Lung Cancer - Pathology

Question 1

What are primary lung cancers derived from and what two groups are they classically divided into?

Answer 1

Epithelial origin

Classically divided into Small Cell Carcinoma (SCC) and Non-small cell lung cancer (NSCLC)

Question 2

What specific cancers fall under the umbrella of non-small cell lung cancer?

Answer 2

1. Squamous Cell Carcinoma
2. Adenocarcinoma
3. Large Cell (Undifferentiated) Carcinoma

Question 3

Why are carcinoid tumors put into a secondary group?

Answer 3

They are still technically carcinomas, but have a much more indolent course than NSCLC and are not associated with smoking

Question 4

What primary lung cancers are associated with neuroendocrine features? What is pathoma’s mnemonic for the paraneoplastic syndromes?

Answer 4

Small Cell Carcinoma & Carcinoid Tumor

Pathoma’s mnemonic - if it starts with an S sound / C sound, it is associated with a paraneoplastic syndrome:

SCC, Carcinoid tumors, and Squamous cell carcinoma (NSCLC)

Question 5

Why is lung cancer so deadly, and why are we hopeful that we can control it better in the future?

Answer 5

Because typically patients present when it is already so advanced in its course

Lung Cancer has a long latency period -> window of opportunity for screening where early cancer may be detected and virtually cured
-also only tends to affect middle aged and elderly

Question 6

What is the primary risk factor for lung cancer, and a few less important ones?

Answer 6

Cigarette smoking

Others:
Radon exposure, asbestos, and air pollution

Question 7

What is the most common subtype of lung cancer? What lung cancers have the highest incidence in smokers vs nonsmokers?

Answer 7

Adenocarcinoma is most common

Nonsmokers - primarily adenocarcinoma

Smokers - primarily squamous cell carcinoma, second highest is small cell carcinoma

Question 8

Of the classical lung cancers, which ones are central vs peripheral? Why?

Answer 8

S = Central

Squamous cell carcinoma and small cell carcinoma tend to be central - arise from respiratory mucosa of main or lobar bronchi

Adenocarcinoma / Large cell carcinoma tend to be peripheral - arise from club cells or Type II pneumocytes - terminal bronchioles / alveoli

Question 9

Which tumors are most likely to present with pleural effusion / chest pain and distant metastases and why?

Answer 9

Pleural effusion / chest pain - Adenocarcinoma, Large cell carcinoma

-> grow more peripherally

Distant metastases - Adenocarinoma, Large cell carcinoma

-> more distal so they present later

Also small cell carcinoma -> since its so aggressive

Question 10

What tumors are associated with cough, hemoptysis, stridor, pneumonia, and dyspnea in their presentation?

Answer 10

Squamous cell carcinoma and small cell carcinoma

-> primary tumors which grow more centrally

Question 11

What is the treatment for small cell carcinoma and why? How do you remember this?

Answer 11

Chemotherapy / radiation is the treatment of choice, because it grows so rapidly it is most affected

Not amenable to surgical resection like NSCLC because the tumor is “so small that the surgeon can’t see them”

Question 12

What is the only type of lung cancer which currently has targetable molecular alterations? What molecular target is this and who is it seen in?

Answer 12

Adenocarcinoma

Seen in non-smokers and women

Molecular target is EGFR mutations (not seen in other cancers) - EGFR inhibitors

Question 13

What is the progression of pathogenesis for squamous cell carcinoma?

Answer 13

Normal mucosa -> squamous metaplasia (smoking) -> mild dysplasia -> progress to CIS -> invasive SqCC

Question 14

What becomes the features of dysplastic cells in SqCC?

Answer 14

Cells become progressively undifferentiated towards the surface, with high N/C ratios and pleomorphism, with mitotic bodies and high proliferative rates

Eventually, squamous differentiation is only seen in the formation of keratin pearls and intracellular bridges

Question 15

What is the current view of the progression of adenocarcinoma?

Answer 15

1. Normal terminal bronchioles / alveoli - Club cells and Type II pneumocytes
2. Atypical adenomatous hyperplasia (AAH)
3. Adenocarcinoma in situ (AIS)
4. Invasive adenocarcinoma

Question 16

What are the features of atypical adenomatous hyperplasia (AAH)?

Answer 16

Pneumocytes become very large, interstitial space proliferates

-> hyperplasia of Type II!! pneumocytes vs Type I, with increasing N/C ratio and hyperchromasia (density of heterochromatin)

Question 17

How does invasive adenocarcinoma look, vs AIS?

Answer 17

AIS - thickening of septae with fibrosis and more atypia of cells, but native alveolar IS structure preserved

Invasive Aca - Neoplastic glands are formed, destroying native alveolar structure, with extensive collagen (desmoplasia) and tissue remodeling

Question 18

Can invasive Aca and AIS coexist?

Answer 18

Yes - relative proportion of invasive Aca vs AIS determines prognosis
-> AIS is a premalignant stage and can be present at the same time

Question 19

What tumor type is most associated with K-Ras mutations? In what patient population?

Answer 19

Adenocarcinoma

• occurs in smokers
• nonsmokers typically don’t have this mutation, but rather EGFR mutations (described previously)

Question 20

What mutation occurs in virtually all lung cancers? Is it the same in all patient populations?

Answer 20

p53 mutations

-different mutations between smokers and nonsmokers

Question 21

What additional mutation is most common in small cell carcinoma which accounts for its invasiveness?

Answer 21

Rb deletions (rapid progression through cell cycle by failure to block E2F-dependent production of cyclin E)

Question 22

What is the only non-invasive method for tissue diagnosis of malignancy? What lesions does it detect most easily?

Answer 22

Sputum cytology

Most easily detects central tumors - i.e. squamous cell carcinoma, small cell carcinoma

Question 23

What other invasive methods can be used for tumor sampling, especially peripheral tumors? What is fine needle aspiration vs biopsy?

Answer 23

Transthoracic sampling of lung - for peripheral tumors (highest sensitivity)

Sampling during bronchoscopy - for more central tumors

Fine needle aspiration - sampling yielding cells

Fine needle biopsy - sampling yielding tissue

Question 24

What forms the intercellular bridges of squamous cell carcinoma?

Answer 24

Desmosomes which cause interlocking of cytoplasmic projections to adjacent cells

Question 25

In what way are squamous cell carcinomas similar to normal squamous epithelia?

Answer 25

Typically grows in nests, with undifferentiated basal cells in the periphery, and progressive differentiation towards center
-> nests will often cavitate and have an exfoliated center of keratinized cells / necrotic debris.

Question 26

In what way does adenocarcinoma seem very similar to regular exocrine glands (its differentiation pattern)

Answer 26

Cells arrange around central lumen, like acini, and secrete mucins, or surfactant (normally secreted by club cells / Type II pneumocytes).

Question 27

What typically has good prognostic value upon identification of an adenocarcinoma?

Answer 27

Growth pattern - i.e. papillary vs acinar vs solid vs micropapillary

Question 28

What accounts for cytoplasmic vacuolization in adenocarcinoma and how is it definitively told apart from SqCC?

Answer 28

cytoplasmic vacuolization - exocrine differentiation with accumulation of intracellular secretory vesicles (i.e. mucin)

Told apart via immunohistochemistry (SqCC will have keratin)

Question 29

What is the pathologic morphology of Large Cell Carcinoma and how is it diagnosed?

Answer 29

Poorly differentiated tumor - no keratin pearls, intercellular bridges, exocrine glands, or mucin

-> a diagnosis of exclusion, thorough sampling is required

Question 30

What are the neuroendocrine tumors and their generally shared morphology? What is the neuroendocrine marker?

Answer 30

Small Cell Carcinoma, and Typical / Atypical Carcinoid tumors

Grow in nests and plates, surrounded by richly vascularized stroma

Neuroendocrine marker - chromogranin

Question 31

What are the specific features which help you to identify a small cell carcinoma (vs carcinoid)?

Answer 31

Small cell size, with very high proliferative / apoptotic rates, high N/C ratio, fine chromatin (homogenously dispersed), and absent or rare nucleoli

• > Extensive necrosis due to such rapid overgrowth of blood supply
• > molding and crush artifacts

Question 32

What are the molding and crush artifacts which are so characteristic of small cell carcinoma?

Answer 32

Molding - cells are growing so fast that they leave their expression on the adjacent cell and appear to mold together

Crush artifact - Threads of crushed DNA will be dispersed across the histological slide

Question 33

What lung neuroendocrine tumor has the best prognosis, and what syndrome is it associated with? Is smoking a risk factor?

Answer 33

Typical carcinoid tumor - associated with Multiple Endocrine Neoplasia 1 (MEN1)

Smoking is not a risk factor for atypical or typical carcinoid tumors

Question 34

What are the typical symptoms of carcinoid tumors at presentation? How does it relate to the morphology of the tumor?

Answer 34

Hemoptysis, dyspnea, and post-obstructive pneumonia secondary to bronchial obstruction

Tumors tend to grow as exophytic, endobronchial masses

-> remember that S sound indicates central involvement

Question 35

What are the histological features of typical carcinoid tumor?

Answer 35

Low grade

• > low N/C ratio
• > prominent granular cytoplasm
• > “salt and pepper” fine chromatin distribution with absent or few nucleoli
• > NO necrosis (vs SCC)
• > low proliferative rate
• > still arranged in nets juxtaposed to rich capillary network

Question 36

What defines something as an Atypical carcinoid tumor?

Answer 36

Has a typical carcinoid morphology, but has EITHER 1. increased mitotic rate or 2. necrosis (typically occurs in punctate, bean-shaped foci)

Question 37

How does the prognosis of atypical carcinoid tumor compare to the other neuroendocrine tumors?

Answer 37

More aggressive than typical carcinoid -> more LN metastases, and grows larger

Less aggressive than small cell carcinoma -> must be less than 10 mitosis per high power field (no mem #)