Overview: It is a rare type of high-grade neuroendocrine carcinoma of the lung.
A rare form of high-grade neuroendocrine carcinoma of the lung that may manifest as cough, sputum, hemoptysis, blood in sputum, chest pain, etc. It is associated with long-term heavy smoking and genetic abnormality, with surgery combined with chemotherapy as the best treatment option for early-stage patients and chemotherapy as the mainstay of treatment for late-stage patients.
Definition
Large cell neuroendocrine carcinoma of the lung is a type of lung neuroendocrine tumor, which belongs to high-grade neuroendocrine carcinoma with high aggressiveness and poor prognosis.
Currently, lung neuroendocrine tumors (NETs) are classified into 4 subtypes: typical carcinoid (TC), atypical carcinoid (AC), small cell lung cancer (SCLC), and large cell neuroendocrine carcinoma (LCNEC).
Approximately 25% of large cell neuroendocrine carcinomas of the lung show a combination of other histologic features pathologically, most commonly small cell lung carcinoma, adenocarcinoma, and squamous cell carcinoma.
Morbidity
Large cell neuroendocrine carcinoma of the lung is relatively rare, with an incidence of approximately 3% of lung cancers [1].
The average age of onset in patients is around 65 years and is highly associated with smoking [3].
Previous studies have shown that about 90% of lung cancers are associated with smoking, and the risk of lung cancer in smokers is 20 times higher than that in nonsmokers [5].
Most of the lesions of large cell neuroendocrine carcinoma of the lung are of peripheral type [3].
Etiology
Causes
The exact etiology is unknown and may be related to the following factors.
Smoking
Smoking is the most common cause of lung large cell neuroendocrine carcinoma. Smoking tobacco in the form of cigarettes, cigars, or pipes can cause the disease.
Genetic abnormalities
Studies have shown that in lung large cell neuroendocrine carcinoma, most of the mutated genes are oncogenes and are associated with smoking.
Mutations found to be significant are in TP53, RB1, STK11, KEAP1 and genes on the RAS (KRAS/NRAS/HRAS) pathway.
In lung large cell neuroendocrine carcinoma not only mutations but also amplification of a large number of genes were present. Some of the genes with a high percentage of amplification are MYC, MYCL1, NKX2-1, FGFR1 and IRS2.
Compared to other lung neuroendocrine tumors, large cell neuroendocrine carcinoma of the lung has specific genetic alterations, including ADAMTS12 (20%), ADAMTS2 (15%), GAS7 (12%), and NTM (10%); of these, GAS7 and NTM are involved in neuroendocrine differentiation.
Symptoms
Main Symptoms
Clinical symptoms and signs of lung large cell neuroendocrine carcinoma are nonspecific, mainly related to the site of the lesion and the size of the mass, and may include the following manifestations.
Cough and sputum
Cough and sputum are common symptoms when patients with large cell neuroendocrine carcinoma consult the doctor.
Cough and sputum are the first symptoms when patients consult the doctor.
Hemoptysis and blood in sputum
Usually manifested as blood in sputum, hemoptysis is rare.
Chest tightness, chest pain
Some patients may manifest chest pain, chest tightness, shortness of breath or even dyspnea.
Other symptoms
Some advanced cancer patients may develop cachexia, which manifests as extreme emaciation, weakness, generalized failure and other symptoms.
Consultation
Department of Medicine
Thoracic Surgery
Please consult the Department of Thoracic Surgery if nodules or space-occupying lesions in the lungs are found on chest imaging (X-ray, chest CT, etc.) during a routine physical examination or other tests.
Medical Oncology
When the diagnosis of large cell neuroendocrine carcinoma of the lung is confirmed, and radiotherapy, chemotherapy and other comprehensive internal medicine treatments are needed, please consult the Department of Medical Oncology.
Respiratory Medicine
Please consult the Department of Respiratory Medicine when symptoms such as cough, sputum, hemoptysis, blood in sputum and chest pain occur.
Preparation for medical treatment
Consultation: Registration, Preparation of documents, Frequently Asked Questions
Tips for Medical Consultation
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 a cough and for how long?
Is there blood in the sputum?
Is there chest tightness or chest pain?
Has there been a recent change in weight? How is the appetite?
List of medical history
Is there any smoking, for how long and how many cigarettes per day?
Is there a family history of malignant tumors?
Any drug or food allergies?
Checklist
Test results in the last six months, which can be brought to the doctor’s office
Specialty tests: lung biopsy pathology report, chest X-ray or CT report, tumor markers.
Laboratory tests: blood routine, urine routine, stool routine, biochemical tests.
Imaging tests: magnetic resonance imaging (MRI), PET-CT.
Diagnosis
Diagnosis is based on
Medical history
The patient may have a long history of heavy smoking.
Clinical manifestations
Early stage of large cell neuroendocrine carcinoma of the lung has no obvious symptoms. With the progression of the disease, symptoms such as coughing, coughing up sputum, hemoptysis, blood in sputum, chest pain, emaciation and fatigue may appear.
Tumor marker examination
Some studies have shown that the highest positive rate of serum tumor markers in large cell neuroendocrine carcinoma is NSE (76.27%), followed by CYFRA21-1 (60.7%), CEA (46.3%), and the higher positive rate of NSE may be related to the characteristics of LCNEC as a neuroendocrine carcinoma.
Imaging
The imaging manifestations of lung large cell neuroendocrine carcinoma lack specificity, and can occur in any lobe or segment of the lung, with a predominance of peripheral type.
The CT presentation is usually a peripheral mass, aggressive growth, irregular mass shadow, sometimes accompanied by calcification, rarely accompanied by lymph node fusion into a mass, or cavitary lesions.
Fiberoptic bronchoscopy
For central type lung large cell neuroendocrine carcinoma, bronchoscopy can directly observe the lesion inside the bronchus and can take part of the tissue for pathological biopsy.
However, the tumors of this disease are mostly located in the periphery, so sputum cytology and bronchoscopy are not very helpful in diagnosing this disease.
Pathologic examination
LCNEC is difficult to diagnose, and needs to be confirmed by tracheoscopy or lung puncture biopsy sampling or surgical pathology, but tracheoscopy or lung puncture biopsy pathology sometimes the amount of specimen is too small, and a second biopsy is needed, and currently the main method of diagnosing LCNEC is surgery, which is also the preferred method of treatment [1].
Morphologic manifestations
Typical morphological features are organ-like structures, fenestrated and wreath-like arrangements, NSCLC cytologic features, low nucleoplasmic ratios, large numbers of abundant nucleoli and extensive necrosis [3].
Neuroendocrine markers
such as neural cell adhesion molecule (NCAM)/CD56, pheochromocyanin A and synaptophysin are positive in 92%-100%, 80%-85% and 50%-60% of tumors, respectively.
NCAM/CD56 is the most sensitive marker but not specific, while chromogranin A and synaptophysin are the most reliable markers for diagnosing LCNEC [6].
Others
In rare cases (5%-7%), LCNEC tumors may have therapeutically significant genetic alterations, including KRAS, EGFR or MET mutations and EML4-ALK rearrangements [11].
Differential diagnosis.
Large cell neuroendocrine carcinoma of the lung should be differentiated from carcinoid and small cell lung cancer.
Carcinoid tumor
Similarities: both may present with symptoms such as cough, blood in sputum, and chest pain.
Differences: Carcinoid tumors (including typical carcinoid tumors and atypical carcinoid tumors) are mostly seen in middle-aged women and non-smokers, and most of them manifest as nodules or masses in and around the bronchial cavity, with central type being the most common, clear boundary, calcification being more common, and homogeneous enhancement of the lesion after enhanced scanning.
Small cell lung cancer
Similarity: both of them can manifest symptoms such as cough, blood in sputum and chest pain.
Differences: Small cell lung cancer is the most malignant lung cancer, and the central type is more common, with smaller primary foci and extensive mediastinal and hilar lymph nodes and distant metastases.
Treatment
Treatment objective: maximize tumor resection, improve patients’ quality of life and prolong survival time.
Treatment principle: once the diagnosis of lung large cell neuroendocrine carcinoma is clear, treatment should be started as early as possible, and surgical resection combined with chemotherapy is the preferred treatment.
Surgery
A retrospective data analysis shows that surgery is beneficial to the prognosis of patients with stage I, II and III lung large cell neuroendocrine carcinoma, and surgery combined with chemotherapy is the best treatment plan for patients with stage I, II and III lung large cell neuroendocrine carcinoma.
Some studies have shown that surgery should be advocated for patients with early-stage (stage I, II, and III) LCNEC, and that platinum + etoposide-based adjuvant therapy would benefit the patients.
Chemotherapy
In lung large cell neuroendocrine carcinoma, there is no standard guideline recommending the optimal treatment program. Nowadays, there are two commonly used clinical regimens:
One is the conventional chemotherapy regimen for non-small cell lung cancer, such as pemetrexed, gemcitabine combined with platinum-containing chemotherapy regimen.
The other is conventional chemotherapy for small cell lung cancer, such as etoposide combined with platinum-containing chemotherapy.
Radiation therapy
For patients with positive mediastinal lymph nodes (stage III) after resection of the tumor and for patients with stage III tumors that cannot be resected, a combination of radiation therapy in addition to etoposide/cisplatin chemotherapy is usually required, rather than chemotherapy alone.
Targeted therapy
There are limited data on the treatment of patients with large cell neuroendocrine carcinoma of the lung identified with mutations in KRAS, EGFR, ALK, or other therapeutically significant driver genes, and the choice of treatment in this setting depends on a variety of factors, including which therapeutic stage it is, disease progression, functional status, and patient preference.
In general, targeted therapies may be used at the discretion of patients with limited disease burden or more gradual disease progression, as well as patients who wish to avoid toxicities associated with other treatments, as seen in driver gene-positive non-small cell lung cancer.
Immunotherapy
Studies have shown that patients with large cell neuroendocrine carcinoma of the lung have a higher rate of positive programmed death receptor 1 ligand (PD-L1) expression than those with small cell lung cancer, and that this correlates with prognosis and may be an effective treatment option.
Although there are no data to support the decision to immunotherapeutically treat LCNEC based on PD-L1 expression measured by immunohistochemistry, there are still a number of clinical studies exploring the use of immunotherapy for LCNEC, which need to be validated with more data.
Prognosis
Cure status
Early manifestations of lung large cell neuroendocrine carcinoma are nonspecific and characterized by high malignancy and relatively difficult diagnosis. Most patients have local infiltration or distant metastasis at the time of diagnosis, with a high morbidity and mortality rate, a short average survival period, and a poor prognosis.
Most studies have shown that the stage-matched survival of LCNEC is worse than that of non-small cell lung cancer and other large cell carcinomas, but similar to that of small cell lung cancer [12].
The 5-year survival rate of lung large cell neuroendocrine carcinoma has been reported in the literature to be 15% to 57%. Even in patients with stage I LCNEC, the 5-year survival rate is only 27% to 67% [2].
Special reminder.
The 5-year survival rate refers to the proportion of patients whose tumors survive for more than 5 years after various comprehensive treatments, and does not mean that patients can only survive for 5 years.
Survival rates are statistics used in clinical studies, usually based on the results of previous studies in large populations with a particular cancer (e.g., staging), and these statistics do not predict nor represent the survival of any individual.
Prognostic Factors
Prognostic factors are factors that have an impact on a patient’s overall survival and quality of life.
Patients with early clinical staging, no lymph nodes or distant metastases and those who undergo surgery have a higher survival rate and a relatively good prognosis.
Patients with late clinical stage, lymph nodes and distant metastases and without surgery have a lower survival rate and a relatively poor prognosis.
Daily
Daily management
Lifestyle
Quit smoking and drinking, avoid exertion, have a regular routine, avoid staying up late and get enough sleep.
Maintain a healthy weight, take appropriate activities such as slow walking, tai chi, qigong, breathing exercises, etc., and avoid crowded places.
Diet management
Reasonable dietary arrangements, so as to achieve a light diet, balanced nutrition, and a variety of food types.
Intake of vitamin-rich fresh fruits and vegetables can supplement the vitamins needed by the body and promote recovery.
Eat more protein-rich food, such as eggs, milk, lean meat and fish.
Cold, raw, stimulating, pickled, fried and deep-fried foods, such as fried chicken and chili peppers, should be avoided.
Psychological support
Maintain a good mood and mindset and face the disease positively.
Learn to confide in friends and family members to avoid excessive pressure, which may cause mental illness, and seek help from psychiatrists if necessary.
Patients should establish a correct understanding of the disease, accept treatment positively, and do work and housework to the best of their ability during and after treatment, so as to reintegrate into their social roles.
Family members should provide adequate companionship to the patient, create a cozy family atmosphere, comfort the patient and help him/her get through the difficult time.
Disease monitoring
Patients should pay attention to the sputum condition and seek medical attention if there is blood in the sputum or even hemoptysis again.
In addition, if symptoms such as cough, sputum, chest pain and chest tightness occur, they should consult a doctor promptly.
Follow-up examination
Follow-ups are important for patients to help the doctor assess the efficacy of the treatment and to monitor for recurrence.
The time of follow-up should be set by the specialist.
Review items: tumor markers, chest X-ray, chest CT, chest MRI and other tests can help determine whether there is recurrence.
Prevention
To address the causes of large cell neuroendocrine carcinoma of the lung, one can start by reducing or avoiding the risk factors that cause the disease.
Smoking cessation
Smoking is an important risk factor for the disease. One should quit smoking (including cigarettes, e-cigarettes, etc.) and stay away from passive smoking.
Regular screening
Annual health checkups are recommended and may help reduce the incidence of the disease.