• Cavitating Mass

• A cavitating lung lesion is a gas-filled space that develops within a pulmonary nodule, mass, or area of consolidation.
• This process is visible on imaging studies as a lucency or low-attenuation area within a denser parenchymal opacity.

Comment

• In the context of primary lung malignancies, cavitation is most frequently associated with squamous cell carcinoma.
• The mechanism is often attributed to rapid tumor growth that outstrips its blood supply, leading to central necrosis and subsequent expulsion of necrotic material via the airways.
• A thick, irregular wall of the cavity is a feature that strongly suggests malignancy over infectious or inflammatory etiologies.
• You, J., Korean J Thorac Cardiovasc Surg, 2002.

• Mass

• In thoracic radiology, a mass is defined as any abnormal, circumscribed lesion that measures more than 3 cm in diameter.
• Lesions that are 3 cm or smaller are referred to as nodules.

Comment

• The distinction between a nodule and a mass is based on a clinically useful size threshold, though it is arbitrary.
• Lesions larger than 3 cm have a higher likelihood of being malignant.
• The most common cause of a pulmonary mass is lung cancer, but benign causes like infections or granulomas must be considered.
• Walter J, Zentralbl Chir, 2009.

• Centrilobular Emphysema

• A form of pulmonary emphysema characterized by the destruction of the proximal respiratory bronchioles at the center of the pulmonary lobule.
• On CT, it appears as small, round, centrilobular lucencies, often without visible walls, and with an upper lung zone predilection.

Comment

• This is the most common type of emphysema and is strongly associated with smoking.
• It is a major subtype of Chronic Obstructive Pulmonary Disease (COPD) and is associated with significant airflow obstruction.
• Centrilobular emphysema is significantly associated with an increased risk of lung cancer.
• High-resolution CT (HRCT) is the standard imaging modality for its detection and classification.
• Bergin C, Radiology, 1986.

• Paraseptal Emphysema

• Also known as distal acinar emphysema, it is characterized by emphysematous changes affecting the peripheral parts of the secondary pulmonary lobule.
• It appears as cystic spaces or bullae adjacent to the pleura and interlobular septa.

Comment

• While also associated with smoking, it is generally not linked to significant airflow obstruction when it occurs in isolation.
• It is a primary cause of spontaneous pneumothorax in young adults due to the rupture of subpleural bullae.
• It often coexists with other types of emphysema, particularly centrilobular.
• Yuan T, Radiology, 2022.

• Reticulation

• An imaging pattern in the lung characterized by a network of fine, interlacing linear opacities, resembling a net.
• It results from the thickening of interstitial structures like the interlobular or intralobular septa.

Comment

• Reticulation is a hallmark of interstitial lung disease (ILD) and often indicates pulmonary fibrosis.
• It is not specific to fibrosis and can be seen in acute conditions like pulmonary edema.
• On HRCT, reticulation combined with traction bronchiectasis is a more specific sign of fibrosis.
• The term is derived from the Latin “reticulum,” meaning “net”.
• He, X, Am J Respir Crit Care Med, 2022.

• Ground-Glass Opacity (GGO)

• A hazy increase in lung density on CT imaging that does not obscure the underlying bronchial and vascular structures.
• It can result from partial filling of airspaces or thickening of the interstitium below the resolution of the CT scanner.

Comment

• GGO is a nonspecific finding with a very broad differential diagnosis.
• Acute causes include pulmonary edema, hemorrhage, and infections like viral pneumonia.
• Chronic causes can include interstitial lung diseases, fibrotic processes, and neoplastic conditions such as lepidic adenocarcinoma.
• The clinical context is crucial for narrowing the differential diagnosis when GGO is present.
• Hung JJ, Eur Respir J, 2009.

• Bronchial Wall Thickening

• An imaging finding describing an abnormal increase in the thickness of the walls of the bronchi.
• When seen in cross-section (“end-on”), it can create a “doughnut sign,” also known as peribronchial cuffing.

Comment

• It is a common but nonspecific sign of airway inflammation and can be seen in numerous conditions, including chronic bronchitis, asthma, and infections.
• The finding is an expression of mucous membrane edema, mucus hypersecretion, and inflammation.
• In smokers, it is associated with chronic respiratory symptoms and is a feature of airway remodeling.
• Objective assessment can be performed quantitatively on CT by calculating the broncho-arterial ratio, which is the diameter of the bronchial lumen divided by the diameter of its accompanying artery. In healthy individuals, this ratio is typically around 1:1.
• Other quantitative measures include the wall area percentage (WAP) and the ratio of wall thickness to total bronchial diameter (T/D ratio).
• Hasegawa M, Respir Med, 2020.

• Squamous cell carcinoma is the most common histologic type to cavitate.
• Typically presents as a solitary lesion in the upper lobes.
• Characterized by a thick, irregular wall (often >15 mm).

• Often presents as multiple cavitating nodules.
• Common primary sources are squamous cell carcinomas (e.g., head and neck) and sarcomas.
• Lesions are frequently located in the lower lobes.

• Often caused by aspiration, with common organisms being *Staphylococcus aureus* and anaerobes.
• Typically presents as a solitary cavity with an air-fluid level and surrounding consolidation.
• Patients usually have acute symptoms like fever and poor dentition can be a risk factor.

• Post-primary (reactivation) TB is the most common infectious cause of chronic cavitary disease.
• Cavities are typically found in the apical or posterior segments of the upper lobes.
• Associated findings like tree-in-bud opacities and satellite nodules are common.

• Invasive aspergillosis may cavitate in immunocompromised patients.
• An aspergilloma (fungus ball) can form within a pre-existing cavity.
• Endemic fungi like *Coccidioides* and *Histoplasma* can also cause cavitary lesions.

• Characterized by multiple, peripheral, and often wedge-shaped nodules that cavitate.
• Typically seen in patients with a history of IV drug use or tricuspid valve endocarditis.
• Lesions are often in different stages of cavitation.

• Presents as multiple nodules or masses that frequently cavitate.
• Often associated with sinus, upper airway, and renal involvement.
• Positive ANCA serology is a key diagnostic feature.

• Necrobiotic (rheumatoid) nodules in the lungs can cavitate.
• These nodules are typically peripheral and occur in patients with established, seropositive RA.

• Cavitation can occur within an area of lung that has lost its blood supply due to a pulmonary embolism.
• The lesion is typically wedge-shaped and pleural-based.

• Lesions like bronchogenic cysts or sequestrations can become secondarily infected and appear as cavities.
• These are less common causes, particularly in adults.

• Squamous cell carcinoma (SCC) of the lung is a malignant neoplasm originating from the squamous cells that line the airways.
• It is a subtype of non-small cell lung cancer (NSCLC).
• Constitutes approximately 25-30% of all lung cancers.
• Also known as epidermoid carcinoma.
• Characterized by the transformation of these flat, thin cells, which then multiply uncontrollably.

• The principal etiological agent is tobacco smoke.
• Approximately 80% of cases in men are linked to smoking.
• Approximately 90% of cases in women are linked to smoking.
• The risk decreases the longer an individual has abstained from smoking.
• Other significant risk factors include exposure to secondhand smoke.
• Other significant risk factors include radon.
• Other significant risk factors include asbestos.
• Other significant risk factors include various occupational irritants like mineral and metal dust.

• Involves the malignant transformation of squamous epithelial cells lining the bronchial airways.
• Often preceded by squamous metaplasia and dysplasia due to chronic irritation from carcinogens.
• Tobacco smoke contains numerous carcinogens that induce genetic mutations.
• Mutations in the p53 tumor suppressor gene are frequently observed in SCC.
• p53 mutations are linked to the extensive carcinogen exposure from smoking.
• These genetic alterations lead to uncontrolled cell proliferation.
• These genetic alterations lead to the development of the carcinoma.
• The neoplastic cells are histologically characterized by the presence of keratinization.
• The neoplastic cells are histologically characterized by intercellular bridges (desmosomes).

• Grossly, often presents as a centrally located mass.
• Frequently arising from the segmental or main bronchi.
• This central location can lead to bronchial obstruction.
• Bronchial obstruction may cause post-obstructive pneumonia.
• Bronchial obstruction may cause atelectasis.
• A characteristic feature of SCC is central necrosis.
• Central necrosis leads to the formation of a cavitary lesion.
• Cavitary lesion can sometimes be seen with an air-fluid level on imaging.

• The presence of a tumor in the central airways can cause a persistent cough.
• The presence of a tumor in the central airways can cause hemoptysis.
• The presence of a tumor in the central airways can cause shortness of breath.
• Obstruction of the airways can lead to recurrent respiratory infections.
• Recurrent respiratory infections include bronchitis.
• Recurrent respiratory infections include pneumonia.
• If the tumor secretes parathyroid hormone-related peptide (PTHrP), it can cause hypercalcemia.
• Hypercalcemia is a common paraneoplastic syndrome associated with SCC.
• Advanced disease with metastasis can lead to a variety of symptoms depending on the organs involved.
• Symptoms of advanced disease include bone pain.
• Symptoms of advanced disease include neurological deficits.

• Most commonly appears as a central mass near the hilum.
• Chest radiographs are primary modalities for detection and characterization.
• CT scans are primary modalities for detection and characterization.
• The mass may be solid.
• Characteristically, the mass may be cavitary due to central necrosis.
• Endobronchial growth can lead to signs of airway obstruction.
• Signs of airway obstruction include lobar collapse.
• Signs of airway obstruction include post-obstructive pneumonitis.
• While typically central, a subset of SCCs can present as peripheral nodules or masses.
• PET/CT scans are utilized for staging to assess for metastatic spread.

• Sputum cytology can sometimes identify malignant squamous cells.
• Sputum cytology is especially useful in centrally located tumors that exfoliate into the airways.
• Blood tests may reveal hypercalcemia.
• Hypercalcemia results from the paraneoplastic production of PTH-rP.
• A complete blood count (CBC) may show anemia.
• A complete blood count (CBC) may show thrombocytopenia.
• A complete blood count (CBC) may show neutropenia.
• Molecular testing of tumor tissue is crucial for guiding treatment.
• Molecular testing may include analysis for mutations in genes such as EGFR.
• Molecular testing may include analysis for mutations in genes such as p53.
• Molecular testing may include analysis for mutations in genes such as p16.
• Molecular testing may include analysis for expression levels of PD-L1.

• The treatment modality is contingent upon the stage of the disease at diagnosis.
• For early-stage, localized tumors, surgical resection is the preferred treatment.
• Surgical resection examples include a lobectomy.
• Surgical resection examples include a pneumonectomy.
• In more advanced stages, a multimodal approach is often employed.
• The multimodal approach combines chemotherapy.
• The multimodal approach combines radiation therapy.
• The multimodal approach combines immunotherapy.
• Platinum-based chemotherapy regimens (e.g., cisplatin or carboplatin) are a cornerstone of treatment.
• The advent of immune checkpoint inhibitors, which target the PD-1/PD-L1 pathway, has significantly altered the treatment landscape.
• Immune checkpoint inhibitors are especially for patients with high PD-L1 expression.
• Targeted therapies, such as EGFR inhibitors like afatinib, may be considered in specific patient populations.
• Specific patient populations for targeted therapies include those with relevant mutations who are non-smokers or light smokers.

• The prognosis is heavily dependent on the stage at diagnosis.
• Early detection and treatment can result in favorable outcomes.
• For localized disease (Stage I), the five-year survival rate can be over 80%.
• A significant number of patients are diagnosed at advanced stages, which carries a poorer prognosis.
• The overall five-year survival rate for all stages of NSCLC is approximately 25%.
• For distant (metastatic) disease, the five-year survival rate is around 7%.
• Factors influencing prognosis include the patient’s overall health.
• Factors influencing prognosis include smoking history.
• Factors influencing prognosis include the presence of comorbidities.

• The term “squamous” is derived from the Latin *squamosus*, meaning “scaly.”
• It describes the flat, scale-like appearance of the epithelial cells under microscopic examination.
• 
• “Carcinoma” originates from the Greek *karkinoma*, which means “a crab” or “crayfish.”

This term is attributed to Hippocrates who thought the swollen veins surrounding a tumor resembled the limbs of a crab.

• The suffix “-oma” signifies a tumor or mass.
• “Epidermoid carcinoma” is a synonym.
• It reflects the cell’s resemblance to epidermal keratinocytes.

• In the 19th century, lung cancers were often described based on their gross appearance during autopsy.
• Terms like “encephaloid” (brain-like) were used by René Laennec due to the tissue’s soft consistency.
• “Medullary tumors” were also used by René Laennec.
• Other descriptions included “fungiform tumors.”
• It is a major subtype of non-small cell lung carcinoma (NSCLC).
• It accounts for approximately 25-30% of all lung cancers.

• Prior to the early 20th century, lung cancer was considered an exceedingly rare diagnosis.
• In 1912, Dr. Isaac Adler identified only 374 cases in a comprehensive review of global medical literature.
• Throughout the early 1900s, pathologists and clinicians noted a dramatic increase in lung cancer incidence.
• This rise paralleled the increase in cigarette production and consumption popularized during World War I.

• 
• A landmark moment in thoracic surgery occurred in 1933.
• Dr. Evarts Graham, with Dr. J. J. Singer, performed the first successful total pneumonectomy for lung cancer.
• 
• The patient was a fellow physician, Dr. James Lee Gilmore.
• This event transformed the disease from an inevitably fatal diagnosis to one with a potential surgical cure.
• Suspicions about smoking were raised as early as the 1920s.
• The causal link to smoking was solidified by numerous epidemiological studies in the mid-20th century.
• Drs. Alton Ochsner and Michael DeBakey were early proponents of this connection, presenting their findings in the late 1930s.
• Initially, their claims were met with skepticism, famously by Dr. Evarts Graham himself.
• Dr. Graham joked that the rise in lung cancer also correlated with the sales of nylon stockings.
• The 1964 Report of the Surgeon General’s Advisory Committee on Smoking and Health was a watershed moment.
• It definitively concluded that cigarette smoking is a cause of lung cancer in men.
• This solidified the public health consensus.

• The history of squamous cell carcinoma of the lung is inseparable from the cultural history of tobacco.
• Smoking was once viewed as a sophisticated, even healthy, habit.
• Smoking was promoted by physicians in advertisements.
• Its strong association with masculinity led to significantly higher smoking rates among men in many cultures.
• Smoking prevalence and associated lung cancer mortality vary significantly across different cultures and countries.
• Smoking rates have historically been much higher in men in many Asian countries compared to women, reflecting cultural norms.
• Researchers have noted that the relative risk of developing lung cancer from smoking appears lower in some Asian populations compared to Western ones.
• This phenomenon is termed the “smoking paradox.”
• This is not because tobacco is safer for these populations.
• It may be explained by differences in smoking habits, such as later age of initiation and type of tobacco used.
• The identification of secondhand smoke as a definitive carcinogen occurred in the 1980s.
• This was a major cultural shift, leading to widespread indoor smoking bans.
• It also changed the social perception of public smoking.

• René Laennec (1781-1826) was the inventor of the stethoscope.
• Laennec was one of the first to describe lung tumors as a distinct entity.
• He did this based on his meticulous correlation of clinical observation and postmortem pathology.
•  
• 
• Isaac Adler (1849-1919) published the first monograph on primary lung tumors in 1912.
• His monograph was titled “Primary Malignant Growths of the Lungs and Bronchi.”
• He summarized the world’s knowledge and noted the disease’s increasing frequency.
• Alton Ochsner (1896-1981) and Michael DeBakey (1908-2008) were pioneering surgeons at Charity Hospital in New Orleans.
• They were among the first to strongly advocate for the causal link between cigarette smoking and the rise in bronchogenic carcinoma. 
• They published their observations in 1939.
• 
•  
• Evarts Graham (1883-1957) was a titan of thoracic surgery.
• He performed the first successful pneumonectomy for lung cancer.
• Initially a heavy smoker and a skeptic of the link to cancer, he was later convinced by the evidence.
• Tragically, he himself died of bilateral lung cancer, having quit smoking too late.
• Ernst Wynder (1922-1999), as a medical student at Washington University, worked with Dr. Graham.
• He conducted case-control studies that were instrumental in confirming the association between smoking and lung cancer.

Representations in Arts & Culture

Art History Project
Subject Smoking

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Head of a Skeleton with a Burning Cigarette
Vincent van Gogh

Courbet

Leger

Metzinger

• Literature: The experience of lung cancer is powerfully captured in autobiographical works.

• Literature: “When Breath Becomes Air” by neurosurgeon Paul Kalanithi chronicles his own journey with metastatic lung cancer.
• Literature: Jenny Diski’s memoir “In Gratitude” also reflects on her diagnosis.
•  
• Song & Music: Many famous musicians who were heavy smokers died of lung cancer.
• Song & Music: Examples include George Harrison of The Beatles.
• Song & Music: Another example is the crooner Nat King Cole.
• Song & Music: While their music is not directly about the disease, their deaths brought significant public attention to its risks.
• Song & Music: Donna Summer, a non-smoker, also died of lung cancer.

Famous People who Smoked

• *“Because of our long friendship, you will be interested in knowing that they found that I have cancer in both my lungs. As you know, I stopped smoking several years ago but after having smoked as much as I did for so many years, too much damage had been done.”* – Dr. Evarts Graham, in a letter to Dr. Alton Ochsner two weeks before his death from lung cancer.
• *“Arguably, the most significant advance in this disease has been the recognition that smoking is the causal agent.”* – A reflection on the 100-year history of lung cancer, emphasizing prevention over treatment advances.
• *“If that doesn’t blow your mind.”* – Dr. Christine Lovly, commenting on the significant improvements in lung cancer survival over the past two decades due to advances in targeted therapy and immunotherapy.
• *“Everything can be taken from you except one thing: your attitude to the situation.”* – A quote from a lung cancer survivor, highlighting the psychological fortitude required to face the diagnosis.

• EGFR mutations, particularly exon 19 deletions and L858R point mutations, are hallmark driver mutations for lung adenocarcinoma, especially in non-smokers.
• They are not characteristic of squamous cell carcinoma.

• The fusion oncogene resulting from the translocation between the EML4 and ALK genes is another key driver mutation.
• Found almost exclusively in a subset of lung adenocarcinomas, particularly in younger patients and non-smokers.

• Lung squamous cell carcinomas are characterized by a high mutational burden, frequently involving the inactivation of tumor suppressor genes.
• TP53 is the most commonly mutated gene.
• Amplification of the 3q26 locus, which includes the oncogene SOX2, is a frequent and early event in the development of this cancer.
• Citation: Cancer Genome Atlas Research Network. Nat (2012)

• MET exon 14 skipping mutations are oncogenic drivers found in a small percentage of non-small cell lung cancers.
• They are more typically associated with adenocarcinoma or other NSCLC histologies, not specifically squamous cell carcinoma.

• Mucin production is characteristic of adenocarcinoma of the lung, not squamous cell carcinoma.

• While tumors can arise adjacent to or invade bullae, the cavitation process itself is intrinsic to the tumor’s biology.
• It is not simply air-trapping in a pre-existing space.

• Squamous cell carcinomas are often rapidly growing tumors.
• This proliferation can exceed the capacity of the tumor’s neovasculature.
• Resulting in ischemia and coagulative necrosis at the tumor’s center.
• This necrotic, keratinous debris is then often expelled through a bronchus, leaving a gas-filled cavity.
• Citation: Seban R. PMC (2021)

• While tumor invasion involves enzymatic degradation of the extracellular matrix, this is a mechanism of local spread.
• It is not the principal cause of the large-scale central cavitation seen in these malignancies.

• Calcitriol-mediated hypercalcemia is a recognized paraneoplastic syndrome.
• It is classically associated with lymphomas and other granulomatous diseases, not typically with squamous cell lung cancer.

• While lytic bone metastases can cause hypercalcemia through local cytokine effects.
• Humoral hypercalcemia of malignancy is the most common cause in squamous cell carcinoma, often occurring even without bone metastases.

• Squamous cell carcinoma is the most common solid tumor to cause humoral hypercalcemia of malignancy.
• The tumor cells ectopically produce and secrete Parathyroid Hormone-related Peptide (PTHrP).
• PTHrP mimics the action of PTH on bone and kidney.
• Leading to increased bone resorption and renal calcium reabsorption, resulting in elevated serum calcium.
• Citation: Insogna KL. NEJM (2007)

• Ectopic secretion of authentic PTH by non-parathyroid tumors is an exceedingly rare event.
• It is not the characteristic mechanism for hypercalcemia in lung squamous cell carcinoma.

• A peripheral, sub-solid (ground-glass) nodule in a non-smoking female is the classic presentation for adenocarcinoma, particularly of the lepidic subtype.

• Squamous cell carcinoma has the strongest association with a history of tobacco smoking among the major non-small cell lung cancer subtypes.
• These tumors typically arise centrally from the metaplastic squamous epithelium of larger bronchi.
• They frequently grow to a large size, undergo central necrosis, and form cavities.
• Citation: Travis WD, et al. Am J Surg Pathol (2007)

• While smoking is a synergistic risk factor, asbestos exposure is most strongly and independently linked to malignant pleural mesothelioma.
• It also increases the risk of adenocarcinoma.

• Typical carcinoid tumors are neuroendocrine neoplasms that are not strongly associated with smoking.
• While they can be central or peripheral, they typically appear as well-circumscribed, non-cavitating nodules that are highly vascular.

• A peripheral ground-glass nodule is the classic appearance of adenocarcinoma in situ or minimally invasive adenocarcinoma.
• The “crazy-paving” pattern is more often associated with infectious or inflammatory processes like Pneumocystis pneumonia or alveolar proteinosis.

• Multiple, bilateral nodules of varying sizes are characteristic of pulmonary metastases.

• Squamous cell carcinoma of the lung is classically a centrally located malignancy arising from the larger airways.
• It frequently cavitates, and the cavity typically has a thick (>4 mm) and irregular wall.
• Due to its endobronchial origin, it often causes bronchial obstruction, leading to distal atelectasis or post-obstructive pneumonitis.
• Citation: Gao F, et al. BMC Pulm Med (2019)

• A smoothly marginated, intensely enhancing endobronchial nodule without invasion is more characteristic of a typical carcinoid tumor, which is a neuroendocrine neoplasm.

• While a bacterial abscess can form a thick-walled cavity, it typically presents more acutely with surrounding consolidation and air-fluid levels.
• It is less likely to have associated satellite nodules, which suggest bronchogenic spread of a granulomatous process.

• Granulomatosis with Polyangiitis is an autoimmune vasculitis, not an infectious process.
• It can cause cavitary nodules, but these are often multiple and may be associated with other findings like tracheal stenosis or renal disease.

• Post-primary tuberculosis characteristically presents with thick-walled, irregular cavities, often with an upper lobe predilection.
• The presence of smaller, ill-defined “satellite” nodules and tree-in-bud opacities in the surrounding lung parenchyma, representing endobronchial spread, is a classic feature.
• This can mimic a primary malignancy with local metastases.
• Citation: Nahid P, et al. Am J Respir Crit Care Med (2016)

• Invasive aspergillosis in an immunocompromised host typically presents with the “halo sign” (ground-glass opacity around a nodule) followed by the “air crescent sign” as cavitation occurs.
• It does not typically form thick-walled cavities with extensive satellite nodules in the same manner as tuberculosis.

• Contrast-enhanced CT provides superior anatomic detail and spatial resolution for assessing direct tumor invasion into adjacent structures like the chest wall or mediastinum (T-stage) compared to PET/CT.

• The primary utility of FDG-PET/CT in lung cancer staging lies in its ability to assess metabolic activity.
• It is significantly more sensitive and specific than CT for identifying metastatic involvement in mediastinal and hilar lymph nodes based on their metabolic activity rather than solely on size criteria.
• It is also superior for detecting occult distant metastases (M-stage), which can prevent futile surgical interventions.
• Citation: Lardinois D, et al. J Clin Oncol (2009)

• While FDG PET/CT is excellent at differentiating metabolically active tumor from adjacent collapsed lung, this is not its primary advantage over CT alone for the entire staging process.
• Its main impact is on the N and M stages.

• A PET/CT scan involves a higher radiation dose than a standalone chest CT.
• It is a more expensive imaging modality.
• Its use is justified by its superior staging accuracy, which improves patient management.