**1. Introduction**

Ovarian cancer is the most lethal of all gynecologic malignancies. It accounts for a fifth of all cancer‐related deaths among women in the United States of America. It is estimated that 22,280 women will be diagnosed with ovarian cancer and 14,240 will die of the disease in the United States in 2016 [1]. This makes it a relatively less prevalent but a very deadly form of cancer. About

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90% of all ovarian cancers are epithelial in origin, which are classified into high‐grade serous, low‐grade serous, endometrioid, clear cell, and mucinous subtypes [2]. Of these, the high‐ grade serous ovarian cancer (HGSOC) is the most common subtype and is characterized by mutations in p53 and genomic instability [3]. A detailed characterization of the HGSOC tumors was done by The Cancer Genome Atlas Network, which mapped the deregulated pathways involved. In the past, these tumors were thought to originate from the ovarian surface epithe‐ lium.However,morerecentlyresearchershavestartedtobelievethattheymayactuallyoriginate from the fallopian tube fimbriae based on the analysis of prophylactic salpingo‐oophorecto‐ my samples [4].

One of the reasons for the poor prognosis of ovarian cancer is the fact that most patients are diagnosed late [5]. It is a highly metastatic cancer and more than 70% of ovarian cancer patients are diagnosed with metastasis [6]. As the tumor grows within the peritoneal cavity, the symptoms produced are abdominal pain or bloating and may be confused with other bowel diseases like irritable bowel syndrome [7, 8]. Ovarian cancer is often called 'the silent cancer' or 'the disease that whispers' because of these diffuse symptoms. The presence of high levels of cancer antigen 125 (CA‐125) is used as a diagnostic marker of disease progression. Pelvic ultrasound, MRI, and CT scanning is also used to determine the extent of the disease. Patients undergo a 'debulking' surgery usually conducted by a gynecologic oncologist with a goal to remove as much of the tumor masses as possible from the abdomen [9]. In addition, the tumors are also staged histopathologically as per the International Federation of Gynecology and Obstetrics (FIGO) guidelines (**Table 1**) [10]. Minimal residual disease after the surgery is considered one of the strongest prognostic factors and is highly desirable [11]. The surgery is followed by adjuvant cytotoxic chemotherapy consisting of a combination of carboplatin and paclitaxel. The response to therapy is determined by measuring the serum CA‐125 levels and by imaging techniques [2]. If the disease relapses within 6 months, it is considered chemore‐ sistant and if relapse occurs after 12 months, it is considered chemosensitive. While a majority of the patients respond well initially to chemotherapy, most eventually end up developing chemoresistance [12]. Bowel obstruction by the metastatic tumors is the predominant cause of ovarian cancer‐related mortality [13]. Since many parts of the bowel get affected, it becomes extremely difficult to surgically treat this condition. In addition, extensive ascites is a cause for major discomfort. Palliative measures such as control of nausea, abdominal pain, draining ascites, and modified diet are typically resorted to [2]. Since most of the ovarian cancer patients are diagnosed with advanced disease, in effect, it is metastasis that is being treated [6]. Therefore, a greater understanding of the process and regulation of ovarian cancer metastasis is essential.

Ovarian cancer predominantly metastasizes within the peritoneal cavity and through the pelvic lymph nodes (**Figure 1**) [14, 15]. However, recent evidence suggests the possibility of hematogenous metastasis of ovarian cancer (**Figure 1**) [16]. This chapter will discuss the steps involved in the unique metastatic dissemination of ovarian cancer and will highlight what is known about the regulation of the steps involved.

Stage I: The disease limited to ovaries only


90% of all ovarian cancers are epithelial in origin, which are classified into high‐grade serous, low‐grade serous, endometrioid, clear cell, and mucinous subtypes [2]. Of these, the high‐ grade serous ovarian cancer (HGSOC) is the most common subtype and is characterized by mutations in p53 and genomic instability [3]. A detailed characterization of the HGSOC tumors was done by The Cancer Genome Atlas Network, which mapped the deregulated pathways involved. In the past, these tumors were thought to originate from the ovarian surface epithe‐ lium.However,morerecentlyresearchershavestartedtobelievethattheymayactuallyoriginate from the fallopian tube fimbriae based on the analysis of prophylactic salpingo‐oophorecto‐

One of the reasons for the poor prognosis of ovarian cancer is the fact that most patients are diagnosed late [5]. It is a highly metastatic cancer and more than 70% of ovarian cancer patients are diagnosed with metastasis [6]. As the tumor grows within the peritoneal cavity, the symptoms produced are abdominal pain or bloating and may be confused with other bowel diseases like irritable bowel syndrome [7, 8]. Ovarian cancer is often called 'the silent cancer' or 'the disease that whispers' because of these diffuse symptoms. The presence of high levels of cancer antigen 125 (CA‐125) is used as a diagnostic marker of disease progression. Pelvic ultrasound, MRI, and CT scanning is also used to determine the extent of the disease. Patients undergo a 'debulking' surgery usually conducted by a gynecologic oncologist with a goal to remove as much of the tumor masses as possible from the abdomen [9]. In addition, the tumors are also staged histopathologically as per the International Federation of Gynecology and Obstetrics (FIGO) guidelines (**Table 1**) [10]. Minimal residual disease after the surgery is considered one of the strongest prognostic factors and is highly desirable [11]. The surgery is followed by adjuvant cytotoxic chemotherapy consisting of a combination of carboplatin and paclitaxel. The response to therapy is determined by measuring the serum CA‐125 levels and by imaging techniques [2]. If the disease relapses within 6 months, it is considered chemore‐ sistant and if relapse occurs after 12 months, it is considered chemosensitive. While a majority of the patients respond well initially to chemotherapy, most eventually end up developing chemoresistance [12]. Bowel obstruction by the metastatic tumors is the predominant cause of ovarian cancer‐related mortality [13]. Since many parts of the bowel get affected, it becomes extremely difficult to surgically treat this condition. In addition, extensive ascites is a cause for major discomfort. Palliative measures such as control of nausea, abdominal pain, draining ascites, and modified diet are typically resorted to [2]. Since most of the ovarian cancer patients are diagnosed with advanced disease, in effect, it is metastasis that is being treated [6]. Therefore, a greater understanding of the process and regulation of ovarian cancer metastasis

Ovarian cancer predominantly metastasizes within the peritoneal cavity and through the pelvic lymph nodes (**Figure 1**) [14, 15]. However, recent evidence suggests the possibility of hematogenous metastasis of ovarian cancer (**Figure 1**) [16]. This chapter will discuss the steps involved in the unique metastatic dissemination of ovarian cancer and will highlight what is

my samples [4].

44 Tumor Metastasis

is essential.

known about the regulation of the steps involved.

 • Ic: Tumor on the surface of one or both ovaries/fallopian tubes with ruptured capsule and cancer cells present in peritoneal washings

Stage II: Tumors spread to the pelvis but limited to below the pelvic brim


Stage III: Tumors have spread to the abdomen beyond the pelvis or has metastasized to the lymph nodes or both


Stage IV: Distant metastases: pleural effusions contain cancer cells and metastasis to the liver and spleen parenchyma

**Table 1.** International Federation of Gynecology and Obstetrics staging of ovarian cancer [10].

**Figure 1.** Mechanisms of ovarian cancer metastasis: Transcoelomic dissemination. (1) The cancer cells loose cell–cell contact and exfoliate into the peritoneal cavity. (2) They float in the peritoneal fluid and are carried all over the perito‐ neal cavity. (3) Attachment to the peritoneal organs like the omentum. (4) Formation of the metastatic tumor. Hema‐ togenous metastasis. (A) Invasion and intravasation. (B) Transport of circulating cancer cells through the blood vessels. (C) Extravasation from the omental capillaries. (D) Formation of the metastatic tumor in the omentum.
