    You can choose alectinib, ceritinib, enzatinib, crizotinib, buxtitinib.

  • Patients who are found to be positive for ALK fusion genes during chemotherapy already started in the first line are recommended to be able to complete conventional chemotherapy, including switching to targeted therapy after maintenance therapy or starting targeted therapy after interruption of chemotherapy.
  • ROS1 fusion gene positivity

    • For more information, see the term ROS1 fusion lung cancer.

    Crizotinib is recommended, or platinum-containing two-agent chemotherapy or platinum-containing two-agent chemotherapy + bevacizumab.

    Other gene-positive

    Gene-related drugs

  • MET14 Sevortinib
  • MET14

    • Sevortinib

    BRAF V600 Darafenib in combination with Trametinib

    Ⅱ期

    BRAF V600

    Darafenib in combination with trametinib

    NTRK entrectinib (Entrectinib) larotrectinib (larotrectinib)

    NTRK
  • Entrectinib (Entrectinib) larotrectinib (larotrectinib)
  • RET Selpercatinib (Selpercatinib)
    • RET

    Selpercatinib

    [Reminder] Targeted drugs for the above genes, some of which are currently (2022-08-31) not approved for marketing in China or are not approved for indications regarding non-small cell lung cancer, patients may choose to participate in a clinical trial or adopt a driver gene-negative treatment regimen.

    Treatment of distant metastasis

    The vast majority of patients with stage IV lung large cell carcinoma have distant metastasis, which can be categorized into oligometastasis (only a few distant metastatic lesions) and extensive metastasis (multiple distant metastatic lesions at the same time).

    Oligometastasis

  • For patients with oligometastases, after effective systemic treatment, the use of radiotherapy, surgery and other local treatments can further prolong the survival of patients.
  • Brain or adrenal metastases: Aggressive local treatment, including surgical resection of brain or adrenal metastases, or conventional radiotherapy/SBRT for brain or adrenal metastases, combined with systemic therapy as appropriate.
    • Ⅲ期

    Bone metastases: receive radiotherapy in combination with bisphosphonates. Surgery of the metastases plus radiotherapy is recommended for patients with weight-bearing bone metastases, combined with systemic therapy as indicated.

    Extensive metastasis

    For patients with extensive metastases of large cell carcinoma of lung, the treatment of oligometastases is generally referred to and supplemented by palliative treatment, aiming at relieving symptoms, alleviating pain and improving quality of life.

    Palliative treatment includes taking palliative surgery, chemotherapy, radiotherapy, endocrine therapy, targeted therapy, immunotherapy, and other means that can alleviate patients’ symptoms, such as pain relief treatment.

    Stage I lung large cell carcinoma, which can be divided into Stage IA and Stage IB, is preferred to be resected by radical surgery, and radiotherapy can be chosen if patients are not suitable for surgery.

  • Patients suitable for surgery
  • Surgical treatment
    • There are mainly the following surgical treatment options, which need to be determined according to the specific conditions of patients.
  • Anatomic lobectomy + hilar mediastinal lymph node dissection.
  • Anatomic lobectomy + hilar mediastinal lymph node dissection with minimally invasive techniques (thoracoscopic, robot-assisted).
  • Reoperation is recommended for stage I patients with positive margins, and postoperative combined radiotherapy is recommended for patients who cannot undergo reoperation for any reason.
  • Postoperative treatment
  • For incomplete surgical resection, such as stage I patients with positive margins, reoperation is generally recommended, and for patients who cannot be reopened for any reason, postoperative combined radiotherapy is recommended.
    • If complete surgical resection is performed, the following follow-up treatment options are available depending on the specific situation:

    Stage IA: Patients with completely resected stage IA lung large cell carcinoma are not recommended to routinely apply postoperative adjuvant chemotherapy, radiotherapy and targeted drug therapy.

    Stage IB: Patients with completely resected stage IB lung large cell carcinoma may need to apply postoperative adjuvant chemotherapy due to poor differentiation.

    Patients who are not suitable for surgery

    For patients with severe medical comorbidities, advanced age, refusal of surgery and other contraindications to surgery, stereotactic radiotherapy (SBRT/ASBR) may be performed.

    For stage II lung large cell carcinoma, radical surgical resection is preferred, and radical radiotherapy can be chosen if the patient is not suitable for surgery.

    Patients suitable for surgery

  • The choice of operation is the same as stage I. However, reoperation is recommended for stage II patients with positive margins, and postoperative radiotherapy is recommended for patients who cannot be reopened for any reason.
  • Adjuvant chemotherapy
  • For patients with completely resected stage II large cell lung cancer, 4 cycles of postoperative adjuvant chemotherapy with platinum-containing two-drug regimen is recommended.
    • The starting time of adjuvant chemotherapy is recommended to be when the patient’s physical condition is basically back to normal after surgery, usually 4 to 6 weeks after surgery, and the latest recommendation is not more than 3 months after surgery.
  • Adjuvant targeted therapy
  • For patients with stage II lung large cell carcinoma who are tested positive for EGFR after surgery, adjuvant chemotherapy with ocitinib or ectinib can be considered.
  • Adjuvant immunotherapy
  • Patients with stage II lung large cell carcinoma who test negative for driver genes after surgery, such as positive PD-L1 expression (≥1%) can be treated with adjuvant therapy with atirizumab after platinum-based chemotherapy.
  • Patients who are not suitable for surgery
  • For patients with severe medical comorbidities, advanced age, refusal of surgery and other contraindications to surgery, there are several main treatment options, which need to be tailored to the patient’s specific situation.
  • Radiation therapy followed by chemotherapy with a platinum-containing two-drug regimen.
  • Synchronized radiotherapy: three-dimensional conformal radiotherapy or conformal intensity-modulated radiotherapy + chemotherapy.
  • Stage III lung large cell carcinoma, including stage IIIA, IIIB and IIIC, is divided into resectable and unresectable categories according to whether the tumor has the possibility of surgical resection.
    • Ⅳ期

    Treatment of patients with resectable category

    The resectable category of stage III refers to some stage IIIA and IIIC patients. Depending on the regional lymph node (N), they are further categorized into N0 to 1 and N2 cases.

    The case of N0～1

    For patients with T3 to 4N1 or T4N0 in stage III, the following treatment options are available:

    Surgery + adjuvant chemotherapy.

    Neoadjuvant therapy ± radiotherapy + surgery.

    In the case of N2

    The following treatment options are available for patients with a single group of enlarged mediastinal lymph nodes and <3 cm in diameter in stage N2, or two groups of enlarged mediastinal lymph nodes without fusion and expected to be completely resected:

  • Surgical resection + adjuvant chemotherapy ± postoperative radiotherapy.
  • Neoadjuvant chemotherapy ± radiotherapy + surgery ± adjuvant chemotherapy ± postoperative radiotherapy.

    • For patients with N2 multisite lymph node metastasis who also anticipate the possibility of complete resection, the following treatment options are available:

    Neoadjuvant chemotherapy ± radiotherapy + surgery ± adjuvant chemotherapy ± postoperative radiotherapy.

    Targeted therapy

  • Patients with stage III large cell carcinoma of the lung, after radical surgery, can be treated with adjuvant therapy with oxitinib or ectinib after surgery if the pathologic test is positive for EGFR mutation.
  • Immunotherapy
  • Patients with stage III lung large cell carcinoma, after radical surgery, if the driver gene is negative. If PD-L1 expression is positive (≥1%) adjuvant treatment with atirizumab may be administered after platinum-based chemotherapy.
    • Treatment of patients in the unresectable category

    Definition.

  • Unresectable stages IIIA, IIIB, and IIIC are defined as having the following imaging or lymph node pathology evidence.
  • Multiple ipsilateral mediastinal lymph node metastases into a large mass or multiple metastases (IIIA: T1-2N2 or IIIB: T3-4N2).
    • Contralateral hilar and mediastinal lymph nodes, or ipsilateral and contralateral diagonal or supraclavicular lymph node metastases (IIIB: T1-2N3; IIIC: T3-4N3).

    The lesion invades the heart, aorta, and esophagus (IIIA: T4N0-1).

    Treatment regimen

    Radical simultaneous radiotherapy
    If the patient is in good health, such as a PS score of 0 to 1, the recommended treatment of choice is radical synchronized radiotherapy.If there is no disease progression after simultaneous chemoradiotherapy, the addition of maintenance therapy with divalizumab may be considered.Synchronized chemotherapy regimen: etoposide + cisplatin; vincristine + cisplatin; pemetrexed + cisplatin or carboplatin; paclitaxel analog + cisplatin or carboplatinSequential radiotherapyIf the patient cannot tolerate synchronized radiotherapy, sequential radiotherapy is better than radiotherapy alone.

    Sequential chemotherapy: vincristine + cisplatin; paclitaxel + cisplatin or carboplatin; pemetrexed + cisplatin or carboplatin.

    It is recommended to perform chemotherapy for 2 to 4 cycles for evaluation before radiotherapy.

    If the patient’s physical condition is poor, such as PS 0 to 2 points, radiotherapy alone (three-dimensional conformal radiotherapy) or sequential radiotherapy + chemotherapy can be considered.

    Before starting treatment, patients with stage IV lung large cell carcinoma should obtain tumor tissues for gene mutation testing, such as EGFR, ALK and ROS1, etc., and decide the appropriate treatment strategy according to the above driver gene status.

    Driver gene negative

  • For patients with negative driver genes, platinum-containing two-drug regimens are the standard first-line chemotherapy regimen, and can be combined with anti-vascular therapy such as bevacizumab or vascular endothelial inhibitory protein on top of chemotherapy.
  • Platinum-containing two-drug chemotherapy based on immune checkpoint inhibitors in combination with pemetrexed is recommended for patients with suitable conditions.
    • Immunologic agents

    Commonly used immune checkpoint inhibitors include pembrolizumab, karelizumab, sindilizumab, tirilizumab, atelizumab, and sugilizumab.

    PD-L1 Assay

    PD-L1 expression testing is generally required when using immune checkpoint inhibitors.

    For patients with positive PD-L1 expression (≥1%), pembrolizumab, for example, may be used as a single agent, but the benefit is more pronounced in patients with high PD-L1 expression (≥50%).

    For patients with high PD-L1 expression (≥ 50%), atelizumab can be used as a single agent.

    Driver gene positivity

    EGFR sensitive gene mutation

  • For more information, please refer to the entry EGFR mutant lung cancer.
  • EGFR-TKIs are recommended, and ositinib, gefitinib, erlotinib, ectinib, afatinib, and amitinib are available.

    • For patients with non-classical mutations such as G719X, L861Q, and S768I, afatinib is first recommended.

    For patients with EGFR-sensitive gene mutations detected during the course of first-line chemotherapy already initiated, it is recommended to switch to EGFR-TKIs after completing conventional chemotherapy (including maintenance therapy), or to start targeted therapy after interrupting chemotherapy.

    ALK fusion gene positive

    For more information, please refer to the term ALK fusion lung cancer.You can choose alectinib, ceritinib, enzatinib, crizotinib, buxtitinib.Patients who are found to be positive for ALK fusion genes during chemotherapy already started in the first line are recommended to be able to complete conventional chemotherapy, including switching to targeted therapy after maintenance therapy or starting targeted therapy after interruption of chemotherapy.ROS1 fusion gene positivityFor more information, see the term ROS1 fusion lung cancer.

    Crizotinib is recommended, or platinum-containing two-agent chemotherapy or platinum-containing two-agent chemotherapy + bevacizumab.

  • Other gene-positive

    • Gene-related drugs

    MET14 Sevortinib

    MET14

    Sevortinib

  • BRAF V600 Darafenib in combination with Trametinib
  • BRAF V600
  • Darafenib in combination with trametinib
  • NTRK entrectinib (Entrectinib) larotrectinib (larotrectinib)
  • NTRK

    • Entrectinib (Entrectinib) larotrectinib (larotrectinib)

    RET Selpercatinib (Selpercatinib)

    RET

    Selpercatinib

  • [Reminder] Targeted drugs for the above genes, some of which are currently (2022-08-31) not approved for marketing in China or are not approved for indications regarding non-small cell lung cancer, patients may choose to participate in a clinical trial or adopt a driver gene-negative treatment regimen.
  • Treatment of distant metastasis
  • The vast majority of patients with stage IV lung large cell carcinoma have distant metastasis, which can be categorized into oligometastasis (only a few distant metastatic lesions) and extensive metastasis (multiple distant metastatic lesions at the same time).
  • Oligometastasis
  • For patients with oligometastases, after effective systemic treatment, the use of radiotherapy, surgery and other local treatments can further prolong the survival of patients.

    • Brain or adrenal metastases: Aggressive local treatment, including surgical resection of brain or adrenal metastases, or conventional radiotherapy/SBRT for brain or adrenal metastases, combined with systemic therapy as appropriate.

    Bone metastases: receive radiotherapy in combination with bisphosphonates. Surgery of the metastases plus radiotherapy is recommended for patients with weight-bearing bone metastases, combined with systemic therapy as indicated.

  • Extensive metastasis
  • For patients with extensive metastases of large cell carcinoma of lung, the treatment of oligometastases is generally referred to and supplemented by palliative treatment, aiming at relieving symptoms, alleviating pain and improving quality of life.
  • Palliative treatment includes palliative surgery, chemotherapy, radiotherapy, endocrine therapy, targeted therapy, immunotherapy, and other means that can alleviate the patient’s symptoms, such as pain relief therapy.
  • Prognosis
  • Survival rate

    • Studies on large cell lung cancer

    There is no specific authoritative data on survival due to the small number of lung large cell carcinoma cases, but overall, lung large cell carcinoma is more malignant and has a worse prognosis.

  • Some studies have shown [9]:
  • The 1-, 3- and 5-year survival rates for lung large cell carcinoma were 50.8%, 29.5% and 20.3%, respectively.
  • The 5-year survival rate for each stage: 38.1% for stage I, 20% for stage II, 4.76% for stage III, and 0 for stage IV, and the 5-year survival rate for those treated with comprehensive therapy was 23.3%.

    • 5-year survival rate of non-small cell lung cancer by stages

    Lung large cell carcinoma belongs to one of the types of non-small cell lung cancer, and the data of non-small cell lung cancer can be used to approximate the survival rate of lung large cell carcinoma by stages.

  • According to a study that comprehensively analyzed several large-scale statistics from 2000 to 2012, the 5-year survival rates of non-small cell lung cancer by stages in China are as follows:
  • Stage 5-year survival rate

    • Stage I 75%

    Stage Ⅰ

    75%

  • Stage II 55%
  • Stage II
  • 55%

    • Stage III 20