Lung cancer and mesothelioma: Pathology review

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Case Study0:00–1:22

Two people came to the clinic one day. First is a 65-year-old named Alex, who presents with a two-month history of dry, persistent cough and weight loss of around 7 pounds without dieting.
He also says he coughs up blood sometimes but denies fever, dyspnea, sore throat, rhinorrhea or any chest pain. Alex has a history of asthma and hypertension, and smoked 1 pack of cigarettes daily for 45 years.
On examination, his breath sounds are diminished at the right lung base. The other individual is Clara, who’s an 80-year-old retiree.
Before her retirement, Clara was a construction site supervisor. She complains of increasing shortness of breath, which started ten months ago, and new onset of myalgia located on the right side of her chest.
Physical examination reveals decreased breath sounds in the right lung base along with dullness to percussion. Chest X-rays were ordered for both people.
In Alex’s case, it showed a single, coin-like lesion on the right lung base. Clara’s scan showed pleural effusion, irregular pleural thickening, and two ivory white, calcified pleural plaques at the base of her right lung.Both people have cancer involving the lung.

Physiology1:22–2:27

But first, a bit of physiology. Lining the airways are several types of epithelial cells that serve multiple functions.
These include ciliated cells that have hair-like project called cilia that work to sweep foreign particles and pathogens back to the throat to be swallowed.
Another type, called goblet cells secrete mucin to moisten the airways and trap foreign pathogens. There are also basal cells that are thought to be able to differentiate into other cells in the epithelium, club cells that act to protect the bronchiolar epithelium, and neuroendocrine cells that secrete hormones into the blood.
On the outside, the lungs are covered by the mesothelium which consists of the parietal pleura and the visceral pleura. Between them, there’s the pleural space, where the fluid produced by the epithelial cells is released, which acts as a lubricant to allow the layers to slide effortlessly against each other during respiratory movements.Now, let’s begin with lung cancer.

Pathology2:27–3:23

The two most common types are small cell lung cancer and non-small cell cancer, both sharing common pathophysiology. Cells of the lungs can undergo mutations that cause them to divide uncontrollably and replace the normal healthy lung tissue.
Eventually these cells will form a tumor. To supply it, new blood vessels also develop and this is called angiogenesis.
Sometimes the tumor can metastasize and spread via blood vessels or lymphatics and establish secondary sites throughout the body.
Particularly at risk for lung cancer metastasis are the mediastinum and hilar lymph nodes because of their proximity to the lungs, so remember this as it’s very high yield!
Other common sites include the liver, adrenal glands, bones, and brain.There are many risk factors for lung cancer. Tobacco smoking is the most important one, which accounts for more than 90% of cases of lung cancer.

Risk Factors3:23–4:36

This usually comes in the form of cigarettes, but also includes cigars, pipes, and hookah. There is a dose-dependent linear relationship between lung cancer risk and pack-years, which is the number of cigarette packs per day times the number of years of smoking.
Second-hand smoke also increases the risk of lung cancer. The second leading risk factor for lung cancer is exposure to radon, a colorless, odorless gas which is a natural breakdown product of uranium found in the soil, so it sometimes accumulate in basements.
Other environmental factors include asbestos, a mineral made of long, fibrous crystals that was commonly used for construction until the 1980s in the US.
The most common type of cancer caused by asbestos is adenocarcinoma. Next there’s air pollution and ionizing radiation from medical imaging with chest X rays and CT scans, or during radiation therapy.
The symptoms of lung cancer vary based on the size and location of the tumor, whether or not it has spread to other organs, and whether or not it secretes hormones.

Symptoms4:36–7:14

Initially, individuals may be completely asymptomatic. Over time, in response to the cancer, the body mounts an immune response to fight it off.
This results in the release of inflammatory chemokines like TNF-alpha, IL1-beta, and IL-6. The chemokines cause unintentional weight loss, fever, malaise, and night sweat.
If the primary tumor physically obstructs the airway and presses on surrounding tissue, it can cause coughing, shortness of breath, wheezing.
Since the obstruction can decrease the clearance of mucus, it also increase the risk of developing pneumonia. Sometimes, the tumor obstructs the bronchus and prevents the ventilation for a lobe, or even an entire lung!
This will cause obstruction atelectasis where the lung could collapse. Compression of nearby nerves can cause pain, and compression of specific nerves like the recurrent laryngeal nerve and phrenic nerves can cause hoarseness or difficulty breathing, respectively.
Another high yield fact is that compression of nearby vessels, like the superior vena cava, can prevent blood from draining from the head, leading to facial swelling or puffiness.
If the swelling occurs in the epiglottis, it could cause difficulty breathing and if there’s swelling in the brain, it could cause headaches and altered mental status; both of which can be medical emergencies!
Finally, if tumor necrosis occurs or if cancer cells invade a blood vessel, individuals can experience hemoptysis. A high yield fact is that sometimes a tumor can arise in the superior sulcus, which is the space formed by the subclavian vessels, and these are called Pancoast tumors.
These are most often non-small cell carcinomas and can compress the blood vessels and nerves located in the region. Some important symptoms to remember include arm muscle weakness and paresthesia due to compression of the brachial plexus, and pain that irradiates to the scapula and arm on the affected side.
Since Pancoast tumors near the thoracic inlet can compress cervical sympathetic ganglia, it can lead to Horner syndrome which causes constricted pupil, drooping upper eyelid, which is called ptosis, and anhidrosis, or the inability to sweat.
Ok, now let’s discuss small cell carcinomas, which account for a small percentage of lung cancer. They are associated with amplification of the Myc oncogene and originate from small, ovoidal, neuroendocrine cells.

Small-Cell Carcinoma7:14–9:17

These tumors usually develop centrally in the lung, near a main bronchus. They also grow the fastest and tend to rapidly metastasize to other organs when compared to non-small cell lung cancers.
Small cell carcinomas can sometimes secrete hormones and that can lead to what is called a paraneoplastic syndrome. One example is they can releases adrenocorticotropic hormone or ACTH.
This leads to bilateral adrenal enlargement and an increase in cortisol production. The result is Cushing’s syndrome and some symptoms include elevated blood glucose, high blood pressure, skin hyperpigmentation, easy bruising, osteoporosis, frequent infections from a weakened immune system, and weight gain.
Next, these tumors can also release antidiuretic hormone. This is called syndrome of inappropriate antidiuretic hormone or SIADH, which increases water reabsorption in the renal collecting ducts, leading to high blood pressure, hyponatremia, edema, and concentrated urine.
Finally, small cell carcinoma can trigger the production of autoantibodies against neurons. If cerebellar neurons are affected, it leads to symptoms like ataxia and nystagmus.
If neurons in the cerebrum are affected, then it can lead to symptoms like dementia and seizures. There’s also Lambert-Eaton syndrome where the autoantibodies target voltage gated calcium channels on the presynaptic membrane at the neuromuscular junction.
This condition results in muscle weakness, especially the proximal muscles in the legs, but it also causes double vision, drooping of the eyelids, and difficulty swallowing.The other type is non-small cell carcinomas.

Non-small Cell Carcinoma9:17–11:38

They account for most lung cancers and can be further subdivided into four categories: adenocarcinomas which frequently form glandular structures or have the ability to generate mucin.
They are associated with mutations of the KRAS, EGFR and ALK genes. In squamous cell carcinomas the cells are square shaped and produce keratin; carcinoid tumors arise from mature neuroendocrine cells; and large cell carcinomas where the cancer cells are poorly differentiated and lack the characteristics of the other types.
Now, these carcinomas are also more of a mixed bag in terms of where they’re located. First, adenocarcinomas tend to develop peripherally, in a bronchiole or alveolar wall, and they are associated with non-smokers.
However, it is worth mentioning that even though adenocarcinomas are the most frequent type of lung cancer in non-smokers, the majority of adenocarcinomas occur in smokers.
Adenocarcinomas are also associated with hypertrophic osteoarthropathy, or clubbing of the digits. This is due to abnormal proliferation of skin and periosteal tissues involving the extremities.
A rare subtype of adenocarcinoma is called bronchoalveolar carcinoma and it originates from the columnar, mucin-secreting alveolar cells located in the periphery of the lung.
Its typical presentation includes dyspnea and a cough that produces a large amount of a golden-brown sputum. This type of adenocarcinoma usually has a better prognosis.
Second, squamous cell carcinoma tends to be centrally located. It has the highest association with smoking.
A classic paraneoplastic syndrome associated with this carcinoma is that they release parathyroid hormone related protein.
This protein acts like parathyroid hormone and increases bone resorption which increase calcium levels in the blood, but cause bones to become brittle.
Finally, large cell carcinomas and bronchial carcinoid tumors can be found throughout the lungs but are more common in the periphery.
A high yield fact for carcinoid tumors is that they can secrete serotonin, which leads to increased peristalsis and diarrhea, facial flushing, and wheezing due to bronchoconstriction.Ok, so let’s now switch gears and look at mesothelioma, a cancer of the lung lining.

Mesothelioma11:38–12:49

The most common risk factor is asbestos exposure. But remember that asbestos causes more cases of bronchogenic carcinomas like adenocarcinoma and small cell carcinoma.
Once the small, fibrous asbestos crystals are inhaled, they enter cells in the lungs or mesothelium and get tangled up with the cell’s chromosomes and damage the DNA.
This can lead to mutations that cause the cells to replicate out of control. In the mesothelium, this leads to the growth of small nodules that could form mesothelial plaques.
The plaques can grow rapidly and start to cover the visceral and parietal pleura. Interestingly, these growths start to express a lot of calretinin, a calcium-binding protein, involved in regulating calcium levels within the cell.
Mesothelioma can cause the same symptoms as lung cancer. But it can also cause pneumothorax, and hemorrhagic pleural effusion.Now for diagnosing lung cancer, chest x-ray is a common first step.

Diagnosis12:49–15:13

In most types of lung cancer, x-rays usually shows a parenchymal lesion like a poorly defined nodule, called a coin lesion.
For the bronchoalveolar subtype, a high yield clue is there’s usually hazy infiltrates and thickening of the alveolar walls.
For squamous cell carcinoma, cavitary lesions are common. On chest CT, the lesion appears as a non calcified nodule, and CT will also help to stage the tumor, better define the tumor location, detect mediastinal or hilar lymph node metastasis, and look for evidence of local invasion.
Ok, so diagnosing mesothelioma can also begin with a chest X-ray followed by a CT scan, with key findings being pleural thickening, pleural effusion or pneumothorax.
A key finding that’s high yield is the presence of ivory white, calcified, supradiaphragmatic and pleural plaques, which are pathognomonic of asbestosis, a condition that usually precedes mesothelioma.Once a suspicious lesion is found, a biopsy is needed to see if the tumor is malignant and to identify the type of carcinoma based on histological features.
An important one for small-cell carcinoma is the presence of Kulchitsky cells, which are small dark blue cells. A high yield fact is that they are positive for enolase, neurofilaments, and neuroendocrine markers like synaptophysin and chromogranin.
A biopsy sample for adenocarcinomas will be positive for mucin, squamous cell carcinomas will have keratin pearls and intracellular bridges, and large cell carcinomas will have pleomorphic giant cells.
In mesothelioma, the columnar cells that make up the tumor are joined by desmosomes and are studded with very long microvilli.
A key finding is the presence of psammoma bodies which are laminated, concentric nodules with calcification. Another clue is when immunostained with an antibody to calretinin, the cytoplasm and nuclei of the cancerous cells have a distinctive “fried egg” appearance.
The treatment of small-cell lung cancer can be tricky. Know that surgical removal is not indicated.
This is because small-cell carcinoma is highly aggressive and invasive and most people already present with metastasis when diagnosed, making surgery pointless.

Treatment15:13–16:02

The good news is that these tumors are, however, sensitive to chemotherapy and radiation therapy. In non-small lung cancer, surgery is typically recommended in most stages along with chemotherapy and radiotherapy.
In addition, it’s typical to remove nearby lymph nodes for biopsy inorder to detect metastasis. Mesothelioma treatment also depends heavily on the stage of the disease and it usually combines surgery, chemo, and radiation therapy.
All right, as a quick recap! Lung cancer can be divided into small cell and non-small cell carcinoma.
The tumors can cause airway obstruction, compression of nearby nerves and blood vessels like the superior vena cava. Some types are associated with specific paraneoplastic syndromes and they can also induce an immune response which causes non-specific symptoms like weight loss, fevers, and night sweats.

Review16:02–17:17

Mesothelioma is most often associated with asbestos, and it’s a carcinoma that arises from the pleura. Some symptoms like dyspnea, cough and hemoptysis are similar to lung cancer, but in addition, they can have symptoms similar to pneumothorax.
Diagnosis begins with chest x-rays. In lung cancer, the most common finding is a poorly defined coin lesion.
In mesothelioma, the most common signs include pleural thickening, pleural effusion, pneumothorax, and, more importantly, calcified pleural plaques.
Diagnosis is then confirmed by tumor biopsy. Usually, the tumors are treated with a combination of surgery, chemotherapy, immunotherapy, and radiation, depending on the situation.Back to our cases.
Alex has a two-month history of a dry, persistent cough, hemoptysis, weight loss of around 7 pounds, and progressive tiredness.
All of these can be signs of lung cancer. His long history of smoking and the absence of an infection are further clues.

Summary17:17–18:40

On examination, his breath sounds were diminished at the right lung basis, but more importantly, his chest X-ray showed a coin lesion which is our biggest clue.
A CT and then biopsy should be done to determine the stage and type of lung cancer. Clara, the 80-year-old retiree, has progressive shortness of breath and myalgia on the right side of her chest.
Physical examination revealed decreased breath sounds in the right lung base associated with dullness to percussion. Her x-ray showed pleural effusion, irregular pleural thickening, and two pleural plaques.
These findings suggest mesothelioma and her previous occupation as a construction worker could have exposed her to asbestos, a known risk factor.
A biopsy should also be done for her to confirm the diagnosis. myalgia on the right side of her chest physical examination, revealed decreased breath.
Sounds in the right, lung base associated, with dullness to percussion for x-ray, showed pleural effusion, irregular plural, thickening into pleural plaques these findings suggest mesothelioma and her previous occupation.
As a construction worker could have exposed her to his best, a known risk factor, a biopsy should be done for her to confirm the diagnosis.