The GRACE Lung Cancer Reference Library is made possible by an educational grant from Pfizer, who had no input in its contents.

What is cancer?

One of my patients once told me that she likened her cancer cells to misbehaving children and I think that this was a wise explanation. When a baby is born, it starts as a sperm fertilizing an egg, creating a single cell. That cell is pluripotent, meaning that it is capable of making all of the different kinds of cells that will ultimately be needed in the body. The cell will divide, then divide again, then divide again. In the process, the “daughter” cells become increasingly specialized. By birth, a baby has many different kinds of cells, each with very specialized functions and most of them have lost the ability to divide further or spread to other parts of the body. They are programmed to die in response to signals from other cells.

Each of these cells is a little factory, performing its specified functions. The tools that the cell uses to carry out these functions are called proteins. In order to make a protein, the cell starts with the DNA blueprint that is housed in a structure called the nucleus. The nucleus can be thought of us a little fortress-enclosed island containing stacks of blueprints in a big lake that is the cell. The DNA is transcribed (copied) into stuff called RNA, which travels out of the nucleus into the cytoplasm (which could be thought of like the water in the lake). In the lake, the RNA attaches to a structure called the ribosome (think of it as a small, floating protein factory) where it is translated into a protein.

Like a criminal, a cancer cell starts its life as a normal cell and then goes bad. It does so because of changes to its DNA that we call mutations. It takes multiple mutations for a cell to turn bad and become a cancer cell; the number probably varies greatly from one type of cancer to another. Thus, a person can be born with one or two of these changes, creating a genetic predisposition to cancer. Other changes come throughout life — by bad luck or through exposure to chemicals that can induce mutations, such as smoking, asbestos, radon, and cooking fumes.

As a cell goes bad, it becomes more immature, in some ways more like the cells of a developing embryo. It loses some of its differentiation and learns/relearns things that it was supposed to have forgotten, such as how to migrate (metastasize). It forgets things that it was supposed to know—like to die when its time comes. In these ways, it transforms from a well-behaved cell fulfilling a useful function into a cancer cell.

Naming Cancer, My Grandmother in Mexico, and Bank Robbers

Any cell in the body can go bad and become cancerous. Colon cells make colon cancer when they go bad and lung cells become lung cancer when they go bad. Just as an American tourist visiting Mexico is called an American tourist, and not a Mexican, cancer cells are always called by wherever they started. Thus, a lung cancer cell that metastasizes (spreads) to the liver is always called metastatic lung cancer, not liver cancer. This matters, because lung cancer spread to the liver behaves differently than colon cancer spread to the liver, just as my grandmother behaves differently on a vacation to Mexico than a college student on spring break there (at least I hope so).

There’s an important caveat to make here about the predictability of cancer behavior. Let’s say that a three-time bank robber is released from prison. Many of us may worry that he will commit another bank robbery. If his next crime is instead murder, we might be a little surprised, but we shouldn’t be shocked— bad behavior can escalate. The same is true of cancer cells; they have certain tendencies that can help us to predict what they may do, but really, they can do almost anything. Just because a certain cancer doesn’t normally spread to, say, the spleen, it does not rule out that one day it could decide to go there.

What are the kinds of lung cancer?

The kind of normal cell that the cancer cell starts as determines the kind of cancer cell that it becomes. Each of these kinds of cancers behaves differently and is treated differently. Patients have certain natural questions — “What kind of cancer do I have?”; “What can I expect?”; What’s the best treatment?”. In order to be able to answer these questions, the doctor needs to know what kind of cells make up the cancer. Only a biopsy can do this. The biopsy differentiates not only between the different kinds of lung cancer, which we will discuss shortly, but also rules out cancers that started in other parts of the body and later spread to the lung.

The most common type of lung cancer is non-small cell lung cancer (NSCLC). There are three major types of NSCLC: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Adenocarcinomas start as the glandular cells of the lung: they tend to secrete stuff like mucin; bronchioalveolar carcinoma, or BAC is one particular subtype of adenocarcinoma. Squamous cell carcinoma is derived from the squamous epithelium (tough cells that line organs to protect them). There is a debate in the pathologic community regarding the origins and nature of large cell carcinoma; they may not all come from the same kind of cell, and thus might not really represent a single kind of cancer. After NSCLC, the next most common type is small cell lung cancer (SCLC), which derives from normal neuroendocrine cells (cells that secrete hormones). Finally, there are several rarer types. Mesothelioma is dervived from the cells that form the pleura, or lining of the lung. Thymoma and thymic carcinoma are derived from the thymus; they are subdivided based on the kinds of cells that make them up.

No patient needs to be able to identify their cancer under the microscope (to be fair, for the most part, neither does the medical oncologist—specialized pathologists do this!). However, for the sake of understanding and making this all a bit more real, some images are provided of the most common subtypes below.

(click on image to enlarge)

Sometimes the cancer cells look a lot like the normal cells from which they were derived: these are called well differentiated. Others go so far backwards in their differentiation that it’s really hard, or even impossible to determine by appearance what kind of normal cell they once were: these are called poorly differentiated. The other reasons that the pathologist sometimes cannot tell the subtype for sure is that they receive a very small amount of tissue. In this case, the cancer has a subtype, and additional biopsy material is needed to tell what it is.

Some cancer cells bear markers on their surface that tell us something about their nature. These get complicated, but since they’re often a part of pathology reports, I want to cover the most important ones:

CK7 and CK20 - CKs are cytokeratins, markers common to carcinomas. Sometimes when the site of origin of an adenocarcinoma isn’t certain, CK7 and CK20 can help. The typical lung pattern is CK7+ and CK20-.

TTF-1 (thyroid transcription factor-1) - 85% of adenocarcinoma of the lung and a minority of squamous cell cancers will bear this marker. Most non-lung cancers do not express TTF-1 (prominent exceptions include thyroid cancer and cancers of the female genitourinary tract).

p63 - A marker for squamous cell carcinoma that is being used increasingly commonly

There are also specific genetic changes for which a pathologist can test: EGFR mutation, K-RAS mutation and EML4/ALK translocation. These can help predict efficacy of the drugs erlotinib (tarceva), gefitinib (iressa) and crizotinib (PF-02341066). Further discussion of these changes and drugs is beyond the scope of this introduction but will be covered under the treatment sections and has been extensively covered in previous posts on GRACE.

Pathology has been also been covered on GRACE in several podcasts. For more information, see: Interview with Lung Cancer Pathologist Matthew Horton, Pt 1: Intro to NSCLC Subtypes and Interview with Dr. Matthew Horton, Pathologist, Part 2: Neuroendocrine Lung Tumors & Bronchioloalveolar Carcinoma, and Part 3: Transitioning to Molecular Pathology.

What is staging?
Staging refers to the location of the cancer. There are three components to staging:
T: Where and how big the original mass is
N: Which nodes the cancer has spread to
M: Whether the cancer has spread distantly or not

The staging systems are designed and revised to predict average survival. I don’t use these statistics when counseling patients, because I don’t think that they really convey useful information. By the nature of an average, half of the patients do better than the average, and half do worse. Survival in lung cancer is extremely unpredictable and so variable that I think that in counseling an individual patient, these numbers lie more than convey meaningful information. Further, these statistics upset some patients. So, for those who want it, click here to see median NSCLC survival by stage.

Staging does help us to make practical decisions. The greatest determinant of best treatment is through stage. Small, local cancers are treated surgically. Larger tumors and those with nodal involvement are best treated with surgery followed by adjuvant chemotherapy. Locally advanced tumors (stage III) are often treated with some combination of chemotherapy, radiation, and surgery. Finally, the mainstay of treatment for metastatic cancer is chemotherapy. Unfortunately, the new staging system is amazingly complicated—far more so than it needs to be for understanding your cancer and its best treatment. So, I present the full staging system, slightly simplified, below as a reference, but feel free to skip down below to the more functional definitions (below the definitions of T, N, and M staging).

T Stage:
T1- Tumour < 3cm
T2- Tumour > 3cm, but < 7cm. A tumor can also become T2 at < 3cm, but with certain high risk features.
T3- The tumour can become T3 either by being > 7cm or by having additional high risk features (invasion of chest wall, diaphgram, phrenic nerve, mediastinal pleural, parietal pericardium and several others)
T4- Tumours become T4 by invading important nearby organs: mediastinum (the center of the chest), heart, great vessels (big blood vessels), trachea (your breathing tube), recurrent laryngeal nerve (invasion of this nerve makes some lung cancer patients hoarse), esophagus (eating tube), vertebral body (back), and carina (the place where your trachea, or main breathing tube, branches into two big breathing tubes that supply each lung). A tumor can also become T4 by spreading to another lobe of the lung on the same side as the primary tumor.

N Stage: (Even if you’re choosing to read this technical part, please see the simplified nodal chart below—otherwise, this is technical mumbo jumbo of the 1st order!)
N0- No spread to nodes
N1- Spread to peribronchial and/or hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension on the same side as the tumor
N2- Spread to mediastinal and/or subcarinal lymph node(s) on the same side as the tumor
N3- Spread to mediastinal or hilar nodes on the opposite side as the tumor. Any scalene or supraclavicular node.

M stage:
M0: No distant mets
M1: Any distant spread. Any malignant pleural or pericardial effusion (fluid around the lung or heart that contains cancer cells)

In my simplified system, we focus only on the “breakpoints” that change decision making. Believe it or not, the formal staging system, complex as it is, doesn’t even include all of them! It really focuses on predicting survival, not on deciding the right treatment. The names and numbers of the nodes are provided to help you match your imaging and pathology report up and understand them. For now, please focus only on the three different colored arrows in the diagram; they’re all you need to know! If a node is blue, it’s N1; orange, N2; and purple, N3. Since most of staging comes from the nodal status, if you know this, you’re most of the way there!

The T, N, and M numbers can be put together to get the stage I-IV system that many people like. The system is great because it’s simple, but when I’m seeing a patient, my biggest question isn’t so much their roman numeral stage, but what I should do to best improve their survival. I therefore prefer a simple explanation of where the tumor is that is more functional. this is described below for non-small-cell lung cancer. Because these roman numerals are important to some, the equivalency table follows.

Node negative tumor <4cm (Stage I): Standard of care is surgery only.

Node negative tumor >4cm (Stage I-II): Controversial. Many (including me) believe that chemotherapy improves outcomes after surgery.

Any node positivity: If surgery is the primary treatment modality, chemotherapy should also be given to patients who can tolerate it, to reduce risk of recurrence

Stage IIIa: Any N2 (orange on diagram) node. This is the most controversial stage in lung cancer. Most patients are treated with the combination of chemotherapy and radiation. There is emerging data that some patients may benefit from surgery in addition to chemoradiation. Chemotherapy followed by surgery is a reasonable option for some patients. This controversy is well covered in the reference library.

Stage IIIb: Any N3 node. The majority of oncologists believe that chemotherapy and radiation together are the best treatment. A small minority advocate for chemoradiotherapy followed by surgery. For more information, see Dr. Pinder's post on the subject.

Stage IV: Distant spread or fluid collection around the lung (pleural effusion) or heart (pericardial effusion) with cancer cells. Chemotherapy is the right therapy for most patients. Patients with a single focus of spread to brain or adrenal may have a small chance of cure with aggressive modalities that include local treatments like surgery and/or radiation.

The TNM system does technically apply also to small-cell-lung-cancer, but most oncologist favor a MUCH simplified staging system:

Limited Stage disease: The cancer can be encompassed in a single radiation field. It is treatable with the goal of therapy cure.

Extensive Stage disease: The cancer cannot be encompassed within a single radiation field. It is not typically curable, but is treatable, with the goals of therapy being better quality of life and longer duration of life.

We have plenty more information on workup and staging of lung cancer. Mesothelioma, thymoma and thymic carcinoma have their own staging systems, that I will leave to future chapters dedicated to these cancers.

Basics of looking at CT Imaging:

Many patients like to see their own imaging—it makes the cancer more real and leads to greater understanding. While it takes many years of training to properly read a CT scan, the basics are fairly easy.

The CT scanner slices your body front to back to create what doctors call cross-sectional imaging. Top is top, bottom is bottom, but left and right are reversed. Another way to look at it is to imagine that your head is in the back of the computer monitor and your feet are coming out of it towards you. On a CT, things that are dense are white and things that are not dense are black. So the air outside of your body and in your lungs is black. Your bones are white. The markings found throughout the lung are normal blood vessels. Masses in the middle of the lung, such as the one shown below, are not normal.

PET scanning has gained in popularity in lung cancer. In a PET scan, the patient is given sugar that has a radiolabel to detect it on imaging. The scanner then picks up where the sugar goes. Cancer cells, among many other causes such as inflammation and infection, use more sugar than normal cells and so they light up. PET is really good at finding small sites of disease and can help push thinking about whether something seen on CT is really cancer. However, the CT images obtained during a PET are actually lower resolution than those obtained with a plain CT and they lack IV contrast. For this reason, PET is not always better than CT — it depends on what question your oncologist is trying to ask. If you need to drive a nail in, use a hammer; if you need to get a screw in, use a screwdriver. Different questions/tasks will lead your oncologist to select a particular tool.

So there you have the basics: the “what” and “where” of lung cancer. This chapter will be updated based on new data, comments/feedback, and the evolving needs of the GRACE community (Initially authored April, 2010, last updated April 2011).

We thank Pfizer for their support for the GRACE Lung Cancer Reference Library.