Introduction - **Understanding Lung Cancer: A Complex Disease**
Lung cancer is a diverse group of malignant conditions, primarily categorized into small cell lung cancer (SCLC) comprising 13% of cases, and nonsmall cell lung cancer (NSCLC) making up 86% of cases. Additionally, there are rare thoracic malignancies like mesothelioma and lower-grade neuroendocrine tumors that fall under this umbrella.
In 2016, the American Cancer Society estimated that 224,390 individuals in the United States would be diagnosed with lung cancer, and tragically, 158,080 would succumb to this disease. It's important to note that lung cancer is not a single entity but rather a collection of distinct cancers, each with its unique characteristics.
Historically, lung cancer has posed a significant health challenge. In the case of men, the age-adjusted death rate for lung cancer hit its peak in 1990 at approximately 90 deaths per 100,000 individuals and has since declined to 60 per 100,000. In contrast, for women, the incidence reached a plateau around 1998, stabilizing at 53 per 100,000. These shifts can be attributed, in part, to changing smoking patterns.
Although there has been a decrease in smoking rates in developed countries, lung cancer persists as the leading cause of cancer-related fatalities in both men and women in the United States. This sobering fact also holds true globally, where lung cancer ranks as the top cause of cancer-related death. It underscores the critical need for ongoing research, early detection, and innovative treatment approaches in the battle against lung cancer.
**Lung Cancer and Non-Smokers: A Unique Perspective**
Lung cancer isn't exclusively linked to smoking; it can also be associated with other factors such as exposure to wood smoke, past chest radiotherapy, and certain metals like arsenic, chromium, nickel, beryllium, and cadmium. Nevertheless, it's essential to recognize that the contribution of these factors to the overall occurrence of lung cancer is relatively minor.
Now, let's delve into a specific group: individuals who have never smoked. Surprisingly, an estimated 25,000 deaths occur annually in the United States due to lung cancer among non-smokers. If considered separately, this would rank as the seventh leading cause of cancer-related deaths. Remarkably, 10% to 20% of all lung cancers are not linked to tobacco or other environmental exposures.
Interestingly, it's uncertain whether the incidence of lung cancer in never-smokers is on the rise or if it has always existed at a level that was previously undetected. In the early 1900s, before smoking became widespread, lung cancer diagnoses might have been overlooked or even confused with tuberculosis. Additionally, some populations seem more susceptible to developing lung cancer without smoking, such as women more than men, and African Americans and Asians more than Caucasians. Researchers have identified potential genetic factors that may make certain individuals more prone to this form of lung cancer.
While risk factors for lung cancer in never-smokers include exposure to secondhand smoke, radon, air pollution, occupational hazards, and genetic predisposition, the majority of patients in this category have no identifiable direct cause. What's intriguing is that the biology of lung cancer in non-smokers differs from that of smoking-related lung cancer. Adenocarcinoma, a subtype of nonsmall cell lung cancer (NSCLC), is the most common histological type among non-smokers. Notably, these tumors appear less complex than those in smokers and are more likely to possess specific genetic mutations that can be targeted with precision treatments (refer to "Molecular Changes in Nonsmall Cell Lung Cancer").
In summary, lung cancer is a multifaceted disease with various risk factors, and understanding its occurrence in non-smokers provides valuable insights into its complex nature. While smoking remains a predominant cause, it's evident that other factors, including genetics, play significant roles in shaping the landscape of lung cancer.
**Clinical Indicators and Paraneoplastic Syndromes in Lung Cancer**
*Clinical Detection of Lung Cancer Symptoms:*
In individuals who are heavy smokers, the symptoms of lung cancer often resemble the effects of chronic tobacco use. Many patients initially present with cough, worsening difficulty in breathing, or coughing up blood (hemoptysis), which can also be symptoms of conditions like bronchitis or pneumonia. However, symptoms such as significant weight loss, chest pain, bone pain, hoarseness, or neurological issues should trigger a more extensive medical evaluation as they often correspond to invasive or metastatic lung cancer.
*Paraneoplastic Syndromes:*
Paraneoplastic syndromes are more frequently observed in patients with Small Cell Lung Cancer (SCLC) but can occur in both types of lung cancer.
*Hematologic Abnormalities:*
Leukocytosis, an elevated white blood cell count, has been detected in up to 15% of Non-Small Cell Lung Cancer (NSCLC) patients, possibly due to the tumor's secretion of granulocyte colony-stimulating factor. In some cases, this condition leads to white blood cell counts over three times the upper limit of normal, referred to as a leukemoid reaction. Anemia is another common finding, affecting up to 40% of NSCLC patients, while thrombocytosis (elevated platelet count) is observed in up to 15% of cases.
*Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH):*
Around 10% of SCLC patients may secrete antidiuretic hormone, leading to severe hyponatremia (low sodium levels) even when fluid balance is normal (euvolemia). This syndrome responds to treating the underlying cancer, but in the meantime, it can be managed with measures like limiting water intake, certain medications like demeclocycline, and vasopressor receptor antagonists such as tolvaptan or conivaptan. It's crucial to avoid rapid sodium level correction as it can lead to a condition called central pontine myelinolysis.
*Hypercalcemia:*
Hypercalcemia, elevated calcium levels, can result from direct bone involvement by cancer or the secretion of factors that activate bone-resorbing cells (osteoclasts). High levels of parathyroid hormone-related peptide are often associated with NSCLC of squamous histology and can lead to clinical symptoms like excessive thirst, kidney stones, renal failure, nausea, constipation, and in severe cases, confusion or coma. Treatment typically includes intravenous (IV) hydration, bisphosphonates, and/or calcitonin.
*Cushing Syndrome:*
Excessive production of adrenocorticotropic hormone (ACTH) by tumor tissue can cause Cushing syndrome, characterized by symptoms like obesity concentrated around the trunk, hypertension, high blood sugar, low blood potassium levels (hypokalemic alkalosis), and osteoporosis. This is predominantly observed in patients with SCLC and is often a sign of a poor prognosis.
*Pancoast Syndrome:*
Lung tumors originating in the superior sulcus of either lung can damage the brachial plexus and sympathetic ganglia, leading to Pancoast syndrome. This syndrome is marked by shoulder and arm pain, a condition called Horner syndrome affecting one side of the face, bone destruction, and muscle atrophy in the hand. Typically, these tumors arise from NSCLC of squamous histology.
*Thrombosis:*
All cancer patients have an increased risk of developing blood clot-related disorders like deep vein thrombosis and pulmonary embolism. If spontaneous blood clots form without an apparent cause, it's essential to screen for an underlying malignancy. These patients should be treated with low-molecular-weight heparin instead of warfarin.
*Hypertrophic Pulmonary Osteoarthropathy:*
Associated primarily with NSCLC, hypertrophic pulmonary osteoarthropathy exhibits symptoms such as clubbing of the fingers, inflammation of the outer lining of long bones (periostitis), arthritis, and skin thickening. In addition to addressing the underlying malignancy, symptomatic treatment may involve nonsteroidal anti-inflammatory drugs and bisphosphonates.
*Lambert-Eaton Syndrome:*
Lambert-Eaton syndrome (LES) is an uncommon paraneoplastic syndrome, more often associated with SCLC but occasionally seen in NSCLC. It manifests as muscle weakness in the limbs, reduced reflexes, and autonomic changes. While it may resemble myasthenia gravis in presentation, a key differentiator is that muscle strength improves with repeated activity in LES.
**Diagnosis and Screening for Lung Cancer**
*Diagnosis:*
The diagnosis of lung cancer typically begins with the identification of a lung nodule on a chest X-ray (CXR) or a more detailed CT scan. A contrast-enhanced CT scan of the chest provides an overview of the extent of disease within the lung tissue, regional lymph nodes, and potential metastasis to other sites like the bones, liver, or adrenal glands. Positron emission tomography (PET) scans, alone or combined with CT scans (PET/CT), are used to further assess regional or metastatic disease. Except for very small Non-Small Cell Lung Cancers (NSCLC) less than 1 cm in diameter, most patients with lung cancer should also undergo brain imaging, typically a brain MRI. If an MRI is not feasible, a head CT scan with contrast can be performed.
Establishing the diagnosis of NSCLC requires obtaining tissue for histopathologic analysis. In general, physicians aim to make the initial diagnosis through the least invasive method that provides the highest pathologic stage. Thus, patients with a suspected metastasis should have that site biopsied for accurate staging. Patients with potential involvement of mediastinal lymph nodes may undergo diagnostic mediastinoscopy. CT-guided fine-needle biopsy of the lung is often used for diagnosis but carries a risk of complications like pneumothorax and severe pulmonary bleeding. Bronchoscopy, sometimes combined with endobronchial ultrasound, is particularly useful for proximal tumors and can provide information about the primary tumor and lymph node staging. While diagnosis can be made through fine-needle aspiration, advanced molecular testing often requires more substantial tissue samples in the form of non-decalcified core biopsies or surgical specimens.
*Screening:*
Due to the high mortality associated with advanced lung cancer, especially among smokers, several trials have attempted lung cancer screening. While radiologic imaging can detect malignant lung nodules, these tumors tend to be less aggressive than those detected through clinical symptoms.
Early randomized trials, involving over 30,000 patients, utilized combinations of CXR and sputum cytology for screening. However, these studies didn't directly compare screening with no screening. Instead, they examined adding sputum cytology to CXR or variations in screening frequency. The general findings showed increased detection of early-stage lung cancer but no difference in survival rates. For example, the Mayo Lung Project observed more lung cancer-related deaths in the screened group at 20-year follow-up.
These less promising results with CXR screening led to exploration of modern CT scanning techniques. Observational cohort studies showed that CT scans could identify more early-stage lung cancers compared to CXR. However, CT scans also produced more false-positive results, necessitating additional biopsies. These scans often detected very early-stage tumors with potentially better natural outcomes than clinically identified tumors.
In the National Lung Screening Trial, over 50,000 smokers, aged 55 to 74 years, without symptoms, were randomized to undergo annual CXR or low-dose CT screening for three years. The results showed a 20% relative reduction in lung cancer-specific mortality and a 6.7% relative reduction in all-cause mortality with CT screening compared to CXR. These findings have led to the adoption of low-dose CT screenings for lung cancer in some centers.
The US Preventive Services Task Force updated its guidelines in December 2013, recommending annual low-dose CT screening for lung cancer in adults aged 55 to 80 years with a smoking history of 30 pack-years who either currently smoke or quit within the past 15 years. Screening should be discontinued if a person has not smoked for 15 years or if they develop a health issue limiting life expectancy or the ability or willingness to undergo curative lung surgery.
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**This list categorizes different histologic subtypes of Non-Small Cell Lung Cancer (NSCLC) along with their variants. Here's an explanation of each subtype:
**I. Squamous cell carcinoma Variants:**
- **Papillary**: A variant characterized by papillary growth patterns.
- **Clear cell**: A variant with clear cell features.
- **Small cell**: A variant displaying small cell characteristics.
- **Basaloid**: A variant featuring basaloid growth patterns.
**II. Adenocarcinoma:**
- *Preinvasive lesions:*
- **Atypical adenomatous hyperplasia**: Early abnormal growth of glandular cells.
- **Adenocarcinoma in situ (formerly BAC - Bronchioloalveolar carcinoma)**: Noninvasive cancer confined to the air sacs.
- **Nonmucinous**: Without mucus production.
- **Mucinous**: Producing mucus.
- **Mixed mucinous/nonmucinous**: Combining mucus and non-mucus-producing elements.
- **Minimally invasive adenocarcinoma**: Slightly invasive cancer with lepidic predominant growth pattern.
- **Nonmucinous**: Without mucus production.
- **Mucinous**: Producing mucus.
- **Mixed mucinous/nonmucinous**: Combining mucus and non-mucus-producing elements.
- *Invasive adenocarcinoma:*
- **Lepidic predominant**: Formerly nonmucinous BAC pattern, now with more extensive invasion.
- **Acinar predominant**: Characterized by acinar growth patterns.
- **Papillary predominant**: Dominated by papillary growth.
- **Micropapillary predominant**: Predominantly micropapillary growth.
- **Solid predominant with mucin production**: Features solid growth with mucus production.
- **Variants of invasive adenocarcinoma**:
- **Invasive mucinous adenocarcinoma (formerly mucinous BAC)**: Mucin-producing invasive adenocarcinoma.
- **Colloid**: Tumor with gelatinous or mucinous content.
- **Fetal (low and high grade)**: Resembling fetal lung tissue.
- **Enteric**: Displaying characteristics similar to the intestines.
**III. Large cell carcinoma Variants:**
- **Large cell neuroendocrine carcinoma**: A variant with features of both large cell carcinoma and neuroendocrine tumors.
- **Combined large cell neuroendocrine carcinoma**: Combining large cell and neuroendocrine carcinoma elements.
- **Basaloid carcinoma**: Featuring basaloid growth patterns.
- **Lymphoepithelioma-like carcinoma**: Resembling lymphoepithelioma.
- **Clear cell carcinoma**: A variant with clear cell characteristics.
- **Large cell carcinoma with rhabdoid phenotype**: Characterized by rhabdoid cell features.
**IV. Adenosquamous carcinoma**: A tumor consisting of both adenocarcinoma and squamous cell carcinoma components.
**V. Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements**: Tumors showing pleomorphic, sarcomatoid (resembling soft tissue tumors), or sarcomatous (having characteristics of a sarcoma) features.
**VI. Unclassified carcinoma (i.e., poorly differentiated)**: Tumors that cannot be classified into the specific subtypes mentioned above and are generally poorly differentiated.
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**Nonsmall Cell Lung Cancer (NSCLC): Pathology and Staging**
**Pathology Histology of NSCLC:**
- NSCLC accounts for approximately 86% of primary lung tumors.
- It encompasses various morphologic subtypes, mainly adenocarcinoma and squamous cell carcinoma.
- Historically, histologic subtypes didn't impact treatment decisions, but certain therapies now show efficacy in specific histologic subtypes.
**Molecular Changes in NSCLC:**
- Clinically evident NSCLC exhibits numerous genomic abnormalities, with a high mutation rate, often exceeding 10 somatic mutations per megabase of DNA.
- These include dominant driver oncogenes like EGFR, KRAS, ALK, ROS1, RET HER2, BRAF, and MET, which are crucial for tumor growth.
- EGFR mutations, for example, occur in 10-15% of US NSCLC and 40-50% in Asian countries, frequently in never-smokers, women, and Asians, often associated with adenocarcinoma histology.
- EGFR mutations result in constant activation of EGFR signaling, driving tumor growth and preventing apoptosis.
- Small-molecule tyrosine kinase inhibitors (TKIs) like gefitinib, erlotinib, and afatinib are highly effective against various EGFR mutations.
**Staging of NSCLC:**
- Lung cancer staging follows the American Joint Committee on Cancer, seventh edition, staging system.
- Staging aims to determine the extent of disease, crucial for treatment decisions.
- If metastatic disease is confirmed, curative treatment is usually not an option.
- Due to the prevalence of metastatic disease (25-30% of lung cancer cases), even small tumors require comprehensive workup.
- Workup typically includes chest CT with IV contrast (common for diagnosis), PET with CT localization, head MRI with contrast (or head CT if MRI isn't feasible), pulmonary function testing (for potential surgery), and laboratory workup to rule out other health issues.
- Surgical candidates often underwent mediastinoscopy in the past to check for mediastinal nodal involvement.
- PET and PET/CT scans now identify lymph node involvement and metastatic disease, reducing unnecessary surgeries.
- A PET/CT scan with no enlarged mediastinal lymph nodes and no PET activity in the mediastinum has a low false-negative rate (5%).
**Small Cell Lung Cancer (SCLC)**
**Pathology of Small Cell Lung Cancer:**
- SCLC is an aggressive neuroendocrine tumor originating in the lungs.
- Strongly linked to smoking, it differs from NSCLC by its small cell size and the presence of neuroendocrine markers like chromogranin A and synaptophysin.
- Lower-grade neuroendocrine tumors (carcinoid tumors) from the lungs exist but are managed differently due to their slower growth and resistance to typical treatments.
**Diagnosis and Staging of Small Cell Lung Cancer:**
- Staging involves chest, abdomen, pelvis CT scans, cranial imaging, and bone or PET scans.
- Two categories: limited stage (confined to a single radiation field) and extensive stage (wider spread, often with metastases).
- SCLC frequently comes with paraneoplastic syndromes like inappropriate antidiuretic hormone secretion and Cushing syndrome.
**Treatment of Limited-Stage Small Cell Lung Cancer:**
- Standard care: concurrent full-dose chemotherapy (cisplatin and etoposide) with radiotherapy, followed by chemotherapy alone.
- This approach yields an over 80% response rate and a median survival of 14-20 months.
- After 5 years, 15-20% of patients might still be disease-free.
- Surgery isn't effective, as localized tumors tend to recur post-resection.
- Prophylactic cranial irradiation follows chemotherapy and radiation, enhancing overall survival.
**Extensive-Stage Small Cell Lung Cancer:**
- Incurable, with a median survival of 9-11 months.
- Initially treated with platinum-based doublet chemotherapy, but the response rate is higher (70-80%).
- Responding patients benefit from prophylactic cranial irradiation.
- Second-line therapy is more effective if the disease-free interval after initial therapy is longer than 3 months (relapsed disease) and often involves single-agent chemotherapy.
- Targeted therapies are not proven effective, though anti-PD1 immunotherapies might offer some benefits.
- Supportive care is crucial for managing SCLC.