Introduction:

Cancer continues to be one of the most feared diseases of the 20th century and has shown an increasing prevalence in the 21st century. This is highly concerning, with approximately one in four individuals facing a lifetime risk of developing cancer and around 14 million cases reported globally each year. Cancer is a disease that begins with genetic and epigenetic alterations occurring in specific cells, some of which can spread and migrate to other tissues. It is a group of diseases that begin when cells in one part of the body grow uncontrollably. Instead of following the body’s natural system of growth, division, and death, these cells divide irregularly, forming masses or tumors that can interfere with normal body functions. Studies in the past decade, including the work by the PCAWG, have shown that cancer generally begins with a small number of about 5 driving mutations in particular genes, including oncogenes and tumor-suppressor genes. Some cancers can spread to other parts of the body, making early detection and treatment crucial. To explain why cancer cells within a tumor are so diverse, scientists have proposed two main models: The first model suggests that random mutations occur in tumor cells during their development. These mutations create different groups of tumor cells with unique traits for growth and survival. Over time, these groups evolve based on natural selection within the tumor. The second model proposes that tumors start from a single cell with two key abilities: self-renewal (making more of itself) and producing specialized cells. These properties are similar to those of normal stem cells, so they are called cancer stem cells (CSCs). In this model, tumors are organized hierarchically: CSCs create rapidly dividing progenitor cells, which don’t self-renew but can produce various terminal (specialized) cells.

What is cervical cancer and how common is it?

Cervical cancer is the most leading cause of cancer deaths in women globally. Cervical cancer is a major health concern for women worldwide, especially in low- and middle-income countries, or even in wealthier nations, underserved communities often face higher rates of cervical cancer and worse outcomes. Cervical cancer rates vary across the world, being highest in Eastern Africa (including Zimbabwe) and lowest in Western Asia. It is the second most common type of cancer in women in the South East Asia region and a major cause of cancer deaths among women of low and middle income countries (LMICs) like Nepal. Cervical cancer is the third most common cancer in women in the United States, preceded by skin cancer and breast cancer as the first and second most common causes, respectively. In developing countries, cervical cancer is often the most common cancer in women and may constitute up to 25% of all female cancers. Cervical cancer is preceded only by breast cancer as the most common cause of death from cancer in women worldwide. Cervical cancer is divided into two types: cervical squamous cell carcinomas (CSCCs), which are derived from squamous cells, and cervical adenoma, arising from the glandular cells of the cervix. The CSCCs account for more than 80% of cervical cancers with higher morbidity and mortality. It is developed through a defined series of preneoplastic lesions to increase cellular dysplasia, CIN, and to squamous cell carcinoma. Despite the low or high risk, all the HPVs infect the epithelial cells particularly keratinocytes and immortalize them.

Biology of Cervical Cancer:

The association between certain oncogenic high-risk strains of HPV and cervical cancer has been well established. This link between genital HPV infections and cervical cancer was first demonstrated in the early 1980s by Harold zur Hausen, a German virologist.

Human papillomavirus (HPV) begins its replication cycle in the basal layer of the skin's epithelium, known as the stratum germinativum. This layer contains actively dividing cells. For HPV to infect these cells, the skin typically needs to experience minor abrasions or microtrauma, which allow the virus to reach the basal layer. Different HPV strains use various strategies to attach to host cells. For instance, HPV-16 and HPV-33 rely on cell surface heparan sulfate, a sugar molecule, to bind, while α6-integrin has been suggested as a receptor for HPV-6. However, this receptor is not essential for HPV-11 or HPV-33. Other proteins or molecules may also help stabilize the virus's attachment, but the specific factors required for HPV to enter the cell remain unknown. Once inside the basal cells, HPV adopts a largely dormant state. It replicates its DNA slowly, producing only a low number of copies and integrating into the cell’s natural DNA replication cycle. This low-level replication allows the virus to remain inconspicuous in the host’s cells without triggering a strong immune response. As the infected basal cells differentiate and move toward the surface of the skin, the virus's behavior changes dramatically. In the upper layers of the epithelium, called the suprabasal layers, the virus switches to a rapid replication mode known as rolling-circle replication. Here, it amplifies its DNA significantly, produces capsid proteins to form the protective shell of new viral particles, and assembles these particles. By the time the infected cells reach the surface of the skin, they are filled with newly formed viruses, ready to spread to new hosts. This process highlights the intricate and efficient life cycle of HPV, as well as the critical steps where scientists can target treatments or preventive measures, such as vaccines, to disrupt its replication and spread. 

Common Symptoms of Cervical Cancer:

Early on, cervical cancer usually doesn’t have symptoms, making it hard to detect. Symptoms usually begin after the cancer has spread.

When symptoms of early-stage cervical cancer do occur, they may include

• vaginal bleeding after sex

• vaginal bleeding after menopause

• vaginal bleeding between periods or periods that are heavier or longer than normal

• vaginal discharge that is watery and has a strong odor or that contains blood

• pelvic pain or pain during sex

  
  

Symptoms of advanced cervical cancer (cancer has spread beyond the cervix to other parts of the body) may include the symptoms of early-stage cervical cancer and

• difficult or painful bowel movements or bleeding from the rectum when having a bowel movement

• difficult or painful urination or blood in the urine

• dull backache

• swelling of the legs

• pain in the abdomen

• feeling tired

  
  

These symptoms may be caused by many conditions other than cervical cancer. The only way to know is to see a health professional. If it is cervical cancer, ignoring symptoms can delay treatment and make it less effective.

Available treatment:

Cervical cancer treatment varies based on the cancer's stage:

Stage 0 (Carcinoma in Situ): Abnormal cells are present but haven't invaded deeper tissues. Treatment options include laser vaporization, local excision, or intracavitary radiation (brachytherapy). Topical therapies like 5-FU cream or imiquimod may also be used.

Stage I: Cancer is confined to the cervix. Treatment may involve surgery such as conization or hysterectomy or radiation combined with chemotherapy.

Stage II: Cancer has spread beyond the cervix but not to the pelvic wall or lower vagina. Treatment typically includes radiation therapy combined with chemotherapy.

Stage III: Cancer extends to the pelvic wall and/or the lower part of the vagina and may cause kidney issues. The standard treatment is concurrent chemoradiation which is radiation therapy combined with chemotherapy.

Stage IV: Cancer has spread to nearby organs (Stage IVA) or distant organs (Stage IVB). Treatment options include chemotherapy alone or with pembrolizumab if the tumor is PD-L1 positive. If chemotherapy is given alone, it's usually a combination of cisplatin or carboplatin with paclitaxel and bevacizumab. If chemotherapy is given with pembrolizumab, it's usually cisplatin or carboplatin with paclitaxel, with or without bevacizumab.

It's essential to consult with healthcare professionals to determine the most appropriate treatment plan based on individual circumstances.

Conclusion:

Cervical cancer is largely preventable and treatable with appropriate health measures. Early detection and treatment of precancerous lesions can prevent progression to cervical cancer. Identification of precancerous lesions has been primarily by cytologic screening of cervical cells. Understanding how HPV contributes to cervical cancer, being aware of risk factors, and recognizing symptoms are key to empowerment. Vaccination, regular screenings, and practicing safe sex can effectively reduce the risk of developing cervical cancer. Staying informed and proactive about your health can lead to better outcomes and enhance the overall well-being of women everywhere. If you have any questions or concerns about cervical cancer, consult with a healthcare professional for accurate guidance and support.