Choriocarcinoma

Choriocarcinoma also called chorioblastoma, chorioepithelioma or chorionic carcinoma is a rare aggressive and fast-growing cancer that develops from trophoblast cells (syncytiotrophoblasts and cytotrophoblasts cells that help an embryo attach to the uterus and help form the placenta) ¹, ², ³. The placenta is an organ that allows the mother to share nutrients with her fetus. Almost all choriocarcinomas form in a woman’s uterus (womb) after fertilization of an egg by a sperm. Choriocarcinoma primarily occurs in women of reproductive age and is rarely observed in the postmenopausal women ⁴.

Choriocarcinoma can be classified into two main categories ⁵, ⁶, ⁷, ⁸, ⁹:

1. Gestational choriocarcinoma. When choriocarcinoma is associated with pregnancy, it is often considered part of the spectrum of gestational trophoblastic disease; it is then termed gestational choriocarcinoma. Gestational choriocarcinoma originates from the trophoblast of various gestational (pregnancy) events, such as hydatidiform mole, spontaneous abortion, and normal pregnancy. Most cases of choriocarcinoma are intra-uterine and of gestational origin (gestational choriocarcinoma).
2. Non-gestational choriocarcinoma (primary choriocarcinoma or non‐pregnant choriocarcinoma). When choriocarcinoma occurs in the absence of pregnancy, it is termed non-gestational choriocarcinoma and these occur most often in a testis or an ovary. The non-gestational choriocarcinomas are believed to develop from pluripotent germ cells. Non-gestational choriocarcinoma (primary choriocarcinoma) can be further categorized into gonadal choriocarcinoma (testis in males and ovary in females) and extragonadal choriocarcinoma (such as mediastinum and retroperitoneum) based on its origin and primary site ¹⁰, ¹¹. Non-gestational choriocarcinoma of the ovary typically occurs in prepubertal girls and postmenopausal women. Testicular choriocarcinomas are usually present in male patients between ages 15 and 30 ¹². Diagnosing non-gestational uterine choriocarcinoma in children is challenging because of its rarity and nonspecific imaging findings ¹³. Non-gestational choriocarcinoma typically arises in association with reproductive organs:
   • Uterus: Uterine choriocarcinoma (choriocarcinoma of the uterus) ¹⁴
   • Cervix: Primary choriocarcinoma of the uterine cervix ¹⁵
   • Ovary: Choriocarcinoma of the ovary (pure primary ovarian choriocarcinoma) ¹⁶, ¹⁷, ¹⁸
   • Testes: Testicular choriocarcinoma in men
   • Primary occurrence of non-gestational choriocarcinoma outside the reproductive system has been reported but is extremely rare. Such sites include:
     • Brain: Primary intracranial choriocarcinoma
     • Lung: Primary pulmonary choriocarcinoma ¹⁹.
     • Pulmonary arteries: Primary choriocarcinoma of the pulmonary artery ²⁰
     • Stomach: Primary choriocarcinoma of the stomach ²¹, ²²
     • The small intestine: Non-gestational choriocarcinoma in small intestine ²³
     • Pancreas: Primary choriocarcinoma of the pancreas ²¹

It is important to make a distinction between these 2 forms of choriocarcinoma as non-gestational choriocarcinoma (non‐pregnant choriocarcinoma) is very rare and carries a poorer prognosis than gestational choriocarcinoma ²⁴, ²⁵. Unlike the gestational choriocarcinoma, non-gestational choriocarcinoma (non‐pregnant choriocarcinoma) has a poor prognosis in most cases, and most cases have extensive metastases at the time of diagnosis, with a short survival period ²⁴.

Gestational choriocarcinoma is the most common gestational trophoblastic neoplasia. In gestational choriocarcinoma the abnormal fast-growing cancer cells start in the tissue that would normally become the placenta. The placenta is the organ that develops during pregnancy to feed the fetus. It can spread to the muscle layer of the uterus and nearby blood vessels with areas of hemorrhage and necrosis. On imaging, choriocarcinomas appear as vascular solid tumors with cystic, hemorrhagic, and necrotic areas. A significant proportion of choriocarcinoma complications arises from bleeding due to high vascularity in either a primary tumor or its metastases. Columns and sheets of trophoblastic tissue invade normal tissues and spread to distant sites. It may also spread to other parts of the body, such as the lungs, brain, liver, pelvis, vagina, spleen, intestines, and kidney. Most choriocarcinomas have an aneuploid karyotype (abnormal number of chromosomes in the cells), and about three-quarters of them contain a Y chromosome ²⁶. Most follow an hydatidiform mole pregnancy, spontaneous abortion, or ectopic pregnancy; but, about one-quarter of them are preceded by a full-term pregnancy ²⁶. Nearly all gestational trophoblastic diseases that are preceded by nonmolar pregnancies are choriocarcinomas; the rare exceptions generally are placental-site trophoblastic tumors (very rare) ²⁶. Choriocarcinoma increases blood levels of human chorionic gonadotropin (hCG).

Gestational choriocarcinoma is more likely to form in women who have had any of the following ²⁷, ²⁶:

• Molar pregnancy, especially with a complete hydatidiform mole. Choriocarcinoma most often occurs with a complete hydatidiform mole. This is a growth that forms inside a woman’s uterus (womb) at the beginning of a pregnancy. The abnormal tissue from the mole can continue to grow even after attempted removal, and can become cancerous. About one half of all women with a choriocarcinoma had a hydatidiform mole, or molar pregnancy.
• Normal pregnancy, preterm pregnancy or term pregnancy. Choriocarcinoma may also occur shortly after a normal pregnancy, preterm pregnancy or term pregnancy.
• Tubal pregnancy or ectopic pregnancy (the fertilized egg implants in the fallopian tube rather than the uterus).
• Miscarriage or history of abortion. Choriocarcinomas may also occur after an early pregnancy that does not continue (miscarriage).
• Choriocarcinomas may also occur after a genital tumor.

The incidence of choriocarcinoma in Europe and North America is approximately 1 in 20,000 to 1 in 30,000 pregnancies. In Southeast Asia and Japan, the incidence of choriocarcinoma is approximately 9.2 cases per 40,000 pregnancies and 3.3 cases per 40,000 pregnancies respectively ²⁸. In China, the incidence of choriocarcinoma is high approximately 1 case per 2882 pregnancies ²⁹. About 50% of gestational choriocarcinoma arising from molar pregnancies, 25% from previous abortions and ~22% following normal pregnancies ³⁰. Gestational choriocarcinoma grows rapidly and spreads (metastasizes) in the lungs (80%), vagina (30%), brain (10%), liver (10%), kidneys, intestine, pelvis, and vagina ³¹, ³². Approximately 60% to 85% of patients with choriocarcinoma develop lung metastases ³³. However, for patients with lung related symptoms such as coughing up blood (hemoptysis) with or without shortness of breath (dyspnea), choriocarcinoma with lung metastasis is a relatively rare lung cancer diagnosis. In the early stage of choriocarcinoma with lung metastasis, patients usually have no obvious signs or symptoms. Coughing up blood (hemoptysis), shortness of breath (dyspnea), and chest pain may present in severe cases with multiple and larger metastases, and even hemothorax or severe respiratory failure can occur in the most serious cases ²⁸.

Trophoblastic cells have an affinity for blood vessels and therefore the tumors have a tendency to spread (metastasize) via the blood, resulting in early and extensive spread to sites such as the lungs, liver, skin, retroperitoneal lymph nodes, gastrointestinal tract, and central nervous system ³⁴, ³⁵. Choriocarcinoma primarily metastasizes hematogenously ³⁶, ³⁷, ³⁸, ³⁹, ⁴⁰.

Choriocarcinoma metastatic ability is related to its biological characteristics, which are uncontrolled trophoblast stem cells and abnormal hyperplasia ²⁸. These characteristics cause the loss of the original villi structure, vascular damage owing to invasion capability, the continuous infiltration and dissolution of endometrial stromal cells, and myometrium invasion, which leads to early blood vessel invasion and blood borne metastasis ²⁸. Choriocarcinoma cancer embolus sheds in vein reflux to the right side of the heart and then into the pulmonary artery, which embolizes small pulmonary artery branches ²⁸. Then, the choriocarcinoma cell proliferates and invades the blood vessel wall, destroys lung tissue, and causes pulmonary metastases when mixed with hematoma ²⁸. Afterward, the choriocarcinoma cell invades through the small pulmonary vein, returns to the left side of the heart, and transfers through systemic artery to the brain, liver, and every organ of the body. The lung is often the first site of hematogenous metastasis, and other organs are rarely affected ⁴¹. In pathology, the center of lung metastatic lesions often shows clots and necrotic tissue surrounded by two layers of malignant trophoblasts ²⁸. The inner layer is a mononuclear trophoblastic cell layer. Slight nuclear atypia and atypical mitotic figures may be observed, which are irrelevant to the prognosis. The outer layer is the multinucleated syncytiotrophoblast layer, which characteristically lacks chorionic villi and chorionic gonadal hormone promotion, and is positive for human chorionic gonadotropin (hCG) staining ²⁸. Compressed by transmitted lesions, the lung tissue around the lesion often collapse, and bleed, swollen, and inflammatory cell infiltration can be observed ²⁸. Immunohistochemistry is helpful for the differential diagnosis. In syncytiotrophoblast, human chorionic gonadotropin (hCG) is strongly positive, and human placental lactogen (HPL) is weakly positive ⁴². Chorioepithelioma human chorionic gonadotropin (hCG), inhibin and human leukocyte antigen-G, and melanoma cell adhesion molecule (Mel-CAM) are often positive ⁴³. These immunohistochemical tests may play an important role in the differential diagnosis of the disease.

Choriocarcinoma is an aggressive and fast-growing cancer and metastases are frequent, with the lungs being a common site of metastasis. Despite its aggressiveness, chemotherapy is the main treatment option for gestational choriocarcinoma, while non-gestational choriocarcinoma is treated with surgery combined with chemotherapy as determined by disease stage ⁴⁴, ⁴⁵. Chemotherapeutic resistance has been the most important cause of treatment failure in choriocarcinoma ⁴⁶. Since choriocarcinoma is associated with a high incidence of spread of cancer cells from the place where they first formed to another part of the body (metastasis) and recurrence, the recommended management of primary choriocarcinoma is often complete surgical resection followed by chemotherapy.

The management and treatment of choriocarcinoma are based on recommendations set forth by the International Federation of Gynecology and Obstetrics (FIGO). According to the FIGO, gestational trophoblastic neoplasia (choriocarcinoma) can be divided into two groups: the low-risk group and the high-risk group. For low-risk groups, single-agent chemotherapy regimens can be used because the side effects are relatively minor. There are two main first-line chemotherapy options for the treatment of low-risk groups including actinomycin D and methotrexate. Comparing these regimens, Cochrane Review 2012 ⁴⁷ have reported that actinomycin D was associated with significantly higher rates of primary cure than methotrexate (five studies, 513 women). Multidrug therapy is the gold standard first-line therapy in metastatic forms of high-risk choriocarcinoma. Currently, EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine) and fluorouracil-based combination regimens are highly recommended for the treatment of high-risk groups. For the past two decades, the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine) regimen has become the most widely accepted therapeutic regimen, positive responses to which have been obtained in 80% to 85% of patients, with an overall survival rate of approximately 100% ⁴⁸.

In contrast to gestational choriocarcinoma, most cases of non-gestational choriocarcinoma are discovered in the advanced stage, and the cancer tends to progress rapidly and be widely metastatic in the short term. Non-gestational choriocarcinoma has been associated with resistance to chemotherapy and a reduced survival rate ⁴⁹, ⁵⁰. Currently, there is no treatment standard for non-gestational choriocarcinoma, but instead, treatment generally follows that of gestational choriocarcinoma ⁵¹. Surgery is an important means of treating for non-gestational choriocarcinoma because the tumor is exclusively derived from the individual in whom arose. However, considering the large tumor sizes, wide invasion sites and easy blood metastasis of non-gestational choriocarcinoma, radical surgery is usually performed after chemotherapy has reduced blood beta-hCG to normal or near-normal levels to relieve the tumor burden, which can shorten the course of treatment and reduce the recurrence rate. For patients with non-gestational choriocarcinoma especially those with other germ cell tumors, BEP (bleomycin, etoposide, and cisplatin) or PVB (cisplatin, vincristine, and bleomycin) regimens are often used. A more effective combination of chemotherapy should be taken into account and applied to the treatment of extragenital non-gestational choriocarcinoma while simultaneously considering the characteristics of the origin site and the components of other tumors. EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine), VIP (etoposide, ifosfamide, and cisplatin), or 5-Fu+KSM+ etoposide regimens may be selected.

Figure 1. Choriocarcinoma

Footnote: Endometrial biopsy showing choriocarcinoma with decidual reaction

[Source ⁵² ]

Figure 2. Testicular choriocarcinoma

Footnotes: H&E stain photo of choriocarcinoma showing both of the components necessary for the diagnosis – cytotrophoblasts and syncytiotrophoblasts. The syncytiotrophoblasts are multinucleated and have a dark staining cytoplasm. The cytotrophoblasts are mononuclear and have a pale staining cytoplasm ⁵³.

[Source ⁵⁴ ]

Figure 3. Choriocarcinoma pathology

Footnote: Immunohistochemistry analysis of endometrial biopsy specimen. Cytotrophoblasts and syncytiotrophoblasts were stained with beta-human chorionic gonadotrophin (beta-hCG) antibody.

[Source ⁵² ]

Gestational trophoblastic disease

Gestational trophoblastic disease is a group of rare non-cancerous (benign) and cancerous (malignant) growths in which abnormal trophoblast cells grow inside the uterus after fertilization of an egg by a sperm ⁵⁵, ⁵⁶, ⁵⁷, ⁵⁸, ²⁷, ²⁶. In gestational trophoblastic disease, a tumor develops inside the uterus from tissue that forms after fertilization (the joining of sperm and egg) ²⁷, ²⁶. This tissue is made of trophoblast cells and normally surrounds the fertilized egg in the uterus. Trophoblast cells help connect the fertilized egg to the wall of the uterus and form part of the placenta (the organ that passes nutrients from the mother to the fetus). Sometimes there is a problem with the fertilized egg and trophoblast cells. Instead of a healthy fetus developing, a tumor forms. Until there are signs or symptoms of the tumor, the pregnancy will seem like a normal pregnancy ²⁷, ²⁶.

Most gestational trophoblastic disease is not cancer (benign) and does not spread, but some types become cancer (malignant) and spread to nearby tissues or distant parts of the body ²⁷, ²⁶.

Gestational trophoblastic disease is a general term that includes different types of disease ²⁷, ²⁶:

• Hydatidiform Moles also called molar pregnancy. A slow-growing tumor that develops from trophoblastic cells (cells that help an embryo attach to the uterus and help form the placenta) after fertilization of an egg by a sperm. A hydatidiform mole contains many cysts (sacs of fluid). It is usually benign (not cancer) but it may spread to nearby tissues (invasive mole). It may also become a malignant tumor called choriocarcinoma. Hydatidiform mole is the most common type of gestational trophoblastic tumor.
  1. Complete hydatidiform mole
  2. Partial hydatidiform mole
• Gestational Trophoblastic Neoplasia
  1. Invasive moles
  2. Choriocarcinomas
  3. Placental-site trophoblastic tumors (very rare)
  4. Epithelioid trophoblastic tumors (even more rare).

Anything that increases your risk of getting a disease is called a risk factor. Risk factors for gestational trophoblastic disease include the following ⁵⁹:

• Being pregnant when you are younger than 20 or older than 35 years of age.
• Having a personal history of hydatidiform mole.

If a woman has been previously diagnosed with an hydatidiform mole, she carries a 1% risk of hydatidiform mole in subsequent pregnancies. This increases to approximately 25% with more than one prior hydatidiform mole. The risk associated with maternal age is bimodal, with increased risk both for mothers younger than 20 years and older than 35 years (and particularly for mothers >45 years). Relative risks are in the range of 1.1 to 11 for both the younger and older age ranges compared with ages 20 to 35 years. However, a population-based hydatidiform mole registry study suggests that the age-related patterns of the two major types of hydatidiform mole—complete and partial hydatidiform mole—are distinct ⁶⁰. In that study, the rate of complete hydatidiform mole was highest in women younger than 20 years and then decreased monotonically with age ⁶⁰. However, the rates of partial hydatidiform mole increased for the entire age spectrum, suggesting possible differences in etiology. The association with paternal age is inconsistent ⁵⁹. A variety of exposures have been examined, with no clear associations found with tobacco smoking, alcohol consumption, diet, and oral contraceptive use ⁵⁹.

Hydatidiform mole

Hydatidiform mole also called molar pregnancy is the most common type of gestational trophoblastic disease. Hydatidiform moles are slow-growing tumors that look like sacs of fluid. The cause of hydatidiform moles is not known.

Hydatidiform moles may be complete or partial ²⁷, ²⁶:

1. Complete hydatidiform mole forms when sperm fertilizes an egg that does not contain the mother’s DNA. The egg has DNA from the father and the cells that were meant to become the placenta are abnormal.
2. Partial hydatidiform mole forms when sperm fertilizes a normal egg and there are two sets of DNA from the father in the fertilized egg. Only part of the fetus forms and the cells that were meant to become the placenta are abnormal.

Most hydatidiform moles are benign (not cancer), but they sometimes become cancer. Having one or more of the following risk factors increases the risk that a hydatidiform mole will become cancer ²⁷, ²⁶:

• A pregnancy before 20 or after 35 years of age.
• A very high level of beta human chorionic gonadotropin (beta-hCG). Beta human chorionic gonadotropin (beta-hCG) is “the hormone of pregnancy” produced primarily by syncytiotrophoblastic cells of the placenta of a pregnant woman ⁶¹, ⁶², ⁶³. Smaller amounts of human chorionic gonadotropin (hCG) are also produced in the pituitary gland, the liver, and the colon ⁶⁴.
• A large tumor in the uterus.
• An ovarian cyst larger than 6 centimeters.
• High blood pressure during pregnancy (preeclampsia).
• An overactive thyroid gland (extra thyroid hormone is made).
• Severe nausea and vomiting during pregnancy.
• Trophoblastic cells in the blood, which may block small blood vessels.
• Serious blood clotting problems caused by the hydatidiform mole.

Gestational trophoblastic neoplasia

Gestational trophoblastic neoplasia is another type of gestational trophoblastic disease that is almost always malignant (cancerous) ²⁷, ²⁶.

Gestational trophoblastic neoplasia includes the following ²⁷, ²⁶:

1. Invasive moles also called chorioadenoma destruens. Invasive moles (chorioadenoma destruens) are made up of trophoblast cells that grow into the muscle layer of the uterus. Microscopically, these lesions are characterized by hyperplasia of cytotrophoblastic and syncytial elements and persistence of villous structures. They may histologically resemble choriocarcinoma. Invasive moles are more likely to grow and spread than a hydatidiform mole. Rarely, a complete or partial hydatidiform mole may become an invasive mole. Invasive moles have more aggressive behavior than either complete or partial hydatidiform moles, and they are treated similarly to choriocarcinoma (i.e., with chemotherapy). However, unlike choriocarcinoma, invasive moles (chorioadenoma destruens) may disappear without treatment spontaneously.
2. Choriocarcinomas. A choriocarcinoma is a malignant tumor that forms from trophoblast cells and spreads to the muscle layer of the uterus and nearby blood vessels. It may also spread to other parts of the body, such as the brain, lungs, liver, kidney, spleen, intestines, pelvis, or vagina. Choriocarcinoma is one of the causes of cannonball metastases to the lungs. A choriocarcinoma is more likely to form in women who have had any of the following:
   • Molar pregnancy, especially with a complete hydatidiform mole.
   • Normal pregnancy.
   • Tubal pregnancy (the fertilized egg implants in the fallopian tube rather than the uterus).
   • Miscarriage.
3. Placental-site trophoblastic tumors. A placental-site trophoblastic tumor is a rare type of gestational trophoblastic neoplasia that forms where the placenta attaches to the uterus. The tumor forms from trophoblast cells and spreads into the muscle of the uterus and into blood vessels and resembles an exaggerated form of syncytial endometritis. It may also spread to the lungs, pelvis, or lymph nodes. A placental-site trophoblastic tumor grows very slowly and signs or symptoms may appear months or years after a normal pregnancy. Human placental lactogen is present in the tumor cells, whereas immunoperoxidase staining for human chorionic gonadotropin (hCG) is positive in only scattered cells, and elevations in serum human chorionic gonadotropin (hCG) are relatively low compared with the marked elevations seen in choriocarcinoma. Human chorionic gonadotropin (hCG) is not a reliable marker of tumor volume ⁶⁵, ⁶⁶. Placental-site trophoblastic tumors have much lower growth rates than choriocarcinoma, and presentation after a full-term pregnancy is often delayed by months or years. They are generally resistant to chemotherapy. Therefore, hysterectomy is the standard primary treatment if the tumor is confined to the uterus. However, about 35% of placental-site trophoblastic tumors have distant metastases at diagnosis ⁶⁷, ⁶⁶. Common sites of metastasis include the lungs, pelvis, and lymph nodes. Central nervous system, renal, and liver metastases have also been observed.
4. Epithelioid trophoblastic tumors. An epithelioid trophoblastic tumor is an extremely rare type of gestational trophoblastic neoplasia that may be benign (not cancer) or malignant (cancer) ⁶⁸, ⁶⁹. When the tumor is malignant, it may spread to the lungs. Although epithelioid trophoblastic tumor was originally called an atypical choriocarcinoma, epithelioid trophoblastic tumor appears to be less aggressive than choriocarcinoma and is now regarded as a distinct entity. Pathologically, it has a monomorphic cellular pattern of epithelioid cells and may resemble squamous cell cancer of the cervix when arising in the cervical canal. Its clinical behavior appears to be closer to that of placental-site trophoblastic tumor than to choriocarcinoma.

Choriocarcinoma of the uterus

Choriocarcinoma of the uterus also called uterine choriocarcinoma is one of the commonest choriocarcinomas and is often associated with gestational trophoblastic disease ⁷⁰, ⁷¹, ⁷², ⁷³.

Uterine choriocarcinomas typically occur in women of childbearing age as a gestational choriocarcinoma. Most such cases present within one year after a molar or non-molar pregnancy ⁷⁴. Very rarely beyond the reproductive age (menopause), uterine choriocarcinoma can develop from germ cells or from dedifferentiation of endometrial carcinoma into non-gestational choriocarcinoma ⁷⁴, ⁷⁵.

As with choriocarcinomas in general, uterine choriocarcinoma is a highly vascular tumor. The tumor comprises of trophoblastic cells. On histology, there is an absence of chorionic villi compared with other forms of gestational trophoblastic disease

In the case of gestational choriocarcinoma, approximately 5% of cases of complete hydatidiform mole are followed by choriocarcinoma. Only about half the cases of choriocarcinoma arise from a complete hydatidiform mole. An additional 25% of cases arise after normal pregnancies, and 25% follow miscarriage or ectopic pregnancy.

Choriocarcinoma of the uterus often appears as a mass enlarging the uterus. Sometimes it manifests as a discrete, central, infiltrative mass. Its heterogeneous appearance correlates with necrosis and hemorrhage that characterize these lesions. Cystic areas from necrosis and hemorrhage may be present. The ovaries can be shown enlarged due to cysts secondary to increased levels of human chorionic gonadotropin (hCG).

Non-gestational choriocarcinoma

Non-gestational choriocarcinoma also called primary choriocarcinoma is choriocarcinoma occurring in the absence of pregnancy after fertilization of an egg by a sperm.

In women, non-gestational choriocarcinoma often tend to occur in the ovary ⁷⁶. Most ovarian non-gestational choriocarcinomas occur in mixed form with teratoma, endodermal sinus tumor, embryonal carcinoma or dysgerminoma components. Very rarely it can occur as a pure primary ovarian choriocarcinoma. A pure primary ovarian choriocarcinoma is an extremely rare form of ovarian cancer. It falls under the subcategory of ovarian germ cell tumors. A pure primary ovarian choriocarcinoma accounts for less than 1% of ovarian cancers.

In men, non-gestational choriocarcinoma is extremely rare manifesting with specific signs such as an increase in the amount of breast gland tissue in boys or men (gynecomastia), testicular atrophy, and loss of libido ⁶, ⁷⁷, ¹⁹. Nongestational choriocarcinoma in men can be further categorized into gonadal choriocarcinoma (testis) and extragonadal choriocarcinoma such as mediastinal choriocarcinoma and retroperitoneal choriocarcinoma based on its origin and primary site ¹⁰, ¹¹. The presentation typically includes elevated serum beta human chorionic gonadotropin (beta-hCG) levels, widespread metastatic disease, and a rapid progression of the condition ⁷⁸, ⁷⁹.

The mechanism of non-gestational choriocarcinoma has long been debated, and no conclusions have been reached. 3 hypotheses exist ⁸⁰:

1. These tumors might arise from retained primordial germ cells that migrate abnormally during embryogenesis ⁸¹, ⁸². This theory might explain the occurrence of choriocarcinomas in midline structures such as the mediastinum, retroperitoneum, and the pineal gland; however, it cannot explain other choriocarcinoma locations such as the lung, liver, or stomach.
2. The tumor results from the metastasis of choriocarcinoma from the gonads, accompanied by the spontaneous regression of the primary choriocarcinoma in the gonads ⁸¹.
3. The tumor might be a cancer that originally develops as a nontrophoblastic neoplasm and transforms into a choriocarcinoma ⁸³, ⁸⁴.

The latter theories seem more feasible with regard to explaining the occurrences of stomach and lung choriocarcinomas.

According to the data collected at a hospital in China, the incidence ratio of nongestational choriocarcinoma to gestational choriocarcinoma was 1:79 ⁸⁵. The male/female ratio was 13:33 among patients with nongestational choriocarcinoma.

The literature revealed that nongestational choriocarcinoma is a rare cancer that occurs at different sites. Nongestational choriocarcinoma can occur in the testis with the testis being the most common primary site at 36.2% (41/113), followed by the mediastinum (14/113), stomach (13/113), liver (12/113), lung (11/113), brain (8/113), small intestine (6/113), and other sites (8/113) ⁸⁵. Nongestational choriocarcinoma can occur at different ages, from neonates to 80 years old; the median age found in the literature was 34 years old ⁸⁵. The peak age of occurrence was from 20 to 29 years, followed by 30 to 39 years ⁸⁶, ⁸⁷. Patients in the former age group with suspicious symptoms should be checked for serum beta human chorionic gonadotropin (beta-hCG) to exclude nongestational choriocarcinoma, because the cancer rapidly progresses and can lead to early metastasis and death if undiagnosed ⁸⁸. Beta human chorionic gonadotropin (beta-hCG) has an important diagnostic value because nongestational choriocarcinoma can also secrete beta-hCG; thus, the proportion of patients with elevated serum beta-hCG levels is high (96.4%) ⁸⁶.

Non-gestational choriocarcinoma typically arises in association with reproductive organs:

• Uterus: Uterine choriocarcinoma (choriocarcinoma of the uterus) ¹⁴
• Cervix: Primary choriocarcinoma of the uterine cervix ¹⁵
• Ovary: Choriocarcinoma of the ovary (pure primary ovarian choriocarcinoma) ¹⁷
• Testes: Testicular choriocarcinoma in men

Primary occurrence of non-gestational choriocarcinoma outside the reproductive system has been reported but is extremely rare. Such sites include:

• Brain: Primary intracranial choriocarcinoma
• Lung: Primary pulmonary choriocarcinoma ¹⁹.
• Pulmonary arteries: Primary choriocarcinoma of the pulmonary artery ²⁰
• Stomach: Primary choriocarcinoma of the stomach ²¹, ²²
• The small intestine: Non-gestational choriocarcinoma in small intestine ²³
• Pancreas: Primary choriocarcinoma of the pancreas ²¹.

Ovarian choriocarcinoma

Ovarian choriocarcinoma is a rare sub type of ovarian germ cell tumor. Ovarian choriocarcinoma account for less than 1% of ovarian tumors. Pure ovarian choriocarcinoma can be classified into two groups based on origin: gestational ovarian choriocarcinoma or nongestational ovarian choriocarcinoma ⁸⁹. Pure ovarian choriocarcinoma tumors may occur during or outside of pregnancy.

Gestational ovarian choriocarcinoma may represent as either a spread (metastasis) from uterine choriocarcinoma or much rarely as primary choriocarcinoma following an ovarian ectopic pregnancy including hydatidiform mole ⁹⁰, ⁹¹, ⁹², ⁹³, ⁹⁴, ²⁸, ⁹⁵.

The nongestational pure ovarian choriocarcinoma also called primary ovarian choriocarcinoma emerges presumably from malignant germ cell tumor and the prognosis is thought to be worse than that of the gestational ovarian choriocarcinoma in patients with metastatic disease ⁸⁹. But nongestational pure ovarian choriocarcinoma is extremely rare because most malignant germ cell tumors are mixed-type and consisting of various malignant components, including immature teratoma, dysgerminoma, yolk sac tumor, and choriocarcinoma ⁹⁶, ⁹⁷, ⁹⁸.

Ovarian choriocarcinoma tumors are formed from placental trophoblastic elements. While most gestational choriocarcinomas show blood borne spread, the non-gestational choriocarcinoma tends to follow the lymphatic system.

Diagnosing pure ovarian choriocarcinoma as gestational or nongestational is essential, because the sensitivities to chemotherapy and prognosis of these two types appear to differ despite the identical pathological findings ⁹⁹, ¹⁰⁰. A history of past pregnancies is crucial. However, even with such information, determining whether the choriocarcinoma is gestational or nongestational is difficult based on the pregnancy history alone, except in cases of teen girls or women who are sexually immature, have never had sexual intercourse, or are unable to conceive, because a few spontaneous abortions pass unrecognized. In pre-menarchal girls ( without their first period), the ovarian choriocarcinomas manifest with early appearance of the signs of sexual development (approximately 50% of cases) and other symptoms associated with excessive hormone production. Serum beta human chorionic gonadotropin (beta-hCG) levels are often elevated.

Gestational and non-gestational choriocarcinoma is histologically identical. The only way to distinguish an ovarian gestational choriocarcinoma (as in gestational choriocarcinoma arising from prior ectopic pregnancy within the ovary) and a non-gestational ovarian choriocarcinoma is by DNA short tandem repeat analysis (DNA STR analysis). Recently, DNA STR analysis has been utilized to clarify the origin of choriocarcinoma and to differentiate gestational and pure nongestational choriocarcinoma when definitive evidence has not been forthcoming from pathological or other clinical findings ⁹⁹, ¹⁰¹, ¹⁰², ¹⁰³, ¹⁰⁴, ¹⁰⁵, ¹⁰⁶. Because the genome in nongestational choriocarcinoma comprises only a maternal (mother’s) allele, whereas gestational choriocarcinoma contains a paternal (father’s) allele, DNA STR analysis can precisely distinguish these two types of choriocarcinoma ⁸⁹.

Nongestational pure choriocarcinoma of ovary (primary ovarian choriocarcinoma) is extremely rare, especially with metastatic disease ⁹⁷, ¹⁰⁷, ¹⁰⁸, ¹⁰⁹, ¹¹⁰, ¹¹¹, ¹¹².

Nongestational pure choriocarcinoma of ovary (primary ovarian choriocarcinoma) prognosis is widely considered to be worse than that of gestational choriocarcinoma despite these two types of choriocarcinoma being pathologically identical ⁸⁹. If this is the case, such differences may be because the genome of gestational choriocarcinoma is totally or partially different from that of the patient, whereas nongestational choriocarcinoma is genetically identical to the patient, leading to differences in host immunoreactions ⁸⁹. However, given with rarity of these pathological entities, no reports have analyzed large numbers of choriocarcinoma cases and compared prognoses between types as diagnosed based on DNA analyses ⁸⁹. Combination chemotherapy regimens employing methotrexate, etoposide, and actinomycin-D such as EMA/CO (etoposide, methotrexate, actinomycin-D/cyclophosphamide and vincristine) or MEA (methotrexate, etoposide, and actinomycin-D)are administered as first-line therapies against gestational choriocarcinoma, and the complete response rate for these chemotherapy regimens against gestational choriocarcinoma exceeds 70 % ¹¹³. Regimens including cisplatin such as TP (paclitaxel and cisplatin) and BEP (bleomycin, etoposide, and cisplatin) therapies are applied for resistant or relapsed gestational choriocarcinoma, with an overall survival rate with or without adjuvant (add-on) radiotherapy or surgery of around 90 % ¹¹⁴. Nongestational choriocarcinoma usually develops as a component of mixed-type germ cell tumor, and seems to show favorable prognosis following surgery and BEP regimen ¹¹⁵, ¹¹⁶. When nongestational choriocarcinoma emerges as a pure choriocarcinoma, the tumor behavior seems more aggressive ⁸⁹. Cisplatin regimens are usually used for resistant or relapsed nongestational choriocarcinoma, as well as for gestational choriocarcinoma.

Choriocarcinoma in men

Choriocarcinoma in men also known as non-gestational choriocarcinoma or primary choriocarcinoma is extremely rare and its prognosis is much worse than that of gestational choriocarcinoma. Nongestational choriocarcinoma in men can be further categorized into gonadal choriocarcinoma (testis) and extragonadal choriocarcinoma such as mediastinal choriocarcinoma and retroperitoneal choriocarcinoma based on its origin and primary site ¹⁰, ¹¹. Nongestational choriocarcinoma can occur in the testis with the testis being the most common primary site at 36.2% (41/113), followed by the mediastinum (14/113), stomach (13/113), liver (12/113), lung (11/113), brain (8/113), small intestine (6/113), and other sites (8/113) ⁸⁵. Less than 8% of testicular germ cell tumors contain a choriocarcinoma component, and pure choriocarcinoma accounts for only 0.3% of all primary testicular germ cell tumors ¹¹⁷.

Nongestational choriocarcinoma can occur at different ages, from neonates to 80 years old; the median age found in the literature was 34 years old ⁸⁵. The peak age of occurrence was from 20 to 29 years, followed by 30 to 39 years ⁸⁶, ⁸⁷. Patients in the former age group with suspicious symptoms should be checked for serum beta human chorionic gonadotropin (beta-hCG) to exclude nongestational choriocarcinoma, because the cancer rapidly progresses and can lead to early metastasis and death if undiagnosed ⁸⁸. Beta human chorionic gonadotropin (beta-hCG) has an important diagnostic value because nongestational choriocarcinoma can also secrete beta-hCG; thus, the proportion of patients with elevated serum beta-hCG levels is high (96.4%) ⁸⁶. The determination of serum tumor markers, specifically serum beta human chorionic gonadotropin (beta-hCG) and alpha-fetoprotein (AFP), proves beneficial in choriocarcinoma diagnosis as they are elevated in approximately 80% of cases. However, serum beta human chorionic gonadotropin (beta-hCG) is almost never tested for among males.

Choriocarcinoma in men typically presents with elevated serum beta human chorionic gonadotropin (beta-hCG) levels, widespread metastatic disease, and a rapid progression of the cancer ⁷⁸, ⁷⁹. Monitoring the serum concentration of beta-hCG also aids in assessing treatment response. According to the International Cooperative Organization for Germ Cell Cancer, a beta-hCG level exceeding 50,000 mIU/mL signifies a poor prognosis. Some patients may manifest overactive thyroid (hyperthyroidism) or bilateral gynecomastia, attributed to markedly elevated serum beta-hCG levels, often exceeding 50,000 mIU/mL ¹¹⁸, ¹¹⁹. The elevated beta-hCG levels stimulated supraphysiological testosterone secretion, subsequently aromatized to estradiol, resulting in gynecomastia (an increase in the amount of breast gland tissue in boys or men).

The investigation based on cases in the literature revealed that a preoperative diagnosis did not prolong the median overall survival (10 months vs 18 months). Therefore, male nongestational choriocarcinoma was difficult to diagnosis preoperatively, and a preoperative diagnosis did not change the prognosis ¹⁰.

There is no standard management for males with nongestational choriocarcinoma ¹²⁰. Different treatment strategies were applied across the literature cases. These patients were treated with chemotherapy, radiotherapy, surgery, or some combination of these. The complete resection of the cancer from the primary site and metastases followed by chemotherapy seems to provide patients with the best chance at survival in the treatment of males with nongestational choriocarcinoma ⁸⁵. Furthermore, additional chemotherapy cycles might facilitate better prognosis. Since preoperative diagnosis does not prolong the median overall survival, early surgery without a diagnosis is still beneficial for overall survival. Overall survival (OS) is the length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive. In a clinical trial, measuring the overall survival is one way to see how well a new treatment works.

An analysis of primary gastric choriocarcinoma found that synchronous liver metastasis, residual tumors after surgery, and the absence of chemotherapy significantly predicted reduced overall survival ¹²¹.

Regular long-term clinical follow-up evaluations are important. Serum beta human chorionic gonadotropin (beta-hCG) levels should be used as a marker to assess treatment effectiveness and detect cancer relapse ¹²². Beta human chorionic gonadotropin (beta-hCG) levels decreased to normal ranges among the patients who showed long-term survival and increased among relapsed  patients who died early. Relapse might denote poor prognosis because both relapsed patients died even after intensive chemotherapy had been administered.

Choriocarcinoma testicular cancer

Testicular choriocarcinoma is a very rare and very aggressive fast-growing testicular cancer in adults that is typically seen with extremely highly elevated serum human chorionic gonadotropin (hCG) levels and metastatic disease ¹²³. Testicular choriocarcinoma is a type of non-seminomatous germ cell tumor. More often, choriocarcinoma cells are seen with other types of non-seminoma cells in a mixed germ cell tumor. These mixed tumors tend to have a somewhat better outlook than pure choriocarcinomas, although the presence of choriocarcinoma is always a worrisome finding.

Pure choriocarcinomas are rare at only 1% of all testicular cancers, but they may be found as a component in up to 15% of all mixed germ cell tumors ⁵³. Choriocarcinomas are typically poor-risk (stage 3C) at the time of diagnosis with high serum human chorionic gonadotropin (hCG) levels and non-pulmonary organ metastases ¹²⁴. Unlike other non-seminomatous germ cell tumors, choriocarcinoma can spread via the blood with common sites of metastases, including the lungs, liver, and brain ¹²⁴, ¹²⁵.

Microscopically, testicular choriocarcinoma tumor is composed of both syncytiotrophoblasts and cytotrophoblasts, with the former staining positively for human chorionic gonadotropin (hCG) ¹²³. The human chorionic gonadotropin (hCG) levels may become quite high, resulting in male gynecomastia (an increase in the amount of breast tissue caused by a hormone imbalance in boys or men). Testicular choriocarcinomas are highly vascular and prone to bleed, often spontaneously and sometimes immediately after chemotherapy is initiated. This hemorrhaging can be catastrophic, especially when the bleeding is significant and occurs in the lungs or brain ¹²³. Elevated human chorionic gonadotropin (hCG) levels are usually associated only with seminomas, except for choriocarcinoma and sometimes embryonal carcinoma ¹²³.

Choriocarcinoma testicular cancer causes

The exact cause of testicular cancer is poorly understood. Factors that may increase a man’s risk of developing testicular cancer are:

• Having an undescended testicle (cryptorchidism) (one or both testicles fail to move into the scrotum before birth). The testes form in the belly during fetal development. They typically descend into the scrotum before birth. If you have a testicle that never descended, your risk of testicular cancer is higher. The risk is increased even if you’ve had surgery to move the testicle to the scrotum.
• Exposure to certain chemicals
• Having a family history (especially in a father or brother) of testicular cancer. If testicular cancer runs in your family, you might have an increased risk.
• Personal history of testicular cancer
• HIV infection
• Klinefelter syndrome
• Infertility
• Tobacco use
• Down syndrome
• Having had abnormal development of the testicles.
• Being a young adult. Testicular cancer can happen at any age. But it’s most common in teens and young adults between 15 and 35.
• Being white. Testicular cancer is most common in white people.

The most common risk factor for testis cancer is a history of undescended testicle or cryptorchidism. Normally in the developing male fetus, the testicles form near the kidneys in the abdomen (belly). About the eighth month of pregnancy, the testicles descend, exit the body and settle in the scrotum. About 3% of boys have one or both testicles that fail to make it into the scrotum. Testicles can settle in the abdomen or in the inguinal canal or groin where the testicle exits the body wall and enters the scrotum. Most of the time, an undescended testicle will move down and settle into the scrotum within the first year of life. Sometimes surgery is required to bring down and fix the testicle to the scrotum, this surgery is called an orchiopexy.

Boys with a history of cryptorchidism have an increased risk of testicular cancer. The risk of testicular cancer is not directly related to the fact that the testicle does not descend, but it is believed that the abnormality in descent likely indicates an abnormality in the testicle that makes cancer more likely. This belief is based on the following observations: The testicular cancer usually develops in the undescended testicle (four- to sixfold increased risk of cancer), but the risk of cancer is also higher in the normal testicle (less than twofold increased risk). In addition, generally the higher the testicle, the higher the risk of testicular cancer — intra-abdominal testis have a much higher risk of cancer than those in the inguinal canal. Early surgery (orchiopexy) reduces the risk of testis cancer (two- to threefold risk if the surgery is performed prior to puberty) but does not erase the chance for that boy to develop testicular cancer later in life ¹²⁶.

A family history of testicular cancer is another common risk factor, with an eight- to twelvefold risk if a man has a brother with testicular cancer and a two- to fourfold risk if his father has testicular cancer. While there is not a specific gene linked to testicular cancer, the cancer is highly heritable and can be passed from generation to generation. In addition, the average age at diagnosis is two to three years younger than the general population if a first-degree relative has testicular cancer. However, it should be remembered that testicular cancer is rare, and it is therefore rare for this cancer to run in families.

Men with a personal history of testicular cancer have the highest risk of developing another cancer. Fortunately, only 2% of men will develop cancer in both testicles, but that risk is twelvefold higher than men without testis cancer. In addition, men who develop testis cancer in their 20s or earlier, men with seminoma and men with germ cell neoplasia is situ formerly known as carcinoma in situ (CIS) or intratubular germ cell neoplasia (ITGCN) have a higher risk of developing a second testis cancer.

Choriocarcinoma testicular cancer symptoms

The symptoms of testicular choriocarcinoma tumors are the same as those of testicular cancer. Most testicular cancers present as a mass confined to the one testicle, but it can affect both. Therefore, the most common presentation is a painless testicular mass. Most of these masses can be felt and of significant size (a few to several centimeters). Small, nonpalpable lesions without pain and in the absence of distant disease have a higher likelihood of being a benign tumor. In a number of studies, upwards of 80 percent of nonpalpable, asymptomatic masses that are 2 cm or smaller will be benign tumors. Benign lesions may include testicular cysts, varicocele, small infarcts or small Leydig cell or Sertoli cell tumors. Patients with a significantly enlarged or swollen testicle are most likely to have epididymo-orchitis, especially if the testicle is red or painful. An apparent epididymo-orchitis that is painless or does not respond to antibiotics should be considered suspicious for a testicular cancer.

Testicular choriocarcinoma tumor symptoms include:

• a lump or swelling in your testicle, but it can affect both testicles (>85% of men)
• your testicle getting bigger
• an ache or pain in your testicle or scrotum (the skin that covers the testicles) (about 20% to 30% of men experience a heavy dragging feeling or general ache)
• your scrotum feeling heavy, firm or hard

Other symptoms can include:

• a dull ache or pain in your back, groin or lower tummy
• back pain
• sudden swelling in the scrotum
• losing weight without trying
• a cough
• difficulty breathing or swallowing
• enlargement or tenderness of the breast tissue
• A small percentage present with symptoms of metastatic disease and infertility.

Choriocarcinoma testicular cancer diagnosis

Testicular cancers can be detected during an exam by a doctor too. You’ll need other tests to see if testicular cancer is causing your symptoms.

Tests used to diagnose testicular cancer include:

• Testicular ultrasound (scrotal ultrasound). A testicular ultrasound test uses sound waves to make pictures. It can be used to make pictures of the scrotum and testicles. During an ultrasound you lie on your back with your legs spread. A doctor puts a clear gel on the scrotum. A hand-held probe is moved over the scrotum to make the pictures. Ultrasound gives your doctor more clues about any lumps around the testicle. It can help your doctor see whether the lumps look like something that isn’t cancer or if they look like cancer. An ultrasound shows whether the lumps are inside or outside the testicle. Lumps inside the testicle are more likely to be testicular cancer. Radical orchiectomy (surgery to remove the testicle) should strongly be considered for any intratesticular mass and suspicion of testis cancer.
• Serum testicular tumor markers. A blood test can detect proteins made by testicular cancer cells. This type of test is called a tumor marker test. Tumor markers for testicular cancer include beta-human chorionic gonadotropin (hCGβ), alpha-fetoprotein (AFP) and lactate dehydrogenase (LDH). Having these substances in your blood doesn’t mean you have cancer. Having levels higher than is typical is a clue your doctor uses to understand what’s going on in your body. Serum AFP, LDH, and beta-hCG should be measured before an orchiectomy. Lactate dehydrogenase (LDH) is generally a nonspecific tumor marker that is elevated in 20% to 60% of patients with non seminoma testicular cancer and is generally considered an indicator of bulky disease. Alpha-fetoprotein (AFP) has a half-life of about 6 days, while the half-life of beta-human chorionic gonadotropin (beta-hCG) is 24 to 48 hours. In practical terms, beta-human chorionic gonadotropin (beta-hCG) should begin to return to normal about 1 week after orchiectomy, while alpha-fetoprotein (AFP) will take a minimum of 5 weeks. Alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (beta-hCG) are also elevated in various lung, liver, gut, bone, and live tumors ¹²⁷, ¹²⁸. There are new markers to diagnose and evaluate germ cell tumors, like levels of circulating microRNAs, especially miR-371a-3p. However, their precise role in the management of testicular tumors is yet to be determined ¹²⁹.
• Surgery to remove a testicle through an incision in the groin (Inguinal orchiectomy). If your doctor thinks a lump on your testicle may be cancerous, you might have surgery to remove the testicle through an incision in the groin. NOTE: The surgeon does not cut through the scrotum into the testicle to remove a sample of tissue for biopsy, because if cancer is present, this procedure could cause it to spread into the scrotum and lymph nodes. It’s important to choose a surgeon who has experience with this kind of surgery. The testicle is sent to a lab for testing. A tissue sample from the testicle is then viewed under a microscope to check for cancer cells. If cancer is found, the cell type (seminoma or nonseminoma) is determined in order to help plan treatment.
  • Transscrotal biopsy is not considered appropriate because of the risk of local dissemination of tumor into the scrotum or its spread to inguinal lymph nodes ¹³⁰. A retrospective analysis of reported series in which transscrotal approaches were used showed a small but statistically significant increase in local recurrence rates, compared with when the inguinal approach was used (2.9% vs. 0.4%) ¹³¹. However, distant recurrence and survival rates were indistinguishable in the two approaches ¹³⁰.
• Advanced imaging. Additional imaging can be performed before or after the diagnosis of cancer is confirmed, based on the strength of suspicion for cancer. Imaging of the chest, abdomen and pelvis are typically required to evaluate for spread of testicular cancer — this process is called staging. CT, MRI and X-ray can be used for staging. PET scan or bone scan are not recommended for the routine evaluation of testicular cancer.

Serum tumor markers

Alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (beta-hCG), and lactate dehydrogenase (LDH) play an important role as serum tumor markers in the staging and monitoring of germ cell tumors and should be measured prior to removing the involved testicle ¹³². For patients with nonseminomas, one of the most significant predictors of prognosis is the degree of tumor-marker elevation after the cancerous testicle has been removed ¹³³. Elevated levels of serum tumor markers are often the earliest sign of relapse (recurrence), making these markers useful for monitoring all stages of nonseminomas and metastatic seminomas ¹³⁰.

Significant and unambiguously rising levels of alpha-fetoprotein (AFP) and/or beta-human chorionic gonadotropin (beta-hCG) signal relapsed germ cell tumor in most cases and are an indication for treatment even in the absence of radiological evidence of metastatic disease ¹³⁰. However, tumor marker elevations need to be interpreted with caution. For example, false-positive beta-hCG levels can result from cross reactivity of the assay with luteinizing hormone (LH) in which case an intramuscular injection of testosterone should result in normalization of beta-hCG values ¹³⁰. There are also clinical reports of marijuana use resulting in elevations of serum beta-hCG and some experts recommend querying patients about drug use and retesting beta-hCG levels after a period of abstinence from marijuana use ¹³⁰. Similarly, AFP is chronically mildly elevated in some individuals for unclear reasons and can be substantially elevated by liver disease ¹³⁰.

Alpha-fetoprotein (AFP)

Elevation of serum alpha-fetoprotein (AFP) is seen in 40% to 60% of men with nonseminomas. Seminomas do not produce alpha-fetoprotein (AFP). So if it’s elevated in a patient diagnosed only with seminoma, it means thatnonseminoma testicular cancer elements were missed. Men who have an elevated serum AFP have a mixed germ cell tumor (i.e., nonseminomatous germ cell tumors [NSGCT]) even if the pathology shows a pure seminoma—unless there is a more persuasive explanation for the elevated AFP, such as liver disease ¹³⁰.

Beta-human chorionic gonadotropin (beta-hCG)

Elevation of beta-human chorionic gonadotropin (beta-hCG) is found in approximately 14% of patients with stage 1 pure seminomas before orchiectomy (surgery to remove the testicle) and in about one-half of patients with metastatic seminomas ¹³⁴, ¹³⁵, ¹³⁶. Approximately 40% to 60% of men with nonseminomas have an elevated serum beta-hCG ¹³⁰.

Lactate dehydrogenase (LDH)

Seminomas and nonseminomas alike may result in elevated lactate dehydrogenase (LDH) but such values are of unclear prognostic significance because LDH may be elevated in many conditions unrelated to cancer. A study evaluated the utility of lactate dehydrogenase (LDH) in 499 patients with a testicular germ cell tumor who were undergoing surveillance after orchiectomy or treatment of stage 2 or 3 disease. It found that 7.7% of patients had elevated lactate dehydrogenase (LDH) unrelated to cancer, while only 1.4% of patients had cancer-related increases in LDH ¹³⁷. Among 15 patients with relapsed disease, LDH was elevated in six patients and was the first sign of relapse in one patient ¹³⁷. Over 9% of the men had a persistent false-positive increase in LDH. The positive predictive value for an elevated LDH was 12.8% ¹³⁷.

A second study reported that among 494 patients with stage 1 germ cell tumors who subsequently had a relapse, 125 had an elevated LDH at the time of relapse ¹³⁸. Of these 125 patients, all had other evidence of relapse: 112 had a concurrent rise in AFP and/or beta-hCG, one had computed tomography (CT) evidence of relapse before the elevation in LDH, one had palpable disease on examination, and one complained of back pain that led to imaging that revealed retroperitoneal relapse ¹³⁸. On one hand, measuring LDH appears to have little value for predicting relapse during surveillance of germ cell tumors. On the other hand, for patients with metastatic non-seminoma germ cell tumor (NSGCT), large studies of prognostic models have found the LDH level to be a significant independent predictor of survival ¹³³, ¹³⁹.

Choriocarcinoma testicular cancer treatment

Testicular cancer treatment options depend on the following:

• Whether the tumor is nonseminoma or seminoma.
• The size of the tumor and where it is in the body.
• The blood levels of alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (hCGβ), and lactate dehydrogenase (LDH).
• Whether the tumor has spread to other parts of the body.
• The way the tumor responds to initial treatment.
• Whether the tumor has just been diagnosed or has recurred (come back).

Testicular cancer treatment often involves surgery and chemotherapy. Which treatment options are best for you depends on the type of testicular cancer you have and its stage. Your cancer treatment team will also considers your overall health and your preferences.

Surgery

Surgery to remove the testicle (inguinal orchiectomy) and some of the lymph nodes may be done at diagnosis and staging. Radical inguinal orchiectomy with initial high ligation of the spermatic cord is the procedure of choice in diagnosing and treating a malignant testicular mass ¹⁴⁰. Tumors that have spread to other places in the body may be partly or entirely removed by surgery.

Operations used to treat testicular cancer include:

• Surgery to remove the testicle also called a radical inguinal orchiectomy. It’s the first treatment for most testicular cancers. To remove the testicle, a surgeon makes a cut in the groin. The entire testicle is pulled out through the opening. A prosthetic, gel-filled testicle can be inserted if you choose. This might be the only treatment needed if the cancer hasn’t spread beyond the testicle.
• Surgery to remove nearby lymph nodes. If there’s concern that your cancer may have spread beyond your testicle, you might have surgery to remove some lymph nodes. To remove the lymph nodes, the surgeon makes a cut in the belly. The lymph nodes are tested in a lab to look for cancer. Surgery to remove lymph nodes is often used to treat the nonseminoma type of testicular cancer.

Radical inguinal orchiectomy is the standard procedure for diagnostic and therapeutic purposes. Radical inguinal orchiectomy surgery involves removing the testicle and spermatic cord where it exits the body to identify and likely treat the majority of cancers localized to the testis. Trans scrotal orchiectomy or biopsy of the testicular mass is contraindicated for the risk of tumor seeding of the lymphatic drainage. Spinal or general anesthesia may be used. An inguinal incision is made to expose the external and internal iliac canal. External iliac fascia is opened, revealing the spermatic cord. The spermatic cord is controlled to stop retroperitoneal lymphatic and venous drainage of tumor cells. After that, deliver the testis from the scrotum and ligate vas deferens and spermatic arteries separately. Retroperitoneal lymph node dissection is done if necessary. Reapproximate the external oblique fascia and close the skin in standard fashion. Conduct a follow-up study by staging and referring the patient for appropriate adjuvant therapies.

After the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given chemotherapy or radiation therapy after surgery to kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant (add-on) therapy.

Testicular cancer surgery carries a risk of bleeding and infection. If you have surgery to remove lymph nodes, there’s also a risk that a nerve might be cut. Surgeons take great care to protect the nerves. Sometimes cutting a nerve can’t be avoided. This can lead to problems with ejaculating, but it generally doesn’t affect your ability to get an erection. Ask your surgeon about options for preserving your sperm before surgery.

Ilioinguinal nerve injury can occur if the nerve is damaged during dissection of the spermatic cord. This is more common in men who underwent prior inguinal surgery (usually for an undescended testicle or hernia repair) and can occur during dissection or be inadvertently trapped in the closure of the external oblique fascia. The deficit is often decreased sensation to the medial thigh, scrotum or base of the penis. It is often transient, but can take several weeks or months to improve.

Inguinal hernia can occur if the external oblique fascia is not closed properly or if the closure breaks down. It is important to minimize strenuous activities for two to four weeks to prevent development of a hernia.

Retroperitoneal lymph node dissection (RPLND)

The retroperitoneal lymph nodes are the primary nodal sites involved in the spread of non-seminoma testicular cancer. Removal of these draining lymph nodes results in a high cure rate for testicular tumors. The cure rate for stage 1 non-seminoma testicular cancer is about 93-95% with retroperitoneal lymph node dissection (RPLND) alone. It is generally 3-4 hours of surgery with a mortality rate of less than 1%. Retroperitoneal lymph node dissection (RPLND) involves the dissection of the retroperitoneal lymph nodes with the resulting possibility of retrograde ejaculation, loss of fertility, and incontinence due to disruption of pelvic nerves during the dissection. Retroperitoneal lymph node dissection (RPLND) is still the gold standard for stage 1 non-seminoma testicular cancer for staging and therapeutic purposes. Retroperitoneal lymph node dissection may also be used for stage 2A, but for stage 2B and higher. Initial chemotherapy is the standard of care. In general, patients with residual lymph nodes 1 cm or larger after definitive chemotherapy are candidates for retroperitoneal lymph node dissection (RPLND).

Retroperitoneal lymph node dissection with adjuvant chemotherapy is the mainstay of managing low-stage non-seminomatous germ cell tumors in the United States. Retroperitoneal lymph node dissection (RPLND) is a staging, diagnostic and therapeutic procedure for patients with non-seminoma testicular cancer. One of the benefits of retroperitoneal lymph node dissection (RPLND) surgery is that it helps identify those patients who might benefit from postoperative chemotherapy. Also, men with non-seminoma testicular cancer who do not undergo retroperitoneal lymph node dissection (RPLND) will require more intensive surveillance protocols even for stage 1 disease than similar patients who may only need routine tumor markers and chest x-rays after retroperitoneal lymph node dissection (RPLND) surgery, retroperitoneal relapse rate drops to <1% ¹⁴¹. Some centers will tend to recommend retroperitoneal lymph node dissection (RPLND) in stage 1 nonseminoma testicular cancer over active surveillance or chemotherapy if they have histological risk factors (evidence of vascular invasion in the original testicular malignancy or a significant component of embryonal carcinoma) ¹²³.

Retroperitoneal lymph node dissection (RPLND) is traditionally done as an open surgical procedure with a large midline abdominal incision. Removal of residual masses with retroperitoneal lymph node dissection (RPLND) after chemotherapy is a much more complicated and technically difficult procedure but provides excellent survival in high-risk/high tumor volume cases. Disease-specific survival has been reported as 81%, with 70% having no progression of their cancers ¹⁴², ¹⁴³. Laparoscopic retroperitoneal lymph node dissection (RPLND) has been reported in several series with good results, even when performed after chemotherapy ¹⁴², ¹⁴³.

Modern modifications include a nerve-sparing approach to save the nerves supplying the bladder neck to preserve ejaculatory function and continence ¹⁴⁴. This approach uses a template-based right and left-sided dissection, which preserves sexual function and fertility in over 90% of patients ¹⁴⁵. Other complications from retroperitoneal lymph node dissection (RPLND) surgery include wound infection, bowel ileus, pulmonary embolism, lymphocele, lymphedema, chylous ascites, and hydronephrosis ¹⁴¹.

Complications of retroperitoneal lymph node dissection (RPLND), even in experienced hands, are relatively common at 18% as the surgery is technically demanding and often complicated by patient comorbidities ¹⁴⁶. Postoperative ejaculatory problems are common ¹⁴⁷, ¹⁴⁸, ¹⁴⁹. Erectile dysfunction (the inability to get or maintain an erection long enough to have sexual intercourse) is reported in up to 15% with current nerve-sparing techniques ¹⁴⁹, ¹⁵⁰. Some patients may require resection of the inferior vena cava or aortic tube grafts to replace aortic segments ¹⁵¹, ¹⁵². Referral to tertiary care centers with surgeons experienced in retroperitoneal lymph node dissection (RPLND) surgery is recommended when this procedure is required, as in experienced hands, the outcomes are significantly better ¹⁵³, ¹⁵⁴. An experienced retroperitoneal lymph node dissection (RPLND) surgeon has been defined as one who performs 24 or more of these procedures a year.

Relapses after retroperitoneal lymph node dissection (RPLND) are typically pulmonary metastasis, with a reported incidence of 10% for those with negative nodes and 28% for patients with positive nodal disease ¹⁵⁵. Fortunately, such recurrences are usually curable with systemic chemotherapy.

In clinical stage 1 of non-seminomatous germ cell tumors, the relapse rate is about 64%. Relapsed cases are generally considered high-risk for metastatic disease. In the United States, retroperitoneal lymph node dissection (RPLND) is offered to re-confirm the pathological stage as well as for curative treatment. However, in European countries, patients are usually offered adjuvant chemotherapy consisting of two cycles of bleomycin, etoposide and cisplatin (BEP) chemotherapy, which is generally reserved for non-seminoma testicular cancer with high-risk features, such as vascular invasion. After treatment, 95-97% of patients remain relapse-free, with a cure rate approaching 100%. Adjuvant chemotherapy with two cycles of BEP in the high-risk group can provide a long-term progression-free survival rate of 97% ¹⁵⁶.

Chemotherapy

Chemotherapy treatment uses chemo drugs to kill cancer cells. Chemotherapy travels throughout the body. It can kill cancer cells that may have spread beyond the testicle. Chemotherapy is often used after surgery. It can help kill any cancer cells that are still in the body. When testicular cancer is very advanced, sometimes chemotherapy is used before surgery.

Non-seminomatous germ cell tumors are the most sensitive testicular cancers to cisplatin-based chemotherapy. Patients with elevated serum tumor markers are typically given 3-4 cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy ¹²³. After completion of chemotherapy, tumor markers are repeated to see the decline in values, along with a contrast-enhanced CT scan to evaluate for any residual mass ¹²³. If a mass is present with normal tumor markers, this is considered an indication for retroperitoneal lymph node dissection (RPLND). In patients who developed lung fibrosis (pulmonary fibrosis) or with a history of significant pre-existing lung disease, bleomycin would be contraindicated. If the patient still has elevated markers, second-line chemotherapy, including vincristine, ifosfamide, and cisplatin (VIP), should be considered. Other second and third-line agents include gemcitabine, etoposide, paclitaxel, and oxaliplatin. Chemotherapy also may cause your body to stop making sperm. Chemotherapy causes azoospermia (a complete absence of sperm in the semen) in most patients for at least 2 to 3 years after treatment. Cisplatin and similar alkylating agents are the most injurious to sperm production (spermatogenesis), with Sertoli cells being relatively sensitive but Leydig cells being relatively resistant. Sertoli cells are also very radiosensitive. Overall, fertility is reduced by an average of 30% after chemotherapy treatment for non seminoma testicular cancer ¹⁵⁷, ¹⁵⁸, ¹⁵⁹. Often, sperm production starts again as you get better after cancer treatment. But sometimes losing sperm production is permanent. Ask your doctor about your options for preserving your sperm before chemotherapy.

Side effects of chemotherapy depend on the specific medicines being used. Common side effects include fatigue, hearing loss and an increased risk of infection. Other potential side effects of chemotherapy include peripheral neuropathy, kidney failure, myelosuppression, loss of hearing, increased cardiovascular disorders, and hypogonadism (low testosterone).

Immunotherapy

Immunotherapy is treatment with medicine that helps your body’s immune system kill cancer cells. Your immune system fights off diseases by attacking germs and other cells that shouldn’t be in your body. Cancer cells survive by hiding from the immune system. Immunotherapy helps the immune system cells find and kill the cancer cells.

Immunotherapy is sometimes used for advanced testicular cancer ¹⁶⁰. It might be an option if the cancer doesn’t respond to other treatments.

Surveillance of testicular cancer after treatment

The median time to relapse in non-seminoma testicular cancer patients is 7 months ¹²³. The majority (90%) of non-seminoma testicular cancer patients who develop a recurrence will experience it within the first 2 years after definitive therapy ¹²³. Therefore, the recommended surveillance schedule is relatively intense for the first 2 years. For most patients, this means a physical examination of the remaining testicle, a chest x-ray, CT scan, and serum marker levels every 2 months. Late relapses after the first 2 years are relatively uncommon at only 2% to 4% ¹²³. When present, such recurrences are typically found in the retroperitoneum ¹⁶¹. However, rare instances of very late relapses have been reported up to 24 years after initial definitive therapy ¹⁶².

A more liberal monitoring plan has been suggested for low-risk patients with clinical stage 1 non-seminoma testicular cancer who may be able to avoid most of the routine surveillance CT scans, just performing them at 3 and 12 months rather than the standard scan every 2 months ¹⁶³. While promising, this is not yet the standard, accepted, or recommended protocol ¹²³.

Complete, detailed, and comprehensive reviews of the most recent recommended surveillance guidelines can be found on the NCCN website under “Guidelines for Testicular Cancer” or the American Urological Association Guidelines on Early Stage (Stage I – IIB) Testicular Cancer ¹⁵³.

Testicular cancer prognosis

In the past, testicular cancers were responsible for 11% of all deaths from cancer in men between 25 and 34, with an overall 5-year survival rate of only 64% ¹⁶⁴. After excision and chemotherapy, the current overall prognosis is extremely good, with a 5-year overall survival rate of about 96% ¹⁶⁵. Death rates have been stable over 2014–2020, with a 5-year survival rate of 95.2% ¹⁶⁶.

The prognosis and treatment options of patients with testicular germ cell tumors is determined by the following factors:

• Stage of the cancer (whether it is in or near the testicle or has spread to other places in the body, and blood levels of AFP, beta-hCG, and LDH).
• Histology (seminoma vs. nonseminoma).
• Size of the tumor.
• Number and size of retroperitoneal lymph nodes.
• For nonseminomas, the degree to which serum tumor markers are elevated ¹³³.

For men with disseminated seminomas, the main adverse prognostic variable is the presence of metastases to organs other than the lungs (e.g., bone, liver, or brain). For men with disseminated nonseminomas, the following variables are independently associated with poor prognosis ¹³⁰:

• Metastases to organs other than the lungs.
• Highly elevated serum tumor markers.
• Tumor that originated in the mediastinum rather than the testis.

Even patients with widespread metastases at presentation, including those with brain metastases, may have curable disease and should be treated with this intent ¹⁶⁷.

Testicular tumors are divided into 3 groups, based on how well the tumors are expected to respond to treatment ¹³³, ¹⁶⁸:

• Good Prognosis (disease-free survival at 5 years are roughly 90%)
  
• Intermediate Prognosis (disease-free survival at 5 years are roughly 75%)
  
• Poor Prognosis (disease-free survival at 5 years are roughly 50%)
  

Disease-free survival varies by stage and risk, as follows ¹⁶⁸:

• Stage 1 nonseminoma testicular cancer is highly curable (>99%). Orchiectomy alone will cure about 70% of patients, but the remaining 30% will relapse and require additional treatment. The relapses are highly curable, and postorchiectomy surveillance is a standard treatment option, but some doctor and patients prefer to reduce the risk of relapse by having the patient undergo either a retroperitoneal lymph node dissection (RPLND) or one or two cycles of chemotherapy. Each of these three approaches has unique advantages and disadvantages, and none has been shown to result in longer survival or superior quality of life. Patients with stage 1 non-seminoma testicular cancer typically achieve a 98% disease-free survival rate at 5 years.
• Stage 2 nonseminoma is highly curable (>95%). Men with stage 2 nonseminoma testicular cancer and persistently elevated serum tumor markers are generally treated as having stage 3 non-seminoma testicular cancer and receive chemotherapy. For men with normal serum tumor markers after orchiectomy, nonseminomas are divided into stages 2A, 2B, and 2C for treatment purposes. In general, stage 2A patients undergo retroperitoneal lymph node dissection (RPLND) to confirm the staging. As many as 40% of clinical stage 2A patients will have benign findings at retroperitoneal lymph node dissection (RPLND) and will be restaged as having pathological stage 1 disease ¹⁶⁹. Retroperitoneal lymph node dissection (RPLND) can therefore prevent a significant number of patients with clinical stage 2A disease from receiving unnecessary chemotherapy. In contrast, patients with stage 2B and 2C nonseminoma are usually treated with systemic chemotherapy for disseminated disease because these patients have a higher relapse rate after retroperitoneal lymph node dissection (RPLND). One study reported that by limiting retroperitoneal lymph node dissection (RPLND) to patients with earlier stage 2 disease and normal serum tumor markers, 5-year disease-free survival rates increased from 78% to 100% after retroperitoneal lymph node dissection, while disease-free survival rates did not change significantly among stage 2 patients receiving chemotherapy (100% vs. 98%) ¹⁷⁰. However, the question of whether to treat patients with stage 2 nonseminoma germ cell tumors with retroperitoneal lymph node dissection or chemotherapy has never been subjected to a randomized trial. Patients with stage 2A and 2B non-seminoma testicular cancer typically achieve a 92% disease-free survival rate at 5.5 years. Patients with stage 2C non-seminoma testicular cancer can expect an approximately 92% overall survival rate at 5 years.
• Patients with stage 3 non-seminoma testicular cancer classified as low-risk have a 92% overall survival rate at 5 years; intermediate-risk patients have an 80% overall survival rate at 5 years; high-risk patients have a 48% overall survival rate at 5 years.

In a study from Norway, Mykletun et al ¹⁷¹ reported that, at a mean of 11 years of follow-up, men who survived testicular cancer had no clinically significant difference in quality of life compared with age-matched controls. Overall, only minimal differences were seen in quality of life among recipients of different testicular cancer treatment modalities. The apparently excellent quality-of-life results of this study may offer some reassurance regarding the potential for complications and challenges to patients facing the diagnosis and treatment of testicular cancer.

Testicular cancer can usually be cured in patients who receive adjuvant (add-on) chemotherapy or radiation therapy after their primary treatment.

Certain treatments for testicular cancer can cause infertility that may be permanent. Patients who may wish to have children should consider sperm banking before having treatment. Sperm banking is the process of freezing sperm and storing it for later use.

Good Prognosis

For nonseminoma testicular cancer, all of the following must be true:

• The tumor is found only in the testicle or in the retroperitoneum (area outside or behind the abdominal wall); and
• The tumor has not spread to organs other than the lungs; and
• The levels of all the tumor markers are slightly above normal.
  • AFP < 1000 ng/mL and
  • hCG < 5000 IU/L (1000ng/mL) and
  • LDH < 1.5x upper limit of normal

Intermediate Prognosis

For nonseminoma testicular cancer, all of the following must be true:

• The tumor is found in one testicle only or in the retroperitoneum (area outside or behind the abdominal wall); and
• The tumor has not spread to organs other than the lungs; and
• The level of any one of the tumor markers is more than slightly above normal.
  • AFP > 1000 ng/mL and
  • hCG > 5000 IU/L and < 50’000 IU/L
  • LDH > 1.5x and < 10x upper limit of normal

Poor Prognosis

For nonseminoma testicular cancer, at least one of the following must be true:

• The tumor is in the center of the chest between the lungs; or
• The tumor has spread to organs other than the lungs; or
• The level of any one of the tumor markers is high.
  • AFP > 10’000 ng/mL or
  • hCG > 50’000 IU/L (10’000 ng/mL) or
  • LDH > 10x upper limit of normal

Mediastinal choriocarcinoma

Primary non-gestational mediastinal choriocarcinoma is an extremely rare germ cell cancer that is diagnosed in the absence of a primary tumor in the gonads or metastatic disease in the retroperitoneal lymph nodes ¹⁷², ¹⁷³, ¹⁷⁴, ¹⁷⁵. Mediastinal choriocarcinoma represents 1–4% of all mediastinal tumors and less than 5% of all germ cell cancers ¹⁷⁶. Less than 50 cases of non-gestational mediastinal choriocarcinoma have reported since it was first reported in 1931 until 2022 ¹⁷⁷, ¹⁷⁸, ¹⁷⁹, ¹⁸⁰, ¹⁸¹, ¹⁸².

Primary non-gestational mediastinal choriocarcinoma is noted to be more prevalent in men than in women ¹⁸³ and is a clinically aggressive disease despite treatment ¹⁸⁴. Symptoms at the time of presentation frequently include shortness of breath (dyspnea), chest pain, cough, weakness and other common features of metastatic disease ¹⁸⁵. Metastasis to multiple organs, like lung or brain, has usually already occurred by the time the diagnosis is made ¹⁷³. Serologic tumor markers are important in the diagnosis of mediastinal germ cell tumors with elevated human chorionic gonadotropin (hCG) levels present in 30% of mediastinal non-seminomatous carcinomas can aid in the diagnosis ¹⁸⁶, ¹⁸⁷.

Currently, little data exist regarding the most effective treatment for primary non-gestational mediastinal choriocarcinoma ¹⁸⁸, ¹⁸⁴. Surgery, radiation therapy, and chemotherapy remain the mainstays of treatment at this time though prognosis remains poor despite varied treatment options and modalities ¹⁸⁴. Locoregional radiation therapy and surgery can be used for early stages together with aggressive chemotherapy, while later stages have already missed the locoregional therapy ¹⁸⁹. As might be expected, prognosis tend to improve following a combination of surgery and chemotherapy ¹⁹⁰.

Programmed cell death ligand 1 (PD‐L1) inhibitor is a popular alternative therapy in recent years, and PD‐L1 are commonly expressed in choriocarcinoma tumors ¹⁹¹, ¹⁹². Pan and Hou ¹⁹³ reported a case treated with pembrolizumab after an ineffective induction of conventional EP protocol (etoposide, cisplatin) alone. After two cycles, beta‐hCG levels dropped dramatically but soon increased again. The mediastinal tumor shrank after using pembrolizumab, but the cancer also deteriorated quickly. Han et al. ¹⁹⁴ reported that one male with primary neck choriocarcinoma achieved remission after Pembrolizumab combined with chemotherapy ¹⁸¹.

The prognosis for patients with mediastinal choriocarcinoma appears to be poor with the majority of patients dead within a short follow-up time, showing an overall survival time from 20 days to 115 months ¹⁷³, ¹⁹⁵, ¹⁸⁹, ¹⁹⁶, ¹⁹⁷. Lynch and Blewitt ¹⁹⁸ reported a case of a 26-year-old male who succumbed to mediastinal choriocarcinoma two weeks following the diagnosis of choriocarcinoma; the total duration of the illness had been six weeks. Ramia et al ¹⁹⁹ presented the first case of a patient that presented with appendix metastasis from a choriocarcinoma of the mediastinum who underwent an appendectomy and radical surgery of the mediastinal tumor. However, during chemotherapy the patient showed progressive clinical deterioration and succumbed to the disease five months following the appendectomy.

However, some studies have reported long-term survival with mediastinal choriocarcinoma. Kathuria et al ²⁰⁰ reported a case of mediastinal choriocarcinoma where the patient underwent surgery in association with chemotherapy and at the two-year follow-up, no lymphadenopathy was observed and the other physical observations were unremarkable. In addition, Zheng ²⁰¹ reported a case of a young male with primary anterior mediastinal choriocarcinoma that was accompanied by primary cystoid teratoma. The patient underwent surgery in combination with chemotherapy and survived for at least one year. According to the study by Moran et al ²⁰², no patient survived for more than one year; however, one patient survived for one year, although, a brain tumor, which was potentially metastatic, was identified. The level of beta-hCG is considered to be a major factor affecting the prognosis of primary choriocarcinoma of the posterior mediastinum. The treatment of patients with a combination of surgery combined with chemotherapy together with earlier diagnosis is likely to improve the long-term outcome ²⁰³.

Choriocarcinoma causes

There is no known specific cause of choriocarcinoma. Choriocarcinoma develops from an abnormal trophoblastic population undergoing hyperplasia and anaplasia, most frequently following a molar pregnancy ²⁰⁴. There are 2 forms of choriocarcinoma, gestational and non-gestational choriocarcinoma. Gestational choriocarcinoma arises following a hydatidiform mole, normal pregnancy, or most commonly, spontaneous abortion, while non-gestational choriocarcinoma arises from pluripotent germ cells ²⁰⁵. Non-gestational choriocarcinomas in males or females, in the gonads, or midline structures with pluripotent germ cells ²⁰⁵.

The exact pathogenesis of choriocarcinoma has not been fully explained or understood, but studies have shown cytotrophoblastic cells function as stem cells and undergo malignant transformation. The neoplastic cytotrophoblast further differentiates into intermediate trophoblasts and syncytiotrophoblast ²⁰⁶. The mixture of cells mimics the normal development of a previllous blastocyst, a feature seen in other gestational trophoblastic neoplasms ²⁰⁷.

Overexpression of p53 and MDM2 have been demonstrated in choriocarcinoma, with no evidence of somatic mutation. Other genes implicated with either overexpression or down-regulation via hyper-methylation include NECC1, epidermal growth factor receptor, DOC-2/hDab2, Ras GTPase-activating protein, E-cadherin, HIC-1, p16, and TIMP3. HLA-G is demonstrated at very high levels in choriocarcinoma and functions to change the tumor microenvironment through the inactivation of the local immune system ²⁰⁷.

Choriocarcinoma signs and symptoms

Choriocarcinoma signs and symptoms in female patients include history of pregnancy, elevated beta human chorionic gonadotropin (beta-hCG)levels, abnormal uterine bleeding, and abnormal vaginal bleeding and a uterus that is larger than normal. Patients with choriocarcinoma usually have a history of multiple pregnancies. Primary choriocarcinoma is extremely rare in men, manifesting with specific signs such as painless testicular mass, breast feminization (gynecomastia), testicular atrophy,  and loss of libido.

Check with your doctor if you have any of the following:

• Vaginal bleeding not related to menstruation.
• A uterus that is larger than expected during pregnancy.
• Pain or pressure in the pelvis.
• Severe nausea and vomiting during pregnancy.
• High blood pressure with headache and swelling of feet and hands early in the pregnancy.
• Vaginal bleeding that continues for longer than normal after delivery.
• Fatigue, shortness of breath, dizziness, and a fast or irregular heartbeat caused by anemia.

Malignant extragonadal germ cell tumors may cause signs and symptoms as they grow into nearby areas:

• Chest pain.
• Breathing problems.
• Cough.
• Fever.
• Headache.
• Change in bowel habits.
• Feeling very tired.
• Trouble walking.
• Trouble in seeing or moving the eyes.

Gestational trophoblastic disease sometimes causes an overactive thyroid (hyperthyroidism). Signs and symptoms of an overactive thyroid (hyperthyroidism) include the following:

• Fast or irregular heartbeat.
• Shakiness.
• Sweating.
• Frequent bowel movements.
• Trouble sleeping.
• Feeling anxious or irritable.
• Weight loss.

Choriocarcinoma diagnosis

Your doctor should conduct a thorough history and physical examination of any patient with suspected choriocarcinoma. In women, clinicians should pay particular attention to reproductive history because spontaneous abortions and molar pregnancies increase the risk for choriocarcinoma. Women with post-menopausal bleeding is suspicious. Choriocarcinoma tends to metastasize, and clinicians should note symptoms that arise from other organ systems, for example, coughing up blood (hemoptysis) or gastrointestinal bleeding ²⁸.

Due to elevations in human chorionic gonadotropin (hCG) levels, patients can present with abnormal uterine bleeding, gynecomastia (in men), or overactive thyroid (hyperthyroidism) ²⁰⁸.

Males will present can present with symptoms of metastatic disease, often coughing up blood (hemoptysis), but the liver, gastrointestinal tract, and brain are also frequently involved ⁵³.

The following tests and procedures may be used to find and diagnose suspected choriocarcinoma:

• Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
• Pelvic exam: An exam of the vagina, cervix, uterus, fallopian tubes, ovaries, and rectum. A speculum is inserted into the vagina and the doctor or nurse looks at the vagina and cervix for signs of disease. A Pap test of the cervix is usually done. The doctor also inserts one or two lubricated, gloved fingers of one hand into the vagina and places the other hand over the lower abdomen to feel the size, shape, and position of the uterus and ovaries. The doctor or nurse also inserts a lubricated, gloved finger into the rectum to feel for lumps or abnormal areas.
• Ultrasound exam of the pelvis: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs in the pelvis and make echoes. The echoes form a picture of body tissues called a sonogram. Sometimes a transvaginal ultrasound (TVUS) will be done. For transvaginal ultrasound (TVUS), an ultrasound transducer (probe) is inserted into the vagina to make the sonogram.
• Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease. Blood is also tested to check the complete blood count (CBC), coagulation studies, electrolytes, kidney functions, liver functions and bone marrow.
• Serum tumor marker test: A procedure in which a sample of blood is checked to measure the amounts of certain substances made by organs, tissues, or tumor cells in the body. Certain substances are linked to specific types of cancer when found in increased levels in the body. These are called tumor markers. For gestational trophoblastic disease, the blood is checked for the level of beta human chorionic gonadotropin (beta-hCG), a hormone that is made by the body during pregnancy. Beta-hCG in the blood of a woman who is not pregnant may be a sign of gestational trophoblastic disease.
• Urinalysis: A test to check the color of urine and its contents, such as sugar, protein, blood, bacteria, and the level of beta-hCG.
• Laparoscopy: This is a type of surgery that uses a thin, lighted tube so that a doctor can look at the ovaries and other body parts in the area. This helps the doctor tell if the tumor has spread and plan surgery or other treatments.
• Biopsy. In a biopsy, the doctor takes out a little bit of tissue to check it for cancer cells. A biopsy is the only way to tell for sure if you have cancer. For ovarian cancer, the biopsy is most often done when you have surgery to take out the cancer.

After gestational trophoblastic neoplasia has been diagnosed, tests are done to find out if cancer has spread from where it started to other parts of the body. Currently, patients diagnosed with choriocarcinoma are advised to undergo a chest CT scan to check for lung metastasis, and this approach can often help in the early detection of lung metastasis, particularly in asymptomatic patients.

There are three ways that cancer spreads in the body. Cancer can spread through tissue, the lymph system, and the blood:

• Tissue. The cancer spreads from where it began by growing into nearby areas.
• Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
• Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

The process used to find out the extent or spread of cancer is called staging, The information gathered from the staging process helps determine the stage of disease. For choriocarcinoma, stage is one of the factors used to plan treatment.

The following tests and procedures may be done to help find out the stage of choriocarcinoma ²⁸, ²⁰⁹:

• Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body onto film, making pictures of areas inside the body.
• CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
• MRI (magnetic resonance imaging) with gadolinium also called nuclear magnetic resonance imaging (NMRI): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as brain and spinal cord. A substance called gadolinium is injected into a vein. The gadolinium collects around the cancer cells so they show up brighter in the picture.
• Lumbar puncture also called spinal tap: A procedure used to collect cerebrospinal fluid (CSF) from the spinal column. This is done by placing a needle between two bones in the spine and into the CSF around the spinal cord and removing a sample of the fluid. The sample of cerebrospinal fluid (CSF) is checked under a microscope for signs that the cancer has spread to the brain and spinal cord.

Choriocarcinoma staging

The staging system for choriocarcinoma is the the International Federation of Gynecology and Obstetrics (FIGO) staging system and is as follows ²¹⁰, ²¹¹, ²¹², ²⁰⁹:

• Stage 1: Disease limited to the uterus
• Stage 2: Disease extending beyond the uterus, but confined to genital structures
• Stage 3: Metastasis in the lung with or without involvement of female genital tract
• Stage 4: All metastasis at other locations

Choriocarcinoma risk factor scoring

Choriocarcinoma patients are then stratified into low- and high-risk groups to determine treatment based on the following criteria ²¹¹, ²¹³:

• Age
  • 0: Younger than 39 years old
  • 1: Greater than 39 years old
• Antecedent Pregnancy
  • 0: Mole
  • 1: Abortion
  • 2: Term
• Pregnancy Event to Treatment Interval
  • 0: Less than 4 months
  • 1: 4 to 6 months
  • 2: 7 to 12 months
  • 4: Greater than 1 year
• Pretreatment beta-hCG (mIU/ml)
  • 0: Less than 10³
  • 1: 10³ to 10⁴
  • 2: 10⁴ to 10⁵
  • 4: Greater than 10⁵
• Largest Tumor Mass
  • 0: Less than 3 cm
  • 1: 3 to 4 cm
  • 2: Greater than 5 cm
• Site of Metastases
  • 0: None
  • 1: Spleen, kidney
  • 2: Gastrointestinal (GI) tract
  • 4: Brain, liver
• Number of Metastases
  • 0: None
  • 1: 1 to 4
  • 2: 5 to 8
  • 4: Greater than 8
• Previous Failed Chemotherapy
  • 0: None
  • 2: Single-drug
  • 4: Greater than 2 drugs

Cumulative Score

• Low-risk: Less than 7
• High-risk: Greater than 7

Choriocarcinoma pathology outlines

In the classic case of gestational choriocarcinoma, the tumor is derived from chorionic epithelium. Histologically, choriocarcinoma is distinguished by mononucleated cytotrophoblast cells (including intermediate trophoblast cells) alongside multinucleated syncytiotrophoblasts, with an absence of chorionic villi. The syncytiotrophoblasts are multinucleated and have a dark staining cytoplasm. The cytotrophoblasts are mononuclear and have a pale staining cytoplasm ⁵³. Cytotrophoblast cells organize lamellarily to form a villous structure, while syncytiotrophoblasts secrete beta-hCG and human placental lactogen (HPL), observable at the tumor progression margin ²¹⁴, ²¹⁵, ²¹⁶.

Immunohistochemistry plays a crucial role in the differential diagnosis ²¹⁷. GATA binding protein 3 (GATA-3), Spalt-like transcription factor 4 (SALL-4), Cytokeratin (CK) AE1/AE3, and 3-beta-hydroxysteroid dehydrogenase type 1 (HSD3B1) have been identified as potential immunohistochemical markers for gestational choriocarcinoma ²¹⁸, ²¹⁹. A high Ki-67 proliferation index is noted in over 90% of choriocarcinoma cases ⁵.

Choriocarcinoma treatment

The management and treatment of choriocarcinoma are based on recommendations set forth by the FIGO (International Federation of Gynecology and Obstetrics). According to the FIGO, gestational trophoblastic neoplasia (choriocarcinoma) can be divided into two groups: the low-risk group and the high-risk group. For low-risk groups (cumulative risk factor score less than 7), single-agent chemotherapy regimens can be used because the side effects are relatively minor. There are 2 main first-line chemotherapy options for the treatment of low-risk groups including actinomycin D and methotrexate. Comparing these regimens, Cochrane Review 2012 ⁴⁷ have reported that actinomycin D was associated with significantly higher rates of primary cure than methotrexate (five studies, 513 women). Multidrug therapy is the gold standard first-line therapy in metastatic forms of high-risk choriocarcinoma (cumulative risk factor score greater than 7) ²⁰⁹. Currently, EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine) and fluorouracil-based combination regimens are highly recommended for the treatment of high-risk groups (cumulative risk factor score greater than 7). For the past two decades, the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine) regimen has become the most widely accepted therapeutic regimen, positive responses to which have been obtained in 80% to 85% of patients, with an overall survival rate of approximately 100% ⁴⁸. Surgical resection of either the uterus or metastatic foci is utilized in conjunction with chemotherapy in approximately half of the patients with high-risk choriocarcinoma ²⁰⁹.

In contrast to gestational choriocarcinoma, most cases of non-gestational choriocarcinoma are discovered in the advanced stage, and the cancer tends to progress rapidly and be widely metastatic in the short term. Non-gestational choriocarcinoma has been associated with resistance to chemotherapy and a reduced survival rate ⁴⁹, ⁵⁰. Currently, there is no treatment standard for non-gestational choriocarcinoma, but instead, treatment generally follows that of gestational choriocarcinoma ⁵¹. Surgery is an important means of treating for non-gestational choriocarcinoma because the tumor is exclusively derived from the individual in whom arose. However, considering the large tumor sizes, wide invasion sites and easy blood metastasis of non-gestational choriocarcinoma, radical surgery is usually performed after chemotherapy has reduced blood beta-hCG to normal or near-normal levels to relieve the tumor burden, which can shorten the course of treatment and reduce the recurrence rate. For patients with non-gestational choriocarcinoma especially those with other germ cell tumors, BEP (bleomycin, etoposide, and cisplatin) or PVB (cisplatin, vincristine, and bleomycin) regimens are often used. A more effective combination of chemotherapy should be taken into account and applied to the treatment of extragenital non-gestational choriocarcinoma while simultaneously considering the characteristics of the origin site and the components of other tumors. EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine), VIP (etoposide, ifosfamide, and cisplatin), or 5-Fu+KSM+ etoposide regimens may be selected.

Mello et al. ²²⁰ found that non-gestational choriocarcinoma had resistance to the first line of chemotherapy protocol (methotrexate and folinic acid) but exhibited a positive response to the second line of treatment using actinomycin-D at the 60-months follow-up. Inaba et al. ²²¹ propose neoadjuvant chemotherapy (chemotherapy given as a first step to shrink a tumor before the main treatment) in metastatic ovarian non-gestational choriocarcinoma to reduce tumor volume or high-dose chemotherapy before cytoreductive surgery. Currently, there is no standardized chemotherapy regimen for non-gestational choriocarcinoma in males, with high-intensity chemotherapy regimens commonly employed, similar to those used for female choriocarcinoma ²²². Frequently utilized chemotherapy protocols include EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine) and TP (paclitaxel and cisplatin). It is acknowledged that male patients often develop resistance to cytotoxic chemotherapy, leading to a poor prognosis. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and coughing up blood (hemoptysis) due to lung metastasis at the time of diagnosis correlate with shorter survival times in male patients with non-gestational choriocarcinoma, with a median overall survival of approximately 6 months and a 1-month mortality rate of 23.8% ²²³, ²²⁴, ²²⁵, ²²⁶, ²²⁷, ²²⁸. A consistent phenomenon observed in patients with poor prognoses was a rapid decrease in beta-hCG to a lower level during treatment, followed by a sharp rise of beta-hCG during disease relapse ²²⁹. Liu et al. ²¹⁴ study involving non-gestational ovarian choriocarcinoma suggest that, for patients with metastatic disease, a combination of adjuvant (add-on) chemoradiotherapy with palliative surgery is recommended. If serum beta-hCG drops to a normal level and residual lesions persist, salvage surgery to achieve an R0 status is considered worthwhile.

In a case study of a 41-year-old man diagnosed with testicular choriocarcinoma and multiple metastases, including lung, brain, bone, and retroperitoneal lymph node metastases, the patient received treatment with etoposide, cisplatin, and bleomycin ²²². However, metastases remained uncontrolled, resulting in the patient’s death due to increased intracranial pressure and secondary epilepsy exacerbated by enlarged brain metastases ²²². The patient’s overall survival was a mere 5 months following diagnosis ²²².

Following treatment and hCG normalization, quantitative hCG levels should be checked monthly for one year with a physical exam twice in the same time frame. If a subsequent pregnancy occurs, first-trimester pelvic ultrasound should be performed to confirm uterine location due to the small but present risk of recurrent choriocarcinoma; the placenta should be submitted for histologic examination of recurrence ²⁰⁹.

Choriocarcinoma prognosis

Choriocarcinoma prognosis depends on the following:

• Whether the tumor is gestational choriocarcinoma or non-gestational choriocarcinoma
• The size of the tumor and where it is in the body.
• The blood levels of AFP, beta-hCG, and LDH.
• Whether the tumor has spread to other parts of the body.
• The way the tumor responds to initial treatment.
• Whether the tumor has just been diagnosed or has recurred (come back).

Gestational choriocarcinoma and non-gestational choriocarcinoma have different prognoses, with non-gestational choriocarcinoma having poorer prognosis ²³⁰, ²⁰⁵, ²³¹. Non-gestational choriocarcinoma is also much less sensitive to chemotherapy ²¹³. Gestational choriocarcinoma is considered the most curable gynecologic cancer with an overall survival rate from 82% to 100%, even in the presence of metastatic disease ²³². FIGO (International Federation of Gynecology and Obstetrics) prognostic factors include the age of the patient, the type of antecedent pregnancy, the number of interval months from index pregnancy to the diagnosis of gestational trophoblastic neoplasia, pretreatment beta human chorionic gonadotropin (beta-hCG) levels, tumor size, site of metastases, number of metastases, and history of previous failed chemotherapy ²¹¹.

Low-risk gestational choriocarcinoma has almost 100% survival in women treated with chemotherapy, and high-risk gestational choriocarcinoma patients have 91% to 93% survival when utilizing multi-agent chemotherapy with or without radiation and surgery ²¹³. Adverse risk factors making death more likely include stage 4 disease or a cumulative score greater than 12 in women ²⁰⁹.

In men with mixed germ cell tumors, increasing amounts of choriocarcinoma portend a worse prognosis, with pure choriocarcinomas having the worst prognosis in testicular germ cell neoplasms. An hCG greater than 50,000 mIU/ml also correlates to a worse prognosis in men ⁵³.

Intra-placental choriocarcinoma with metastasis to the infant carries a very poor prognosis, with less than 20% survival ²³³.

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