Matthew+Martini

Jessica Webster is just one of the approximately 56,000 Americans who was diagnosed in 2013 with squamous cell carcinoma, a type of non-small cell lung cancer. She is an active and dedicated 36-year-old single mother of twin boys, Maxwell and Jonathan. After her husband abandoned them one night during dinner at Chili’s when the boys were just learning to speak, she became very protective and now almost never lets them out of her sight. Now nine years later, when she isn’t working full time as a secretary for a local lawyer, she is busy caravanning her two boys to the practice of whatever sport is in season, taking them on road trips to the beach or to the mountains, and teaching them that girls can be better at sports than boys. Over the course of several months Jessica noticed that she had developed a cough and had felt out of breath while walking up the stairs at her home. At first she believed that the shortness of breath and cough was due a lung infection she recently had, but as the infection subsided the cough persisted. Her voice later became hoarse, which she attributed to all the screaming at the boys’ soccer games.
 * Jessica Webster and her Squamous Cell Carcinoma**

Jessica only recently decided to visit the doctor when she started feeling tired and weak during all hours of the day. As the doctor took note of her symptoms, he decided to check Jessica’s lymph nodes.1] Once he discovered that they were quite swollen he ordered a chest CT for further investigation. After the examination of the CT scan, Jessica’s doctor confirmed his diagnosis of a primary tumor in her left lung. He followed up with her by asking if there were any changes to her lifestyle recently or if she had a family history of lung cancer. She explained how only her mother’s father was the only one in her family, to the best of her knowledge, who ever had cancer, and even then it was colon cancer, not lung cancer. She also told him that the last time she smoked was when she was 17 in the girls’ bathroom at school. As the doctor’s questions regarding possible chemical mutagenic exposure proceeded, she continued answering “No, never” to all of the compounds. Following the questions, further tests were conducted in order to determine the type and severity of the tumor. The doctor ordered a fine needle aspiration, in which a small piece of tissue was taken using a needle that passed through her skin into her left lung. The tissue sample was then examined under a microscope and it was determined that Jessica had squamous cell carcinoma, which is characterized by large, flattened, and stratified squamous cells.1] These cells tend to have a high cytoplasm to nucleus ratio as well as the presence of intracytoplasmic keratin. Squamous cell carcinoma most often arises centrally within the main, lobar, segmental or sub segmental bronchi, but some occur peripherally. The tumor generally extends into the lumen of the airway with invasion into the underlying wall.2] Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer accounting for 85% of all lung cancers. Squamous cell carcinoma (SCC), a type of NSCLC, makes up approximately 25% of all lung cancers.

The progression of NSCLC can be classified using a slightly modified version of the classic stages I-IV. Stage I cancer is the least malignant form of SCC with the longest prognosis. At this stage the cancer is located only in the lungs and has not yet spread to any lymph nodes. In stage II, the cancer is still confined to the lungs, but is nearby lymph nodes. Stage III has two different subtypes, A and B. In subtype A, the cancer has spread to the lymph nodes, and is still contained on the same side of the chest where the cancer started. In subtype B, the cancer has spread to the lymph nodes on the opposite side of the chest or above the collarbone. Then there is stage IV. This is the most advanced stage of lung cancer with the shortest prognosis and is characterized by spread to both lungs, to the fluid surrounding the lungs, or other parts of the body.1] Jessica’s cancer is classified as stage IIIA, indicating that her cancer has spread to he lymph nodes, yet remains confined to her left lobe. If left untreated, her cancer will develop into stage IV, and will most likely spread from her lymph nodes to the adrenal glands, the brain, the liver, and bones. Squamous cell carcinoma is not an overly aggressive form of cancer despite the overall poor prognosis. Since SCC is typically diagnosed after the disease has spread, only 16% of patients survive five years or longer following their diagnosis. However, as the cancer is detected earlier, the rate of survival is increased dramatically.3]

The news to Jessica was unbearable, the tightness in her chest was overwhelming, and all she could do was break down in tears as thoughts came racing through her head. One question kept coming to her, “Who was going to take care of the kids?” Jessica had left work for this appointment, but after hearing the diagnosis, she was in no mental state to return to work, so she requested the remainder of the day off. She went home, packed a suitcase with a couple pairs of jeans and her favorite sweater, then picked up her kids prematurely from school and started driving along Interstate 5 towards Lake Tahoe. Two hours later, they finally arrived at their cabin. Jessica was drained both emotionally and physically from the day she has had so far, and it was barely past noon. The kids were extraordinarily hyper after the car ride, so she unleashed them to play outside in the snow. Jessica then meandered over to the couch, pulled out her laptop and started researching NSCLC, specifically SCC. Her mind began to race again; this time trying to calculate which one of the endless outcomes was going to occur. Her fatigue was hitting her harder than her mind could handle, even in this hyperactive state. Reality had started to feel like a dream, she could feel her mind relaxing, her eyes slowly lost focus and all of her muscles relaxed, as she drifted into a slumber.

Jessica woke up abruptly in a cold sweat, her heart pounding, only to realize that her two sons were fast asleep on the couch next to her holding her tight. She realized immediately that she had fallen asleep while on the laptop and immediately starting tapping the space bar in order to determine if the boy’s had seen what she was looking up. The laptop was unresponsive, most likely dead, and there was no charger nearby. She thought to herself that maybe they hadn’t seen that she had been looking up SCC. After realizing that it was only one in the morning, she decided to go back to sleep and play detective in the morning. As she was drifting back into her dreams, she noticed that the boys’ shirts were damp, but was it a result of her cold sweat, or were they very warm. Was it possible they had seen the laptop before it died and the dampness were tears? She couldn’t see any of the tell tale signs of crying, but then again, it was very dark in the room. She knew she had to tell them eventually, but she had no idea when the right time to tell them about such a sensitive issue, especially since she found out within the last 24 hours. She closed her eyes and began contemplating possible ways to approach this and how to do so. Jessica knew she didn’t want to ruin their miniature vacation, by bearing the bad news, so she decided to take them out to dinner when they got back and tell them. This way she could learn more about her new condition before plopping it on them. With an approach to deliver the news in mind, she was able to finally doze off until the sun started peaking through the blinds.

As she reawakened once more, she decided to sneak away from the boys’ who were still asleep on the couch and determine the status of the laptop. She grabbed the laptop off the table, and the charger from her backpack and headed to the kitchen table to continue her research. She was still a little fuzzy on exactly what Stage IIIA was, and she wanted to be prepared to discuss her condition with the doctor the next time she saw him. As she was searching through the internet, she noticed that SCC was more commonly a skin cancer, so she typed in lung following SCC into the Google search and came across a page from cancer.gov with illustrations of the various stages of SCC. Despite the picture being cartoonish in nature, it helped her grasp the notion of what was happening inside of her. She continued to research all aspects of SCC for several hours delving deep into the technical jargon that is so common until her boys finally woke up.

Days passed by just like they used to before she had cancer. She dropped her boys off at school, went to work, picked them up from practice, and cooked dinner. This cyclical lifestyle ensued until the dreaded appointment with the oncologist. Jessica wasn’t too sure why she was so afraid of going; possibly because last time she went to a doctor she received bad news. But then again, she can’t receive worse news than cancer, so as the hours leading up to her appointment passed by; she pushed any and all negative thoughts out of her head. As she was sitting in the waiting room, she began to look around. It was the most generic waiting room she had possibly ever seen. This waiting room had no defining characteristics, no oomph, and no nothing. It was the definition of standard, which made her think that maybe she chose the wrong doctor. Does his choice of decoration reflect on his ability to be an oncologist? Has she just rested her entire life in the hands of a subpar oncologist rather than a superb one? Her mind began to race again until finally a nurse came out and told her that the doctor will see her now. Jessica was led along the long corridor, until they reached a nook in the wall, where they paused momentarily to take her vitals. They then continued until they finally reached room 6. The nurse offered her a seat and told her that the doctor would be with her momentarily. Within five minutes a tall man in a white coat walks into the room. He looks to be in his late 50’s, with graying hair, that hasn’t begun to thin yet. He introduced himself as Daniel Klein, her oncologist, but asked her to please call him Dan.

Dan first began by asking her the general go to questions regarding her well being, which started to worry Jessica because maybe there was nothing special about him. That impression did not last long as he then quickly delved into the facts regarding SCC. He began by saying that there are two main types of SCC in the lungs. These types are determinant of the primary location of the tumor, and whether it originated along the periphery or in the central region of the lungs. Dan continued by telling her that since he first began he has seen over 200 surgically resected SCC patients, 95 of which were located centrally, and 109 were along the periphery. He then opened his folder and began to show her various figures and tables of different statistics of patients he has seen, some relevant, some not as much. It was very apparent that this man has taken extraordinary detail of each patient that his office has seen. The first table that was presented to her was for those who had the peripheral type compared to those who had the central type. On average, those who had the peripheral type were older, had a lower pathologic stage, lower lymphatic vessel involvement, as well as lower rate of lymph node metastasis. However, despite all the positive factors, the mean survival rate was identical as the central type according to the Kaplan-Meier plot. He paused momentarily to mention that if she has any questions, she should feel free to interject. Dan then continued by saying based off the histological growth pattern he has observed, there are three subgroups within the peripheral type. These include the alveolar space-filling type, the expanding type, and the combined type. The alveolar space-filling type is “characterized by filling of the alveolar space without destroying the preexisting elastic framework of the alveolar septa, which is a morphologic hallmark for noninvasive carcinoma of the lung”5] Of the three subtypes, the alveolar space-filling type had the most favorable prognosis due to the fact that it showed neither lymphatic vessel invasion nor lymph node metastasis. At this point in time, Jessica stopped him and began to ask about the central type and the other two subtypes of the peripheral type because he hadn’t bothered at all to mention them. Dan responded by saying that her prior doctor had confirmed that she has the alveolar space-filling type, so he wanted to make the best use of time by only mentioning the relevant facts for the cancer she had. Hearing the good news, Jessica could barely keep in her excitement. Dan continued once again by saying that her cancer peaked his interest because she never took part in any high-risk activities that often lead to SCC. He noted that there was a study she could participate in that would have her genome partially sequenced to help identify possible pathways that could have gone awry that led to the formation of the tumor. She agreed to participate in the study without hesitation and within minutes he had collected a sample of DNA, packaged it up, and handed it to the nurse to send it off to get sequenced.

Jessica having always been an inquisitive person, decided to look up common pathways of patients with SCC as soon as she returned home. She stumbled across a site by the name of tumor portal, which lists the most common, highly mutated pathway, along with the percentage of patients it occurs in. Jessica couldn’t help but wonder if her sequence would eventually contribute to this data. She noted that this would be a good question for Dan and then began to explore the website. She noticed that a common mutation in SCC is TP53, with 83% of patients affected. She then clicked on the link to see a description of the function of TP53. She read how the gene TP53 encodes for a tumor suppressor protein that limits transcriptional activation and DNA binding. The protein that is made responds to cellular stresses in order to regulate the expression of target genes. It has the ability to induce “ cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism.”6] TP53 is simply another tumor suppressor gene that has the ability to prevent a cell from entering the cell cycle by sensing damaged DNA. A loss in TP53 function prevents these checkpoints from happening, allowing damaged, possibly even more detrimental DNA to be replicated and reproduced thus dramatically worsening the prognosis. Following TP53, she continued to scroll through the various potential genes, none of which seemed very significant at 20% or lower, especially after TP53. She then realized that it was already time to pick up the kids from practice and headed out. She decided that she would save some time by waiting to see which pathways were present in her and to only look the relevant ones up.

Jessica anxiously awaited her results calling Dan once a day to see if he had any new news. Each time she hung up disappointed that the results still weren't in until one day Dan told her that he had something interesting to share with her and that that he send her an email with the information. The moment of truth, what mutations did she possess and how would it affect her treatment. She refreshed her inbox twenty times in the next five minutes until she saw the name Daniel Klein so prominently displayed in bold. She quickly clicked on the email and discovered that she contained mutations in the TP53, PIK3CA, and RB1 genes. She went back onto Tumor Portal and looked up PIK3CA, which is mutated in only 15% of patients. In conjuction with TP53, her cancer is similar to only 12% of other patients. This isn’t even considering RB1, which is present in only 6% of patients with SCC. It was at this point that she realized how unique each cancer truly is. She began reading that PIK3CA stands for Phosphatidylinositol 3-kinase and is a gene that encodes for a protein catalyst subunit. The catalyst uses ATP to phosphorylate AKT.”6] Not fully understanding what AKT is or does, she continued her research on PIK3. She stumbled across several images of the pathway with different types of arrows point in several different directions along with lines with a bar at the end. She was able to deduce from even further research that the arrows represent the continuation of a process, while the T’s represent the prevention of the process. Jessica understood from the diagrams, that PIK3CA is an important factor in promoting proliferation, and growth and preventing apoptosis, so this gene must be enhanced in some way to put her cells in overdrive. She noticed that there was a gene by the name of PTEN, which prevented the PI3K pathway from continuing, and immediately thought that there might be a way to enhance her PTEN, or stop her PI3K. When the PI3K pathway is mutated in a way, that prevents PTEN from slowing the cascade, AKT remains active allowing cellular growth to run rampant Now it was time to look up her third and final mutation in her RB1 gene. Similar to TP53, RB1 is not involved in the initiation of cancer, rqther when it is mutated, it allows for an expedited progression. She saw the this gene encodes for a protein that is a negative regulator of the cell cycle, or in other words, that it does not promote the cell cycle. Jessica continued reading the information on RB1, despite the fact that she knew she would understand a minimal amount. She read “ The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1.”6] E2F1 is a known promoter and regulator of gene expression, so if the protein Rb1, is hyperphosphorylated rather than hypophosphorylated, then Rb1, will be unable to bind to E2F1. The binding process can be compared to a ball in a baseball glove. When Rb1, is hypophosphorylated, that is the equivalent of the glove being empty. When the glove is empty, it is very easy to catch a ball. However, as Rb1 becomes more and more phosphorylated, it has a harder time binding. Each phosphorylation event can be compared to a ball in the glove. When there is a single ball in the glove, there is still a good chance a second ball can be caught, but as that number increases to say five, there is now a very low chance that another ball will fit. In cancer, it is as if there is never any balls in the glove, which means that E2F1, will easily be phosphorylated and the cell cycle will continue, even when it shouldn’t. Despite having heard an overall favorable prognosis from her oncologist, Jessica’s heart was at an all time low after reading the somber explanations of her cancer.

Dan opened up his folder and began flipping through pages of scribbles, diagrams, and figures. He eventually reached what he was looking for, paused for a moment, and looked up at Jessica just in time to see a tear rolling down her cheek. This was the first she was going to hear how to attempt to cure her disease, and she was very unsure how to feel about it. She was angry with herself for not visiting the doctor earlier when she first started experiencing her symptoms. She was upset that she was given such a burden even though she’s struggling to maintain her life as it is. She was scared that her future treatment might not work. She was sad that her boys might end up growing up without a mother and a father. She was frustrated with how little control she has over her own life. She was simply an overflowing pot of emotions ready to crack from the all of the stress. Dan leaned over and put his hand on her shoulder and told her that she has very little to worry about. Given that Jessica was diagnosed with stage IIIA squamous cell carcinoma in the periphery of her lungs, she had a variety of options for treatments each with varying rewards and consequences. Dan began by telling Jessica that her cancer was deemed resectable, which means that since the cancer was in only one lung, and that since it had not yet spread to other organs, it could be removed safely and effectively.

Dan proceeded to explain how there are five different types of surgeries, all slightly different, and each with varying degrees of aggressiveness.10] not handle missing an entire lung. Jessica on the other hand had stage IIIA, so any surgeries that removed only a small portion of her lung were not viable options. Dan explained how none of the previously mentioned surgeries were fits for her cancer, but the remaining two are, and that the choice is hers. Jessica could choose a pneumonectomy, which involves slicing out the entire lung, or a sleeve resection approach, which is the removal of several lobes, and portions of the airway.11]  The sleeve resection surgery preserves more lung function than the pneumonectomy. As Dan told Jessica her two options for surgery, she sat there and contemplated them. She was a hyperactive mother, constantly participating in outdoor sports with her sons. If she got her entire lung removed would she still be able to keep up with them? Even if she got sections of her lung removed how much of a difference would she feel compared to her entire lung being gone. She wanted to be able to experience life with her sons, but there would be no life to live if her cancer persisted. Then again, what is life if you can’t experience it. To Jessica, the most important thing is to be cured so she can support her boys both emotionally and financially until they grow up even if that means she can’t experience life to the fullest. So she told Dan to choose the most aggressive form of treatment, with the highest success rate. Dan explained how there is a direct correlation with the shear amount of lung mass removed and the rate of total remission of the cancer, meaning that since her primary goal is to be cured, a pneumonectomy would be the logical approach.

Surgery alone is not effective in the removal of cancer, so a combination approach needs to be applied. Chemotherapy, a common combination with surgery, annihilates of cancer cells and all cells in its path by damaging the DNA. In Jessica’s situation she is taking a systemic combination regimen of docetaxel and cisplatin, a platinum-based drug. Every seven days the drugs are slowly injected into her blood stream, and as the drugs course through her veins the pathway that allows replication is blocked like a prison cell blocks in a prisoner. The cells will inevitably die from excessive DNA damage with no chance of escape. The chemotherapy kills a significant amount of the cancer and the healthy tissue surrounding it allowing a surgeon to remove the tumor with more ease. Radiation therapy is more like burning. Radiation is the use of high energy beams to burn away areas where cancer is present and can target small or large targets. In Jessica’s situation, her cancer has overtaken a significant portion of her lung, but following her surgery it comprises a small area. Utilizing CT imaging and using image-guided radiation therapy, any small regions deemed potential homes for what once was Jessica’s cancer are burned away in a fashion similar to when pest control comes to fumigate problematic regions rather than tarp up the entire house. There are two options that can be combined with surgery. The first being surgery followed by chemotherapy and postoperative radiation therapy (PORT) in order to kill any potential cancer cells that evaded the scalpel of the surgeon.12] The second is when chemotherapy is applied prior to surgery to reduce the size of the tumor, and then PORT after the surgery to remove straggling cancer cells. Since Jessica’s cancer is so large, chemotherapy will be applied prior to surgery in order to shrink the tumor to a more manageable size.

Associated with any surgery is a lasting pain from the incision, but the type of surgery determines the size of the incision, which will the directly affect the amount of pain as well as the duration. A common solution is prescription pain medication to ease the pain until the effects of the surgery wear off. Another common side affect of pneumectomies is peripheral neuropathy, which is the numbness and pain in the extremities. This is a result of nerve damage due to the lack of oxygen in these regions for a prolonged period of time. In addition, chest tubes need to be inserted during surgery to keep the chest cavity free of all form of fluid that collect following lung surgery. The tubes are connected to a machine that gently sucks the fluid from the chest.13] These tubes are left in place for a few days until the fluid has stopped draining. At this point in time, the patient will begin to feel significantly better, but that is the extent of the recovery since in reality, an entire lung is missing. To compensate the shortness of breath that is often felt deep breathing exercises are recommended and taught during physical therapy to help improve current lung function. Time truly heals all illnesses because over a long period of time, the remaining tissue in the lung will expand, making it easier to breathe. Two and a half years following her surgery, Jessica is cancer free, continues to get regular check-ups, and can still participate in nearly every activity she used to.

** apercu: The ease of a breath is a precious gift that is often taken for granted. **

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^] 11. Bryant A, Veronesi G, Cerfolio R. Section 28: Robotic Surgery: Techniques and Results for Resection of Lung Cancer. In Pass HI, Ball D, Sca gliotti GV, eds. The IASLC Multidisciplinary Approach to Thoracic Oncology. Aurora, CO: IASLC Press, 2014: 395-401.<[]>

^] 12. Brunelli A, Postmus PE. Section 26: Preoperative Functional Evaluation of the Surgical Candidate. In Pass HI, Ball D, Scagliotti GV, eds. The IASLC Multidisciplinary Approach to Thoracic Oncology. Aurora, CO: IASLC Press, 2014: 373-383.

^] 13. Lung Surgery. U.S. National Library of Medicine website. []. Updated June 2, 2014. Accessed March 7, 2016.