Premalignancies

ALSO KNOWN AS: Premalignant lesions, dysplasia, neoplasia, neoplasms, dysplastic syndromes, neoplastic syndromes

RELATED CONDITIONS: Myelodysplastic syndromes in blood and bone marrow

DEFINITION: Premalignancies are caused by the abnormal maturation of cells in a particular tissue. Premalignant cells are often immature and undifferentiated. An area with abnormal cells of this kind is called a premalignant lesion or a neoplasm. The condition is called dysplasia, when the abnormal cells are limited to the tissue of origin. Myelodysplastic syndromes arise when abnormal, immature stem cells, called blasts, are present in the bone marrow or blood. In these syndromes, the abnormal blast cells crowd out the normal mature cells and platelets, resulting in anemia and a loss of immune function.

Risk factors: General risk factors for premalignancies include exposure to environmental pollutants and tobacco smoke, older age, and a family history of certain cancers (essentially, the same risk factors as for cancer development). Premalignancies for certain types of cancers have specific risk factors.

Epidermal premalignant lesions in actinic keratosis are usually caused by sun damage, and basal cell lesions probably arise because of deoxyribonucleic acid (DNA) damage from ultraviolet radiation.

For colorectal cancer, people with a family history of premalignant lesions or polyps are at greater risk of having polyps and colorectal cancer. Individuals who have had inflammatory bowel disease (ulcerative colitis and Crohn's disease) for more than eight years are also at greater risk of developing premalignant polyps and colorectal cancer.

Risk factors for gastrointestinal premalignant lesions include gastritis caused by infection with the bacterium Helicobacter pylori and gastroesophageal reflux disease (GERD), which can progress to a condition called Barrett's esophagus—the only known premalignant condition for esophageal adenocarcinoma. Risk factors for Barrett's esophagus include being male, White, over fifty, smoking, obesity, and having a history of reflux symptoms lasting over five years.

Risk factors for myelodysplastic syndromes include being a man over sixty, having had prior treatment with chemotherapy or radiation therapy, and being exposed to tobacco smoke, pesticides, mercury, and lead.

Etiology and the disease process: Genetic abnormalities in the cell disrupt its normal maturation process, causing it to become premalignant. The traditional theory is that cancer progresses through a series of steps, from premalignant lesions to carcinoma in situ (localized cancer) and then to invasive carcinoma. Some researchers challenge this theory, arguing that most molecular changes in the cancer transformation process occur in premalignant lesions. For example, genetic analysis of premalignant lesions in mice has shown that gene abnormalities and changes in protein expression in the premalignant cells can be linked to the particular phenotype of the cancer cell (that is, the physical and biochemical characteristics of the cell). One study in mice showed the molecular profiles (genes and proteins) of lesions in different stages of breast cancer had many similarities, suggesting that there may be a limited number of molecular changes associated with tumor progression.

Different cell types give rise to premalignant lesions in varied ways. In skin cancer, basal cell lesions are the most common premalignancy. These premalignant lesions occur in the basal epithelium of the skin, usually the lower trunk and thighs. The premalignancies look like basal epithelium cells surrounded by a fibrous stroma called fibroepithelial premalignant tumors of Pinkus. Research indicates premalignant cells have abnormal cell cycle regulation, most likely initiating their transformation from normal cells. In cancer progression, these abnormal, aggressive basal cells grow until they predominate in the lesion, and the premalignant lesion becomes invasive basal cell epithelioma.

Other premalignant tumors occur in the epidermis. Epidermal premalignant lesions can take the form of Bowen disease, where abnormal cells are present throughout the epidermis and can potentially develop into invasive squamous cell carcinoma. Bowen disease predominantly occurs in the lower limbs and resembles dermatitis or psoriasis with scaly patches. Epidermal premalignant lesions can also be in the form of actinic keratosis, where abnormal cells do not penetrate the entire epidermis and have a small probability (2 to 5 percent) of developing cancer. Sun damage usually causes actinic keratosis.

Gastrointestinal premalignant lesions can arise from gastritis caused by infection with H. pylori. Another condition that can result in premalignancy is gastroesophageal reflux disease, which involves the backflow of stomach acids up the esophagus, causing damage to the squamous epithelial cells lining the esophagus. This tissue damage can progress to Barrett’s esophagus, where normal esophageal squamous epithelial cells are replaced with specialized columnar epithelium containing goblet cells. This condition is often accompanied by dysplasia or metaplasia, and people with Barrett's esophagus have a 0.5 percent risk of developing esophageal cancer (esophageal adenocarcinoma).

The etiology of colorectal cancer is still unclear, but it appears to involve a genetic component, with approximately 25 percent of colorectal cancer patients having a family member with the disease. Other factors, such as diet, the composition of bile acids, and exposure to carcinogens, are being studied. Individuals who have the rare familial adenomatous polyposis (FAP) syndrome, which is a hereditary genetic defect in which people develop hundreds to thousands of colorectal polyps at a young age, are at higher risk for developing colorectal cancer. These individuals account for 1 percent of colorectal cancer cases annually.

Incidence: Incidence varies depending on the cell type from which the premalignancy arises.

Symptoms: Symptoms vary depending on the organ in which the premalignant lesions occur. For example, Bowen's disease predominantly occurs in the lower limbs and resembles dermatitis or psoriasis, with scaly patches. Epidermal premalignant lesions characterize actinic keratosis and can manifest as single or multiple scaly papules.

Premalignant lesions called polyps are often discovered in the colon during a routine colonoscopy. Other signs of polyps include blood in the stool. Removal of these premalignant polyps considerably decreases the probability of developing cancer.

Symptoms of myelodysplastic syndromes include shortness of breath (also known as dyspnea), fatigue, pale skin, bruising or bleeding readily, petechiae (pinpoint spots under the skin due to bleeding), fever, and frequent infections.

Screening and diagnosis: Routine skin examinations can detect premalignant skin lesions, which can be excised before developing into skin cancer. The ABCD and seven-point checklists provide guidelines for classifying lesions according to their risk of developing malignant melanoma. The ABCD checklist has four criteria—A for asymmetry (if the lesion is bisected, asymmetry of the two halves predisposes for malignancy), B for border irregularity (an uneven border is a risk factor), C for color variation (more than one color is a risk factor), and D for diameter (diameter greater than 6 millimeters (mm) is a warning sign). The seven-point checklist for malignant melanoma includes three major signs (change in size, shape, or color) and four minor signs (inflammation, crusting or bleeding, sensory change, and a diameter over seven mm). In addition to the criteria in these checklists, the lesion's shape may indicate malignancy. A more geometrically angular shape may be associated with a higher risk of malignant melanoma.

A range of screening and diagnostic tests help detect gastrointestinal lesions. Premalignancies associated with Barrett's esophagus can be detected using endoscopic screening. Patients who are found to have Barrett's esophagus and dysplasia can undergo treatment to prevent progression to esophageal cancer. Premalignant lesions (called polyps) are often discovered during a colonoscopy for colorectal cancer screening. They can also be found via sigmoidoscopy, in which a flexible tube with a camera is inserted into the rectum and lower colon. A small tissue sample can be taken at the same time. Another method of discovering polyps is the fecal occult blood test, which looks for blood in the stool. If blood is present, a colonoscopy is performed. Other methods include computed tomographic colonography (CTC or virtual colonography), which involves scanning the colon by CT to produce a three-dimensional image that can be analyzed for polyps, and a double-contrast barium enema, in which the patient ingests barium and X-rays are taken to look at the colon and rectum. Double-contrast barium enema testing is not as sensitive as a colonoscopy and is usually not used.

Treatment and therapy: Premalignant Skin lesions can be excised if they are basal cell-derived, or they can be subjected to cryotherapy, excision, curettage, or topical 5-fluorouracil application if they are of the squamous cell carcinoma type.

Carbon dioxide laser surgery can treat premalignant and malignant oral lesions. This non-invasive method is associated with less pain, bleeding, and edema and lower recurrence rates and risk of infection. Patients who have Barrett's esophagus and dysplasia can undergo ablative therapy, which includes acid-reducing drugs (including aspirin), proton pump inhibitors, antireflux surgery, or esophagectomy for more severe conditions.

For colorectal premalignancies, surgery removes infected parts of the colon. For patients with familial adenomatous polyposis (FAP), sometimes the entire colon is removed (colectomy) to reduce the risk of cancer progression. Drugs such as the COX-2 inhibitors, including celecoxib (Celebrex) and sulindac (Clinoril), have the potential to reduce colorectal cancer risk and could be appropriate for some people.

Prognosis, prevention, and outcomes: Detecting and treating premalignancy creates a much better prognosis than not detecting these tumors until they have become malignant or metastasized. The timely treatment of premalignant lesions can allow patients to live disease-free for a long period.

To help prevent premalignant skin lesions, people should avoid excessive ultraviolet light exposure by using sunscreen and protective clothing, staying out of the sun during peak ultraviolet-B radiation hours, and avoiding suntanning.

A diet high in fiber and low in fat may aid in the prevention of colorectal cancer. Individuals at risk for this type of cancer because of family history or long-standing inflammatory bowel disease should regularly undergo colonoscopy to check for polyps, which helps prevent malignancies from developing. Other gastrointestinal premalignancies can be prevented by early infection treatment with H. pylori and taking steps to prevent or alleviate gastroesophageal reflux.

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