Q1: What is the specific content of VALSG staging of small cell lung cancer?
A1: VALSG staging divides SCLC into limited stage and spread stage. Limited stage SCLC is characterized by tumor involvement limited to one side of the chest cavity (with or without local spread) and no distant metastasis outside the chest. If regional and ipsilateral supraclavicular enlarged lymph nodes can be covered in a single safe and adequate radiation treatment field, it is also considered limited stage SCLC. all other cases are classified as diffuse stage SCLC, characterized by malignant pleural effusion, malignant pericardial effusion, enlarged contralateral hilar and supraclavicular lymph nodes, and metastases that cannot be treated in a single radiation field. However, the International Association for the Study of Lung Cancer modified the VALSG staging in 1989 (VALSG staging revision, also known as IASLC staging), and the most important change was that contralateral mediastinal or supraclavicular lymph node enlargement and ipsilateral pleural effusion (whether benign, or malignant) were classified as limited stage SCLC, and diffuse stage SCLC was a lesion beyond the scope of limited stage SCLC. However, the complexity of clinical disease makes these two staging often in mixed use.
VALSG staging.
Limited stage SCLC
confined to a single radiation field
confined to the ipsilateral mediastinum
ipsilateral mediastinal or supraclavicular lymph node enlargement
Diffuse stage SCLC
Not confined to a single radiation field
Contralateral mediastinal or supraclavicular lymph node enlargement
Malignant pleural fluid or pericardial effusion
Metastatic foci
VALSG staging revision.
Limited stage SCLC
Confined to a single radiation field
ipsilateral mediastinal or supraclavicular lymph node enlargement
Contralateral mediastinal or supraclavicular lymph node enlargement
Ipsilateral pleural fluid (either benign or malignant)
Diffuse stage SCLC
Not confined to a single radiation field
Metastatic foci
Q2: What are the specifics of TNM staging of lung cancer in the 7th edition of AJCC?
A2: The International Association for the Study of Lung Cancer (IASLC) recommends the current AJCC 7th edition TNM staging of lung cancer to replace the VALSG staging. Although some studies (enrolling about 10,000 patients between 1995 and 2005) have shown that the stage-specific survival rate of the AJCC TNM staging of lung cancer is significantly higher than that of the VALSG staging, the TNM staging does not often change the clinical management plan and is less useful than the VALSG staging in assessing prognosis. VALSG staging is also less useful in assessing prognosis. It is also useful in determining whether a patient can undergo surgical resection.
AJCC 7th edition TNM staging of lung cancer.
T-stage for primary tumors.
Tx: primary tumor cannot be assessed, or cancer cells are present in sputum or bronchial washings, but imaging and bronchoscopy do not reveal a primary tumor
T0: no evidence of primary tumor
Tis: carcinoma in situ
T1: tumor ≤3 cm in maximum diameter, surrounded by lung or dirty pleura, no evidence of invasion of more proximal lobe bronchi by bronchoscopy (i.e., no invasion of main bronchi)
T1a: maximum tumor diameter ≤2 cm
T1b: tumor diameter >2 cm but ≤3 cm
T2: tumor >3 cm but ≤7 cm in maximum diameter, or with any of the following features: involvement of the main bronchus but tumor ≥2 cm from the tracheal ramus, invasion of the dirty pleura and spread to the hilar region but without involvement of the whole lung in atelectasis or obstructive pneumonia.
T2a: tumor with maximum diameter >3 cm but ≤5 cm
T2b: tumor diameter >5 cm but ≤7 cm
T3: tumor with maximum diameter >7 cm, or direct invasion of mural pleura, chest wall (including supraglottic sulcus tumor), diaphragm, phrenic nerve, mediastinal pleura and mural pericardium; or tumor located in the main bronchus, <2 cm from the tracheal bulge, but not involving the tracheal bulge; or involvement of the whole lung with atelectasis or obstructive lung lobes or single or multiple scattered pulmonary nodules in the lung lobes where the tumor is located.
T4: Tumor of any size invading the mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body or tracheal ramus; or single or multiple scattered pulmonary nodules in other lung lobes ipsilateral to the lobe where the tumor is located.
Lymph node N-stage.
Nx: lymph node metastasis cannot be assessed
N0: no regional lymph node metastasis
N1: metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary lymph nodes, including direct invasion by the primary tumor
N2: metastasis to ipsilateral mediastinal and/or subserosal lymph nodes
N3: metastasis to contralateral mediastinal lymph nodes, contralateral hilar lymph nodes, ipsilateral or contralateral ramus or supraclavicular lymph nodes
Metastasis M stage.
M0: no distant metastasis
M1: with distant metastases
M1a: scattered single or multiple tumor nodules in the contralateral lobe; pleural nodules or malignant pleural fluid, pericardial effusion
M1b: distant (extrathoracic) metastasis
Clinical staging.
Occult stage: Tx N0 M0
Stage 0: Tis N0 M0
Stage Ⅰa: T1 N0 M0
Stage Ⅰb: T2a N0 M0
Phase IIa: T1 N1 M0, T2b N0 M0, T2a N1 M0
Phase IIb: T2b N1 M0, T3 N0 M0
Stage IIIa: T1 to 2 N2 M0, T3 N1 to 2 M0, T4 N0 to 1 M0
Stage IIIb: T4 N2 M0, any T N3 M0
Stage IV: any T any N M1
Q3: What are the characteristics of small cell lung cancer as a pulmonary neuroendocrine tumor?
A3：The 2004 WHO tumor classification classifies the four major types of pulmonary neuroendocrine tumors into three histological grades. Low-grade malignant tumors include typical carcinoid tumors, intermediate-grade tumors include atypical carcinoid tumors, and high-grade tumors include large cell neuroendocrine tumors and SCLC.
SCLC can secrete biologically active substances such as hormones, and can also present with immune-mediated destruction of neural tissue caused by antibodies or cell-mediated immune responses. SIADH is characterized by hypoconcentrated urine, decreased plasma osmolality, and isotonic hyponatremia due to overproduction of antidiuretic hormone. Other endocrine paraneoplastic syndromes include Cushing’s syndrome secondary to ectopic pro-adrenocorticotropic hormone and acromegaly due to ectopic growth hormone-releasing peptide. Neurological paraneoplastic syndromes include autonomic immune neuropathy (Eaton-Lambert syndrome), encephalomyelitis and limbic lobe encephalitis. Patients with these syndromes have a rapid progression of loss of behavior, and the onset of neurological symptoms often precedes the diagnosis of lung cancer by up to 2 years, although these symptoms can improve after lung cancer treatment. Typical systemic symptoms often include weight loss, malaise and malignant fluid, which can also be seen in all lung cancer patients. Relatively specific symptoms are those of pulmonary neuroendocrine tumor manifestations in Q3. The presence of Superior Vena Cava Syndrome (SVCS) should be considered in SCLC, which occurs in 10% of patients with aggressive or advanced tumors, but other tumors can also lead to SVCS, when invasion of the esophagus and mediastinal structures such as the recurrent laryngeal nerve and trachea leads to dysphagia and hoarseness. Q5: Doctors always recommend pathology and immunohistochemistry for SCLC, what are the benefits? To treat SCLC, the pathological type of tumor should be diagnosed first, and then the tumor staging should be done. Under light microscopy, SCLC appears as small blue round, ovoid or spindle-shaped cells with sparse cytoplasm, smooth margins, finely granular nuclear chromatin and no or inconspicuous nucleoli. Among pulmonary neuroendocrine tumors, SCLC has the most active nuclear divisions (>10 nuclear divisions per 10x high-powered view; 10 median nuclear divisions per 10x high-powered view) and the most typical extensive necrosis.
The WHO classifies SCLC into two subtypes: pure SCLC and mixed SCLC. most tumors are pure SCLC because there are often limited tissue specimens available for pathological analysis, while mixed SCLC is rare. Mixed SCLC is characterized by the presence of non-SCLC components such as adenocarcinoma, squamous carcinoma, large cell carcinoma, spindle cell carcinoma, or giant cell carcinoma within the tumor. To diagnose mixed SCLC-large cell carcinoma, at least 10% of the tumor must have a large or giant cell component, but for other lung cancer subtypes such as adenocarcinoma, squamous carcinoma, and spindle cell carcinoma, the percentage of large or giant cell component is not as important for diagnosis. Immunohistochemical analysis for the diagnosis of SCLC typically includes antibodies to whole cell keratin such as AE1/AE3, CD56, chromogranin-synuclein, thyroid transcription factor 1 (TTF-1) and Ki-67. If the specimen is negative for antibodies to whole cell keratin, then other tumors such as lymphoma (CD45 and CD20), primitive neuroectodermal tumors (CD99) and melanoma (S100). Nearly 80% of SCLCs are TTF-1 positive, and the Ki-67 proliferation index of SCLC ranges from 80% to 100%, which can be used to differentiate SCLC from carcinoid tumors. Immunohistochemical analysis can distinguish SCLC from basal-like squamous cell carcinoma. For example, SCLC is seen to express neuroendocrine markers and TTF-1, whereas basal-like squamous cell carcinoma expresses p63 (4A4) and high molecular weight cytokeratin (CK5/6 or 34bE12).