Tumor Metastasis - An Overview

Introduction:

A tumor can appear as an abnormal mass of tissue that occurs when cells divide more rapidly and should or do not die in their time. Tumors can vary in size, they can be a tiny nodule or a large mass, depending on the type, and they can appear anywhere in the body. Tumor metastasis consists of a series of individual biological processes that shift tumor cells from the primary neoplasm (abnormal mass of tissue) to a distant location. Tumor cells invade the tissue surrounding the primary tumor, and enter either the lymphatics or the bloodstream, survive and ultimately arrest the circulation, then extravasate into tissue and grow at the new site.

What Are the Types of Tumors?

There are three types of tumors:

• Benign: These types of tumors are not cancerous, and they do not invade the tissue nearby or spread to different parts of the body. Generally, they do not reappear after being removed.

• Premalignant: In these types of tumors, the cells are not cancerous, but they can potentially become malignant in the future.

• Malignant: These types of tumors are cancerous. The cells grow and also spread to other parts of the body.

What Are the Types of Tumor Spread?

There are two types:

1. Direct Spread - It is also known as local invasion. It is the ability to invade and destroy adjacent tissues. Local invasion is further divided into benign tumors and malignant tumors. Benign tumors are encapsulated and circumscribed masses, while malignant tumors are enlarged, well-differentiated, and partially encapsulated. Characteristically malignant tumors can be differentiated from benign tumors by their method of invasion, infiltration, and destruction.

2. Distant Spread - It is also known as metastasis. It is the spread of tumors by invasion in a way that discontinuous secondary tumor masses are formed at the site of lodgment. Benign tumors cannot metastasize, but malignant tumors can, except glioma of the central nervous system and basal cell carcinoma of the skin.

What Are the Routes of Spread in Metastasis?

Metastasis has three types of spread:

• Lymphatic spread.

• Hematogenous spread.

• Spread along body cavities and natural passage.

1. Lymphatic Spread - All types of carcinomas spread through the lymphatic spread. Lymphatic spread is further divided into lymphatic permeation and lymphatic emboli. In lymphatic permeation, the cancer cells invade the walls of lymphatics, and they may grow in lymphatic channels. In lymphatic emboli, a small part of the tumor gets detached from it and carried to the lymph nodes. The emboli then get lodged in the subcapsular sinus and grow.

2. Hematogenous Spread - It is also called blood-borne metastasis and is commonly seen in sarcomas. Blood-borne metastasis commonly occurs in the liver, lungs, brain, bone, kidney, and thyroid.

3. Spread Through Body Cavities and Natural Passage - It is further divided into:

• Transcoelomic Spread - The tumor fragments of the tumor cells break off to be carried in the coelomic fluid. For example, carcinoma of the stomach to both ovaries and carcinoma of the ovary to the peritoneal cavity.

• Epithelium-Lined Surface Spread - It rarely occurs because it is difficult to spread along the epithelium-lined surface as the intact epithelium and mucous coat are resistant to penetration by the tumor cell. For example, the fallopian tube from the endometrium varies.

• Spread via CSF- The spread is through the release of tumor fragments. For example, ependyma and leptomeninges.

• Implantation - The spread is through a surgeon’s scalpel or needle.

What Are the Characteristics of Hematogenous Spread?

1. Systemic Vein - The systemic vein drains blood from the limbs, head, neck, and pelvis into the lungs.

2. Portal Vein - The portal vein drains blood from the bowel, spleen, and pancreas into the liver.

3. Pulmonary Vein - The blood in the pulmonary vein carrying cancer cells from the lungs reaches the left side of the heart and flows in the systemic circulation from secondary mass in other parts of the body.

4. Arterial Spread - It occurs rarely. The tumor cells pass through the pulmonary capillary bed or pulmonary arterial branches. For example, cancer cells in the kidney, adrenal, bones, limbs, and uterus drained by the systemic vein spread to the pulmonary artery to the lungs.

What Are the Characteristics of Lymphatic Spread?

1. Regional Nodal Metastasis - In this type, the tumor drains to regional lymph nodes. For example, carcinoma breast to axillary lymph node and carcinoma thyroid to the lateral cervical lymph node.

2. Skip Metastasis - It is the enlargement of distant lymph nodes because of obliteration or obstruction of lymphatics by inflammation or radiation.

3. Retrograde Metastasis - It is due to the obstruction of lymphatics by tumor cells, and lymph flow is disturbed. The tumor cell spreads against the flow of lymph nodes. For example, carcinoma prostate spreads to the supraclavicular lymph node.

4. Virchow’s Lymph Node - It is the enlargement of the supraclavicular lymph nodes when cancer has spread to the stomach, colon, or gallbladder.

What Is the Pathophysiology of Tumor Metastasis?

Tumor metastasis is a type of representation of tumor malignancy and one of the causes of tumor-related death. The malignant nature of tumor metastasis is primarily related to the malignant degree of the primary tumor. Still, one of the common factors is that all metastases need to go through a cascade called “invasion-metastasis cascade.”

Tumor metastasis begins when the tumor cells become invasive and lose their ability to adhere to the surrounding matrix, including the basement membrane and extracellular matrix. Tumor cells migrate out of the primary tumor and invade surrounding tissues.

Afterward, disseminated tumor cells penetrate blood vessels or lymph vessels into the circulation and respond to different types of resistance conditions like shear force, anoikis, and immune surveillance.

Only a small proportion of tumor cells can survive in harsh circulation conditions. After successfully entering the secondary site, tumor cells attach to the endothelium of the target organ and exudate and migrate into the organ parenchyma, which is the “pre-metastatic niche.” They either enter a long-term dormant state as a single cell or enter micrometastasis as multiple cells and finally start to grow continuously to form clinical metastases.

At the beginning of the whole metastasis process, the essential thing is that a group of invasive and plastic tumor cells are in the cancer nest, referred to as metastasis-initiating cells. Cancer stem cells have been proven to have the above characteristics and play an important role in tumor metastasis.

In addition to the role of the tumor itself, numerous factors, such as genetic ablation, immune escape, abnormal epigenetic modifications, and changes in the growth environment, induce metastasis.

What Is Tumor-To-Tumor Metastasis?

A tumor-to-tumor metastasis also called a collision tumor, is a rare type of metastatic process in which a primary malignant tumor metastasizes to another tumor. The most common recipient of these types of metastases is meningiomas, with the most common donor tumors being breast and lung cancers. However, many different donors like renal cell carcinoma, prostate cancer, and recipient tumors like renal cell carcinoma, thymoma, and uterine leiomyoma have been reported. The clinical presentation and radiologic features are highly variable. The treatment involves tumor resection.

Conclusion:

Metastasis research has entered a stage of remarkable progress. Over the past years, the comprehension of the pathways that narrate the invasion-metastasis cascade has evolved to a detailed molecular circuitry diagram with clear central control nodes. Accordingly, it can be predicted that metastatic behavior will be understood through numerous organizing principles.