Pulmonary and Pleural tumors

Question 1

Etiology of lung cancer and factors that play into it?

Answer 1

While smoking cigarettes is far and away the most common etiology of lung carcinoma and its early precursor lesions, only 10% of heavy smokers (defined as > 40 pack years) develop lung cancer. It’s likely a host of known and unknown environmental and hereditary factors are in play.

 Heme-containing cytochrome P-450 oxidase system has many proteins, and polymorphisms in these proteins (CYP1A1, etc.) may allow for increased conversion of inhaled pro-carcinogens into active carcinogens

 Variably unquantifiable environmental factors include second-hand smoke, various occupational exposures, urban living, chemicals/components in building materials, radon gas in homes, etc.

All of these factors make it very difficult to understand the natural history of lung neoplasia in contemporary society.

Question 2

Molecular alterations and precursor lesions seen?

Answer 2

Various pulmonary epithelial cells acquire mutations over time that allow for neoplastic development and ‘progression.’ Because early or ‘benign’ mutations can be found in many pulmonary cells types, the concept of a neoplasia-inducing field affect develops across the respiratory tract, leading to synchronous lesions developing in different areas of the lung. Note that most precursor lesions don’t develop into carcinoma, and currently it isn’t known which ones will.

Precursors: squamous metaplasia goes to squamous dysplasia which goes to carcinoma in-situ then SCC

 atypical adenomatous hyperplasia goes to adenocarcinoma in-situ adenocarcinoma

 neuroendocrine cell hyperplasia which goes to neuroendocrine carcinoma (low grade)

Question 3

Atypical adenomatous hyperplasia is?

Answer 3

Atypical Adenomatous Hyperplasia (AAH)
This is the earliest lesion of the adenocarcinoma sequence.

 < or = 0.5 cm

 Pneumocyte hyperplasia with mild dysplasia; accompanying slight fibrosis in the interalveolar septae

 Seen adjacent to, or away from, higher grade lesions

 Reasonably common finding

 Usually an incidental finding

Question 4

explain Adenocarcinoma in-situ/Minimally invasive adenocarcinoma?

Answer 4

 Lepidic growth pattern (growth pattern is along the alveolar lining)

 3 cm or less; no lymphovascular or pleural invasion

 Stromal invasion absent in AIS (left image below); stromal invasion < 5mm in MIA (right image below, ‘A’ for alveolar space, circle of invasion)

 5 year disease free survival: at or near 100%

Question 5

Explain adenocarcinoma?

Answer 5

Adenocarcinoma
This is the most common type of pulmonary malignancy, and the type that would more typically arise in non-smokers, females, and young males. Patients typically present with fatigue, cough, weight loss, dyspnea, chest pain, and hemoptysis.

 radiographic findings usually include a peripheral mass, with or without pleural involvement

 arises from normal cells lining the bronchi, bronchioles, or alveoli (and therefore may produce mucins)

Question 6

Molecular genetics of adenocarcinoma?

Answer 6

Our understanding of molecular alterations has exploded in recent years. Adenocarcinoma has several clinically relevant driver mutations (see pie chart below), and because of targeted therapies developed explicitly towards these mutations, molecular/mutational testing of tumors is now routine. Adenocarcinoma commonly has alterations in the tyrosine kinase receptor signal transduction pathway (see below), and our understanding of this pathway gives us great insight into malignancies arising in many organ systems, not just the pulmonary system.

Question 7

Adenocarcinoma gross appearance?

Answer 7

Grossly, adenocarcinoma typically is white-tan-yellow, solid, peripheral, and a single or multiple nodules.

 Necrosis and/or cavitation is not usual

 Tumors may involve adjacent pleura (and thereby increase the pathologic stage)

Question 8

Microscopic appearance of adenocarcinoma?

Answer 8

Microscopically, several patterns can be seen including glandular/acinar (below left), papillary, micropapillary (upper right), lepidic, solid, and mucinous. Most primary adenocarcinomas show a prominent area of central desmoplasia, and often show lepidic growth at the periphery, as tumor cells grow/spread out along the alveolar scaffolding. These growth features help distinguish primary pulmonary adenocarcinoma from a metastatic adenocarcinoma (a very important clinical distinction!). Additionally, immunohistochemical studies looking for typically adenocarcinoma-expressed antigens can be done (TTF-1 positivity, lower right).

Question 9

what are the images showing?

Answer 9

Normal goes to metaplasia with early dysplasia which goes to invasive squamous malignancy

Question 10

Centrally arising SCC is commonly associated with? Mutations in? gross appearance?

Answer 10

Centrally arising SCC is very commonly associated with cigarette smoking, and the metaplasia-dysplasia-malignancy sequence typifies its growth.

 Mutations in TP53, CDKN2A, and FGFR1

 Grossly, lesions are centrally located (i.e., near the entrance of the large vessels and main bronchus) and can show cavitation (right image); obstruction/compression of vital structures can easily occur; are usually gray-white and very firm  Microscopically, generic squamous cell carcinoma is seen, with larger cells with (usually) eosinophilic cytoplasm, keratin pearl formation (upper right image) and intercellular bridges

Question 11

What comprises the Non-small cell lung carcinoma?

Answer 11

Note: SCC, along with adenocarcinoma and other lesions with epithelial morphology, comprise the category known as non-small cell lung carcinoma (NSCLC). While these were often treated/conceptualized as ‘one’ disease in the past, those days are gone. However, the acronym and verbiage of NSCLC still exists and can be used relevantly, especially when making broad distinctions from small cell lung carcinoma (SCLC).

Question 12

Explain tumors of mixed histology and large cell carcinomas?

Answer 12

Tumors of Mixed Histology and Large Cell Carcinoma
Malignancies arising in many organs systems can develop hybrid or mixed morphologies, and pulmonary carcinomas have a particular propensity for this process.
 10% of lung cancers are mixed histology

 diagnosis of exclusion

 different mixtures include squamous cell carcinoma, patterns of adenocarcinoma, and small cell carcinoma

Question 13

Explain this image?

Answer 13

Image: basophilic cells of signet-ring cell adenocarcinoma (more on left) mixed with larger, esosinophilic cells of squamous cell carcinoma (more on right)

Question 14

Large cell carcinoma is what?

Answer 14

Another subtype of pulmonary carcinoma, large cell carcinoma (LCC), appears to be a mutationally-progressing, undifferentiated common pathway for both adenocarcinoma and squamous cell carcinoma.
 when ancillary/additional studies cannot help define a lesion as adenocarcinoma or SCC, but a small cell carcinoma can be ruled out, these undifferentiated lesions are called LCC

 diagnosis of exclusion

Question 15

explain neuroendocrine proliferation/Low Grade Neuroendocrine carcinoma?

Answer 15

Cells of neuroendocrine type are distributed throughout the respiratory tract – from nasal epithelium and laryngeal mucosa all the way down to the respiratory bronchioles. These cells play a role in hypoxia detection, receive neural inputs, and subsequently release hormones that regulate blood blow, regulate bronchial wall tone, etc. Neuroendocrine cells are not well visualized on H&E stains.

Question 16

explain this image?

Answer 16

Image: neuroendocrine cells in the respiratory mucosa, stained with chromogranin (a neuroendocrine immunohistochemical stain);

Question 17

Explain the features of low grade neuroendocrine tumors?

Answer 17

 arises from neuroendocrine cells or foci of neuroendocrine cell hyperplasia, account for 1-5% of lung tumors

 AKA: carcinoid tumor (or slightly higher grade atypical carcinoid tumor)

 Patients are typically < 40 years old, and many (1/3) are non-smokers

 Typically grow intraluminally and endobronchially – cough, hemoptysis, obstruction

 Functional lesions can produce carcinoid syndrome (flushing, diarrhea and cyanosis) in a minority of patients

Question 18

explain this image?

Answer 18

Image: solid, trabecular (cords), and rosettes of uniform cells with moderate cytoplasm, typical of carcinoid tumor. Atypical carcinoids would have increased pleomorphism, increased mitotic activity, and increased disorganized growth

Question 19

Explain Small Cell Carcinoma (SCLC, High Grade Neuroendocrine Carcinoma)?

Answer 19

This highly aggressive carcinoma also likely arises from neuroendocrine cells lining the airways, and can arise both centrally and peripherally. In contrast to adenocarcinoma and squamous cell carcinoma, there isn’t a well-established pre-invasive phase (ie., low grade NE carcinoma doesn’t evolve into SCC).
 strongly associated with cigarette smoking

 TP53, RB, and MYC mutations (profiles similar to SCC)

 high propensity for hilar/mediastinal node involvement or distant mets on presentation

 many associated paraneoplastic syndromes, such as the production of ACTH (Cushing syndrome), ADH (SIADH) or autoantibodies, such as against neuronal calcium channels (Lambert-Eaton myasthenic syndrome)

Question 20

Explain the gross/microscopic and staining pattern of SCC?

Answer 20

 Grossly, flesh-colored tumors that show invasion throughout the involved tissue (below right); can spread over the surface of the lung, into the mediastinum, etc

 Microscopically (below left), small blue cells with very scanty cytoplasm; chromatin is dispersed in small dots of color, so called ‘salt and pepper’ chromatin typical of neuroendocrine cells in general; very dishesive, fragile cells that fall apart from one another and have a tendency to press against one another, distorting cell bodies and nuclei, so called nuclear molding; high mitotic activity

 stain positively for neuroendocrine markers (chromogranin, synaptophysin, neuron specific enolase, etc.)

Question 21

Explain a harmatoma? Gross and micrscopic appearance?

Answer 21

Recall that a hamartoma is a disorganized mass of mature tissue whose cellular components are native to the region in which it’s arising. In the lung, hamartomas are usually found incidentally, when working up the patient for a different reason. Pulmonary hamartomas actually show clonality (gene mutations common to the proliferating cells) indicating they are a true neoplasm.

 classic ‘coin lesion’ – a round, well-defined radio-opaque lesion on chest film

 grossly, the lesions are very well circumscribed and tend to be poorly anchored in the lung parenchyma (below left image); calcifications or pearl gray-blue cartilage may be present

 microscopically, a mixture of smooth muscle cells, bronchial epithelium, connective tissue/collagen, and cartilage; the epithelium is often seen in lines or clefts, indicating it’s likely trapped bronchial epithelium that is compressed as the cellular proliferation expands (below right image)

Question 22

explain metatasis? Features favoring a primary lung malignancy? features favoring metastasis?

Answer 22

As the lung is the most common metastatic site, a regular and critical question that clinicopathologically needs asking: “Is this malignant tumor of the lungs a primary pulmonary tumor or a metastasis?” Usually, this question can be answered, although the primary location of a metastasis may be less obvious until a thorough clinico-radiographic work-up is done.

Features favoring a primary lung malignancy: central desmoplasia; lepidic growth or irregular growth at the periphery of the mass (see below left); immunohistochemistry indicative of pulmonary origin (for TTF-1, napsin, etc.); single lesions

Features favoring a metastasis: multiple masses, particularly located at the lung periphery; multiple masses that radiographically are round and uniform (‘cannonball lesions’); lesions that microscopically look ‘plopped’ into the lung parenchyma (see below right); immunohistochemistry indicative of another location (ER/PR positivity for breast carcinoma, etc.)

Question 23

pleural neoplasia is more important for? what are two situations that the pleua is evaluated in?

Answer 23

Pleural neoplasia in a practical way is more important for its location in direct or metastatic spread of malignancies, rather than for its primary lesions.

Two situations in which the pleura is regularly evaluated:

1) As adenocarcinomas are the most common primary lung lesions and are peripherally located, direct spread into or through overlying pleura is an assessment performed in every lung cancer case.
2) Malignant pleural effusion

Question 24

explain adenocarcinomas and what we look for to see if there is pleural spread?

Answer 24

1) As adenocarcinomas are the most common primary lung lesions and are peripherally located, direct spread into or through overlying pleura is an assessment performed in every lung cancer case.

 Upstaging occurs when pleural involvement is present

 Surgeon may report a puckered area of visceral pleura or that the lung is tethered to the chest wall (likely parietal pleural involvement)

 Direct pleural spread is usually only microscopically present (image right); elastin stain demonstrating pale tumor nests (arrows) on either side of the disrupted and duplicated elastin fibers which help form the barrier between the lungs and the pleura

 Rarely, when metastasis is grossly present (image left; multiple metastatic foci studding the visceral and parietal pleura), this upstaging is evident during procedural evaluation

Question 25

explain malignant pleural effusions?

Answer 25

Direct or metastatic spread can cause different symptomatology if it results in an effusion. Recall an exudative (cell and protein rich) effusion can occur whenever the pleural mesothelium is disrupted, as with tumor, trauma, infection, etc.

 Dyspnea can be severe and debilitating, requiring treatment and palliation

 Neoplasms of the lung, breast, ovary, and lymphoma cause 80% of malignant pleural effusions

 Metastatic tumor and high clinical stage are typical

 Cytology pathologic evaluation is used to confirm the clinical impression, as fluid is removed and microscopically examined for malignant cells

Question 26

Treatments for recurrent malignant pleural effusion?

Answer 26

Question 27

what is malignant mesothelioma?

Answer 27

This is a fairly rare tumor, but a highly litigious one, due to its association with asbestos exposure and its highly occupationally-acquired nature. (Boards alert!) Occupations with significant/possible asbestos exposure include railyard workers, plumbers, general construction workers, brickmasons, electricians, firefighters, miners, longshoremen and shipbuilders, and teachers.

 Arises from visceral or parietal mesothelial cells

 Risk of development in high exposure occupations may be between 5-10%

 Incidence not significantly higher in smokers (in contrast to asbestos-induced lung carcinoma)

 Typically arises several decades after exposure

 A separate process from asbestos-induced restrictive lung disease

 Grossly, as mesothelioma spreads in the pleural space, it tends to encase the lobes of the lungs (right image), can create pleural effusions, and can directly invade other thoracic structures