Lung Cancer 肺癌 (Reading & Sharing)

Lung Cancer is the number one cause of cancer related deaths which is at 22%. Lung Cancer is the most common type of cancer in the world as evidenced by 46,403 new cases diagnosed in the United Kingdom in 2014 as per Jones & Baldwin (2018). Incidence of Lung Caner had shifted from a marked decline in the male population to an increased incidence in the female populace. There is also an improved survival rate of Lung Cancer among patients who have been diagnosed of the disease at different stages from 24.5% to 36.7% in 1995. This one-year survival rate has been attributed to the advancements in diagnosis and treatment (Gavin &Baldwin,2018).

The pathophysiology of Lung Cancer is described in the diagram below (Braun et al., 2017) where 3 toxins predispose the individual to DNA damage that induced mutation then eventually led to lung cancer.

Interestingly, a century ago, the first connection to lung cancer was described by Harting and Hesse. They found high levels of radon gas in the Schnneeburg mines of Germany and the etiological connection between exposure to radioactive gases and lung cancer was conceived (Miller, Y.E., 2005).  Tobacco has been smoked for hundreds of years, but it wasn’t until the industrial revolution, that machine made cigarettes were retailed en masse with an exponential increase in exposure to inhaled tobacco products in humans. It is important to realize that there is a significant time-delay between exposure to tobacco products and the onset of lung cancer, easily 20-25 years. And so, not until the 1940’s did a study, again in Germany, implicate tobacco smoke as a causative factor in lung cancer (Miller, Y.E., 2005).

The current consensus within the scientific and medical communities is that the overall etiology of lung cancer is the following:

• Cigarette smoking is the leading cause of lung cancer. (85-90% of lung cancers)  Of note, the duration of smoking, the intensity (packs per day), and the depth of inhalation all pose an increased risk to the patient.
  • In addition, with cigars and pipes, the carcinogenic particles are large and stay in the posterior pharynx and upper airways causing laryngeal and tonsillar cancers instead of lung cancer.
  • Second-hand smoke is responsible for approximately 20% of cases.
• Environmental risk factors include exposure to asbestos, tar and soot and indoor radon-222. Of note, concomitant smoking multiplies the cancer risk rather than being additive.
• Genetics: There is a genetic susceptibility noted when first-degree relatives have been diagnosed with lung cancer. (J Natl Cancer Institute, 2004)

All three of the above provide the first step in the pathogenesis of lung cancer, a carcinogenic-inducing event.  The second step is a period of a promotion and progression process. Tobacco smoking contributes to both the initiation and the promotion of carcinogenesis (N England J of Med., 2008). Smoking causes a “field effect” on the lung tissue epithelium, providing an opportunity for mutation and transformation. Continued exposure to tobacco carcinogens cause damage to the cellular DNA and the mutation of three genotypes listed below:

• RAS gene ~ encodes proteins with a critical roll in cell signaling. When cells are mutated they grow uncontrollably and evade death.
• P53 gene ~ a tumor suppressor. When mutated allows tumor cells to accumulate.
• Rb gene ~ sends out instructions to make the protein pRB which suppresses tumor cells. (Lowy, D.R., 2013)
• The above sequence of events provides the perfect storm, over 20-25 years, to seed the proliferation of lung cancer.

There are 2 major types of Lung Cancer which are:

1. Non-Small Lung Cancer which includes:
   • Adenocarcinoma 腺癌 which are found in the peripheral bronchiolar and alveolar lung tissue leading to pleural fibrosis and adhesions
   • Squamous cell carcinoma 鳞状细胞癌 which affects the bronchial epithelium (smoking) that leads to metaplasia , dysplasia and carcinoma in situ and invasive tumor
   • Large cell carcinoma 大细胞癌 which shows a  high in anaplasia which is neither adenocarcinoma nor squamous cell carcinoma
2. Small Cell Carcinoma 小细胞癌 is highly malignant epithelial tumor that grows and metastasize rapidly. This is highly linked with smoking.

Clinical manifestations of Lung Cancer include: persistent cough, bloody sputum, chest pain, shortness of breath. Other signs and symptoms are systemic which are hormonal, neurologic, hematologic and chemical disturbances in the body which are otherwise termed as “Paraneoplastic syndrome” 副肿瘤综合症.

See the table below for the Diagnostic Criteria and its purpose (Eckman et al,2013)

Chest x-ray	Shows tumor size and location before S/S appear
Sputum analysis	80% reliable test for Lung Cancer
Bronchoscopy with washings and cytology	May reveal the tumor site; bronchoscopy washings provide specimens for cytologic and histologic study.
Needle Biopsy	Identify peripheral tumors & confirms 80% of the diagnosis of Lung Cancer
Tissue biopsy of metastatic sites	Assess the extent and stage of the Lung Cancer and determine the prognosis and treatment.
Thoracentesis	allows chemical and cytologic examination of pleural fluid.
CT scan	Evaluate mediastinal and hilar lymph node involvement and the extent of Lung Cancer.
Bone, Liver, Brain and Gallium Scans	Detection of Metastasis to the major organs.

Treatment options for Lung Cancer are as follows (Duka et al 2017) (Eckman et al, 2013):

1. Pain Management is recommended for Lung Neoplasm invading the chest wall , which are incurable therefore pain control is the only treatment.
2. Surgery may involve partial lung removal through wedge resection, segmental resection, Lobectomy or total lung removal. Complete surgical resection is the only chance for a cure, but fewer than 25% of patients have positive outcomes.
3. Radiation is used to decrease the size of the tumor prior to surgical debulking. It is useful for stages 1-3 Lung Cancer.
4. Chemotherapy has a dramatic but temporary 7 to 24 months relief for small-cell carcinoma. Drug combinations include cyclophosphamide, doxorubicin, and vincristine; cyclophosphamide, doxorubicin, vincristine, and etoposide; and etoposide, cisplatin, cyclophosphamide, and doxorubicin. Unfortunately, patients usually relapse in 7 to 14 months.
5. Gefitinib 吉非替尼, a drug that was approved for advanced non-small-cell lung cancer blocks growth factor receptor activity. This is an alternative for chemotherapeutic agents if they fail.

Lung cancer has a very poor prognosis. The cellular morphology predicts not only the prognosis but often the treatment plan as well.  The overall 5-year survival rate for lung cancer is 16%.

• NSCLC (Non-Small Lung Cancer)~~ The 5-year survival rate is 48%. Surgical resection of the tumor with clean margins is the first choice, if the patient is medically fit to withstand the operation. This may be a cure. Yet, chemotherapy and radiation may be added to the regime to optimize therapy.
• SCLC (Small Lung Cancer)~~ Patients with this cancer have the poorest prognosis with only a 2-4% survival at 5 years. Most SCLC patients have disseminating disease when diagnosed with a life expectancy of 6 to 9 months with or with out aggressive treatment. This cancer is most often centrally located so surgical resection is not an option.  Chemotherapy is usually the first line treatment with occasional radiation to reduce tumor size and thus symptoms.

One must realize that patients with life threatening illness such as lung cancer, are looking for any and every treatment option available to them and even some that are not. We must care for these patients with utmost expertise, full knowledge of the disease process, compassion and yes, courage. Their life may depend on it.

Community resources to help patients with Lung Cancer are:

1. LUNGevity Foundation – An organization that is dedicated to funding scientific research focused on early detection, more effective treatments, and increasing quality of life and survivorship for people with lung cancer.
2. Inspire –  secure online community where patients and caregivers can connect with others and find support
3. Lung Cancer Alliance – A nonprofit organization committed to innovative research, access to quality care, and growing a network of 500 screening centers to reach more communities.

REFERENCES:

Braun,C.,A.,&Anderson C.,M.(2017) Applied Pathophysiology : a Conceptual Approach      to the Mechanisms of Disease.(3^rd Edition) Baltimore: Wolters Kluwer.

Clic Chest Med. (2002) Retrieved from http://www.ncbi.nim.nih.gov/pubmed/11901021#) 2002 Mar:23(10:65-81, viii.

Community resources retrieved from https://www.livewellwithlungcancer.com/lung-cancer-support.html

Duka, E., Ierardi, A. M., Floridi, C., Terrana, A., Fontana, F., & Carrafiello, G. (2017). The Role of Interventional Oncology in the Management of Lung Cancer. Cardiovascular And Interventional Radiology, 40(2), 153-165. doi:10.1007/s00270-016-1495-y

Eckman, M., & Share, D. (2013). Pathophysiology Made Incredibly Easy!. Philadelphia: LWW.

Jaal, J., Jogi,T., Altraja, A. (2015).  Small Cell Cancer Patient with Profound Hyponatremia and Acute Neurological Symptoms: An effective treatment with Fludrocortisone. Oncological Medicine. http://dx.doi.org/10.1155/2015/286029).

Jones, G. S., & Baldwin, D. R. (2018). Recent advances in the management of lung cancer. Clinical Medicine (London, England), 18(Suppl 2), s41-s46. doi:10.7861/clinmedicine.18-2-s41

Lowy, .R. (2013). Learn about RAS Initiative. NIH/National Cancer Institute.33(3):216-223.

Miller,Y.E., (2005) Pathogenesis of Lung Cancer. Am J of Respi Cell Mol Biology.