Mednotes

L9 Pathology Pulmonary neoplasia (Dame LJ holloway last lecture)

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aliasesL9 Pathology Pulmonary neoplasia (Dame LJ holloway last lecture)

14 min read

Overview

This lecture covers lung cancer as a global disease burden and its risk factors (especially smoking, radon and asbestos), the molecular and morphological pathway of carcinogenesis, the classification and histological features of the major lung cancer subtypes, the local and distant effects tumours produce (including paraneoplastic syndromes), the diagnostic and investigative pathway, asbestos-related lung and pleural disease, and other pulmonary tumours including MALT lymphoma, bronchial carcinoid and metastatic disease.

Global burden and risk factors

  • Cancer overall causes 7.4 million deaths worldwide and is the leading cause of death worldwide (~13% of all deaths); there are more than 100 types of cancer and any part of the body can be affected.
  • Lung cancer is the deadliest cancer type: 1.3 million deaths/year, ahead of stomach (803,000), colorectal (639,000), liver (610,000) and breast (519,000).
  • Mortality rate by cancer type: men — lung 31%, prostate 10%, colorectal 8%, pancreatic 6%, liver 4%; women — lung 26%, breast 15%, colorectal 9%, pancreatic 6%, ovarian 6%.

Risk factors for lung cancer:

  • Smoking cigarettes — increases risk ~20-fold (15–30-fold relative to non-smokers); >85% of lung cancers attributable to tobacco; ~10% of smokers develop lung cancer; risk relates to consumption (inhalation and pack years); there is no safe smoking threshold. Second-hand (“passive”) smoke also raises risk.
  • Radon — a radioactive gas found in soil/rocks; the 2nd most important environmental risk factor in the United States; responsible for nearly 10% of lung cancer deaths in Europe.
  • Asbestos — a toxic mineral fibre.
  • Environmental tobacco exposure.
  • Genetics — a first-degree relative with lung cancer confers a 2-fold increased risk, independent of smoking.
  • Other lung diseases.
  • Prior radiation to the chest area; high doses of radiation generally.
  • Air pollution, including household air pollution from cooking/heating fumes (particularly among non-smoking women in less developed countries).
  • Industrial or chemical carcinogens: asbestos, silica, arsenic.

Sources of background radiation (pie chart): radon gas from rocks 50%, ground and buildings 14%, artificial sources 14.3%, food and drink 11.5%, cosmic rays 10%, other 0.2%. Artificial sources break down into medical uses 14%, nuclear power (including accidents) 0.1%, nuclear weapons tests 0.2%.

  • New Zealand daily smoking prevalence by ethnicity declined across all groups 2006/7–2019/20: Māori ~42%→~32% (consistently highest), Pacific ~27%→~22%, European/other ~19%→~12%, Asian ~11%→~9% (with a dip to ~6% around 2014/15).
  • NZ adult daily smoking fell steadily from 16.4% (2012) to 9.4% (2021). [flag: no on-slide title, only in-chart chart title; source not indicated]
  • NZ youth (15–24 years) daily smoking fell from 19.1% (2012) to 5.9% (2021), with the sharpest drop between 2020 and 2021.
  • As daily smoking fell, daily vaping rose over the same period: 0.9% (2016) to 6.2% (2021) — a substitution trend.
  • New Zealand scrapped its world-first “generational smoking ban” to help fund tax cuts, a reversal reported by TIME, The Guardian, BBC News and Mail Online and criticised by health experts.

Pathogenesis

Genetics of lung cancer: physiological insults feeding into accumulated genetic mutations are environmental (cigarette smoking, ionising radiation e.g. uranium/radon, asbestos) and inherited (Li-Fraumeni syndrome — p53 mutations; polymorphisms in cytochrome P450), together with predisposing disease states (fibrosing lung conditions e.g. pulmonary fibrosis, human papilloma virus) and somatic mutations (EGFR, ALK-EML4, PDL-1, KRAS, ROS-1). The resulting accumulation of genetic mutations produces:

  • Impaired apoptosis of abnormal cells
  • Impaired cell cycle control, allowing uncontrolled proliferation
  • Angiogenesis, feeding the enlarging tumour and providing routes for metastasis
  • Migration, adhesion and invasion, enabling metastasis

This drives a sequential morphological pathway: hyperplasia → metaplasia → dysplasia → carcinoma in situ, which then either compresses/obstructs adjacent structures or metastasises.

Lung carcinogenesis specifically: tobacco carcinogen acts on normal epithelium, which can progress by two routes to lung cancer:

  • Atypical alveolar hyperplasia → premalignant adenomas → lung cancer
  • Bronchial metaplasia → dysplasia → carcinoma in situ → lung cancer

Commonly observed genetic changes across this progression: inappropriate response to external signals, loss of cell cycle control, loss of the apoptosis pathway, loss of contact inhibition, acquisition of the ability to metastasise, angiogenesis, immortality, and autocrine growth loops.

Most primary lung tumours arise centrally, the disease presents late, and it often presents with metastatic disease already established.

Classification and histology

Lung cancer splits into non-small cell carcinoma (NSCLC, 85%, or 80–85% per the summary slide) and small cell carcinoma (SCLC, 15%, or 15–20% per the summary slide). NSCLC comprises three subtypes: squamous cell carcinoma, adenocarcinoma and large cell carcinoma.

  • Squamous cell carcinoma — arises from squamous metaplasia of the bronchial epithelium; central location, usually the major bronchi; shows keratin production and intercellular bridges (keratin pearls on histology); slow growing; presents with cough and infection; local metastases occur only at advanced stages.
  • Adenocarcinoma — arises from mucosal glands; peripheral location; low association with smoking; glandular appearance, may secrete mucus, frequently has a central scar; spreads early and invades pleura.
  • Large cell carcinoma — variable location (peripheral or central); histology shows large polygonal cells with a vesicular nucleus, some cells multinucleated; production of anaplastic large cells; metastasises at an early stage.
  • Small cell carcinoma — strong smoking association; hilar or peripheral location; arises from neuroendocrine tissue; histology shows small cells with scant cytoplasm and nuclei with conspicuous chromatin granules; chromosome 3 short-arm deletion; can secrete ADH, causing hyponatraemia; widely disseminated at diagnosis with early metastases to the central nervous system, liver and bone; poor survival rate; accounts for 15% of lung cancers.

Presenting symptoms by location: peripheral tumours cause referred shoulder pain and pleural invasion; central tumours cause cough, dysphagia, haemoptysis, massive lymphadenopathy and direct mediastinal invasion. Metastatic spread from lung cancer travels to brain, vertebra and liver. [flag: slide has no visible title text — continuation/summary slide]

Diagnosis by subtype (from the diagnostic panels):

  • Squamous cell carcinoma — X-ray; sputum cytology (central lesion with or without haemoptysis, at least 3 specimens); fibreoptic bronchoscopy (conventional, or TNAB — transbronchial needle aspiration biopsy); histopathology confirms production of keratin and intercellular bridges.
  • Adenocarcinoma — fine needle aspiration (FNA) of the peripheral lesion, used for unresectable tumours or patients who will receive preoperative therapy; thoracentesis when there is an accessible pleural effusion.

Local and distant effects, paraneoplastic syndromes

Local effects — bronchial obstruction and pleural involvement, and direct invasion of:

  • Chest wall
  • Nerves: phrenic nerve → diaphragmatic paralysis; left recurrent laryngeal nerve → hoarseness, bovine cough; brachial plexus → Pancoast tumour, T1 damage; cervical sympathetic chain → Horner’s syndrome
  • Mediastinum: superior vena cava (SVC), pericardium
  • Intrapulmonary lymph nodes

Consequences of bronchial obstruction: collapse, endogenous lipoid pneumonia, infection/abscess, bronchiectasis.

Distant effects — distant metastases to liver, adrenals, bone, brain, skin; effects secondary to local spread (neural, vascular); and non-metastatic (paraneoplastic) effects.

Paraneoplastic syndromes — categories: endocrine, neurological, skeletal, haematopoietic, cutaneous, with examples hypercalcaemia, Cushing’s syndrome, peripheral neuropathy and dermatomyositis. Mechanisms: tumour production of protein hormones, tumour metabolism of steroids, tumour production of enzymes or fetal proteins, tumour production of cytokines, tumour stimulation of antibody production, and miscellaneous mechanisms.

Investigations and diagnostic pathway

Investigations: chest X-ray, sputum cytology, bronchoscopy (tissue samples), fine needle aspiration, liquid biopsy, and advanced imaging (CT scanning, MRI, PET).

Cytological features and associated markers by subtype:

  • Adenocarcinoma — gland formation, mucin; markers EGFR (bevacizumab), ALK, KRAS.
  • Squamous cell carcinoma — pink cytoplasm, keratin; epithelial marker, PTH-rp.
  • Small cell carcinoma — little cytoplasm; neuroendocrine markers ACTH, ADH, calcitonin.

Tissue diagnostic pathway: receive, prepare, dissect, sample and process the specimen → gross examination (morphological histologic examination, identify malignancy) → characterise malignancy (is it lung cancer, is it SCLC or not, subtype if not SCLC — via immunohistochemistry, for diagnosis) → molecular characterisation (protein, gene copy number, translocational changes, sequence alterations such as mutation or rearrangement — via immunohistochemistry, in situ hybridisation, mRNA quantification, DNA mutation analysis, for prognosis/prediction). The escalating “levels” of NSCLC diagnosis are: morphology → immunohistochemistry → molecular → therapy choice.

Liquid biopsy: as a tumour progresses from formation through vascularisation to dissemination it releases material into the bloodstream (with exosome release occurring at each stage); this can be sampled as circulating tumour DNA (ctDNA), exosomes, and circulating tumour cells (CTCs).

Asbestos fibres enter the body via inhalation and ingestion through the nose and mouth. Three consequences of exposure:

  • Asbestosis — formation of scar tissue that limits the lungs’ ability to expand and contract, causing breathing difficulty and impairing gas exchange.
  • Malignant mesothelioma — fibres lodge in the lungs, stomach or intestines.
  • Lung cancer — fibres lodge in the alveoli; combined exposure to asbestos and cigarette smoke causes a dramatic increase in lung cancer risk compared with either exposure alone.

Asbestos is carcinogenic in both lung and pleura: cancer forms within the lung tissue while plaques form in the pleura.

In New Zealand, occupational asbestos exposure sources: plumbers/fitters/laggers 39%, carpenters/builders 28%, other 9%, electricians 7.5%, asbestos processors 4.5%, asbestos sprayers 4.5%, watersiders 4.5%, friction products 1%, no known exposure 1%, non-occupational 1%. Asbestos-containing materials are found around the home: cement vent pipes, flues, corrugated roofing, spouting/downpipes, soffits, cladding, wood-burner seals, and vinyl-flooring substrates in bathrooms and kitchens.

Asbestos carcinogenesis mechanism:

  • High doses over short periods → acute inflammatory response → neutrophilic inflammation.
  • Low doses over prolonged exposure → chronic inflammatory response (via alveolar macrophage activation) acting on normal cells → asbestos-induced cellular and DNA damage → cancer cells develop after continued cell exposure. Fibres irritate the mesothelium and generate reactive oxygen/nitrogen species (ROS/RNS).

Mesothelioma-specific mechanism: asbestos acting on mesothelial cells triggers inflammatory cell recruitment and recruits pleural macrophages. Three converging pathways lead to mesothelial cell injury: (1) iron-mediated ROS/RNS production (NO•, HO•, •NOO) directly from asbestos/mesothelial cells; (2) chronic inflammation via cytokines TNF-α, IL-6 and IL-8 from recruited inflammatory cells; (3) macrophage-mediated ROS/RNS production from pleural macrophages. All three converge on mesothelial cell injury → malignant transformation → mesothelioma. [flag: slide has no visible title text — continuation of asbestos carcinogenesis mechanism]

Ferruginous (asbestos) bodies appear on histology as golden-brown, beaded, rod-shaped structures within lung tissue.

Mesothelioma arises in the pleura (also the peritoneum), has a biphasic cellular pattern, and adjacent lung should be examined for asbestos to confirm an asbestos-related aetiology. Three histological patterns of mesothelioma: epithelioid, biphasic (mixed), and sarcomatoid.

Other pulmonary tumours

MALT lymphoma — mucosa-associated lymphoid tissue lymphoma of the lung, showing a dense lymphoid infiltrate with nodular follicle-like aggregates on histology.

Benign tumours: bronchial carcinoid — an endobronchial polypoid tumour; histology shows nests of uniform round cells separated by fibrovascular septae.

Metastatic cancer to the lung — primary tumour types/sites that metastasise to lung include carcinoma, sarcoma, kidney, breast, bowel, melanoma, osteosarcoma, colorectal cancer, prostate cancer, thyroid cancer, renal cancer, and testicular cancer. Cancer cells spread via lymphatic and blood vessels from the primary tumour, producing either a solitary nodule or multiple metastases.

Self-test

  1. List the major risk factors for lung cancer, and state the increase in risk attributable to smoking.
  2. What proportion of lung cancers is attributable to tobacco, and what proportion of smokers go on to develop lung cancer?
  3. What proportion of background radiation exposure comes from radon gas, and why is radon significant as a lung cancer risk factor?
  4. Describe the environmental and inherited factors, disease states, and somatic mutations that feed into the accumulation of genetic mutations in lung cancer pathogenesis, and outline the resulting sequence of morphological change.
  5. Describe the two pathways by which tobacco-carcinogen exposure can progress from normal epithelium to lung cancer.
  6. Distinguish the four main histological types of lung cancer by their typical location (central vs peripheral).
  7. Describe the characteristic histological features and cell of origin of squamous cell carcinoma.
  8. Describe the characteristic histological features of adenocarcinoma, including its typical spread pattern.
  9. Describe the characteristic histological features of large cell carcinoma.
  10. Describe the characteristic features of small cell carcinoma, including its cell of origin, associated cytogenetic abnormality, and early metastatic sites.
  11. Explain why small cell carcinoma can cause hyponatraemia.
  12. For each of the phrenic nerve, left recurrent laryngeal nerve, brachial plexus, and cervical sympathetic chain, state the clinical sign produced when a lung tumour directly invades it.
  13. List the consequences of bronchial obstruction by a lung tumour.
  14. List the categories of paraneoplastic syndrome, with one example clinical manifestation of each category given in the lecture.
  15. Describe the escalating “levels” of diagnostic workup for NSCLC, from morphology to therapy choice.
  16. What is sampled in a liquid biopsy, and at what stage of tumour progression is this material released?
  17. Describe the three possible consequences of asbestos fibre exposure and where the fibres lodge in each case.
  18. Describe the mechanism by which chronic, low-dose asbestos exposure leads to malignant transformation of mesothelial cells.
  19. List the three histological patterns of mesothelioma.
  20. Predict the effect of combined asbestos exposure and cigarette smoking on lung cancer risk, compared with either exposure alone.
  21. A patient presents with a central lung mass, hyponatraemia, and metastases already established in the brain, liver and bone at diagnosis. Identify the most likely histological subtype and justify the answer using its characteristic features.

Answers

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