Choriocarcinoma

Overview

Hippocrates initially identified gestational trophoblastic disorders approximately 400 BC. Choriocarcinoma is an uncommon and severe tumor that is a subtype of gestational trophoblastic illness. The biological activity and prognosis of the two major choriocarcinoma subtypes, gestational and non-gestational, are significantly different. Choriocarcinoma most commonly affects women, although it can occasionally affect men, generally as part of a mixed germ cell tumor.

 

Choriocarcinoma definition

Choriocarcinoma is an uncommon and severe neoplastic trophoblastic illness. The two primary kinds of choriocarcinoma are gestational and non-gestational, and their pathogenesis and prognosis are highly different. Choriocarcinoma is more common in women, although it can develop in men as well, frequently as part of a mixed germ cell tumor.

A malignant, rapidly growing tumor formed by trophoblastic cells (cells that help an embryo attach to the uterus and help form the placenta). Almost of choriocarcinomas develop in the uterus following sperm fertilization of an egg, while a small proportion develop in the testis or ovary. Choriocarcinomas travel from the lungs to other organs via the bloodstream.

Choriocarcinoma is a gestational trophoblastic illness (GTD). GTD refers to a group of tumors that appear during the start of a pregnancy.

GTD consists of two categories:

• A noncancerous tumor that forms in the womb during pregnancy is known as a hydatidiform mole (molar pregnancy). Instead of a baby, an egg develops into a tumor. Molar pregnancies can be partial or full. 
• GTN (gestational trophoblastic neoplasia): These are often malignant, and they frequently expand and spread to other regions of the body. Choriocarcinoma, invasive mole, placental-site trophoblastic tumor, and epithelioid trophoblastic tumor are among them.

Choriocarcinomas are uncommon, rapidly developing cancers that can develop even after a loss or ectopic pregnancy (when the fertilized egg implants outside the uterus)

 

Epidemiology

Choriocarcinoma is an extremely uncommon tumor that occurs in varying degrees over the world. In Europe and North America, around one in every 40,000 pregnant women and one in every 40 patients with hydatidiform moles will develop choriocarcinoma. In Southeast Asia and Japan, 9.2 out of every 40,000 pregnant women and 3.3 out of every 40 patients with hydatidiform moles will develop choriocarcinoma.

In China, one in every 2882 pregnant women develops choriocarcinoma. This is associated with an increased incidence of choriocarcinoma in Asian, American Indian, and African American women. Prior full hydatidiform mole (a 100-fold greater incidence), advanced age, long-term oral contraceptive usage, and blood type A are also risk factors.

Choriocarcinoma accounts for less than 0.1 percent of all primary ovarian neoplasms. Choriocarcinoma can also arise in men, mainly between the ages of 20 and 30. Only around 1% of testicular cancers are pure choriocarcinoma. Mixed germ cell cancers are substantially more common in the testicle, with choriocarcinoma accounting for 15% of these tumors.

 

Etiology

Choriocarcinoma arises from an aberrant trophoblastic population that undergoes hyperplasia and anaplasia, most commonly after a molar pregnancy. Choriocarcinoma is classified into two types: gestational and non-gestational. Non-gestational choriocarcinoma develops from pluripotent germ cells after a hydatidiform mole, normal pregnancy, or, most usually, spontaneous miscarriage, whereas gestational choriocarcinoma develops from pluripotent germ cells. Non-gestational choriocarcinomas can develop in either men or females, in the gonads or in midline tissues containing pluripotent germ cells.

 

Pathophysiology

The exact pathophysiology of choriocarcinoma is unknown, although investigations have demonstrated that cytotrophoblastic cells operate as stem cells and undergo malignant transformation. The cancerous cytotrophoblast develops into intermediate trophoblasts and syncytiotrophoblasts. The cell combination resembles the typical development of a previllous blastocyst, as seen in other gestational trophoblastic neoplasms.

Overexpression of p53 and MDM2 has been seen in choriocarcinoma, although no evidence of somatic mutation has been found.

 

Symptoms of choriocarcinoma

Any patient with suspected choriocarcinoma should have a comprehensive history and physical examination performed by a healthcare expert. Clinicians should pay close attention to the reproductive history of women since spontaneous abortions and molar pregnancies enhance the risk of choriocarcinoma. Postmenopausal bleeding should be treated with suspicion. Choriocarcinoma has a tendency to spread, and doctors should be aware of symptoms that come from other organ systems, such as hemoptysis or gastrointestinal (GI) bleeding.

Patients with elevated human chorionic gonadotropin (hCG) levels may experience irregular uterine bleeding, gynecomastia (in men), or hyperthyroidism.

Males may appear with signs of metastatic illness, most often hemoptysis, although the liver, gastrointestinal system, and brain are all frequently implicated.

 

Diagnosis

Many laboratory tests, such as a complete blood count (CBC), coagulation studies, body chemistries, renal function panels, liver function panels, type and screen, and quantitative hCG, can be used to screen for choriocarcinoma.

The United Kingdom registers and monitors all individuals with hydatidiform or molar pregnancies, and begins treatment for gestational trophoblastic illness based on the following criteria:

• Plateaued or rising hCG following uterine evacuation
• Heavy vaginal bleeding
• Gastrointestinal or intraperitoneal bleeding
• Histologic evidence of choriocarcinoma
• Evidence of metastases in brain, liver, or gastrointestinal tract
• Lung opacities greater than 2 cm
• Serum hCG greater than 20,000 IU/L 4 weeks following evacuation
• Elevated hCG greater than 6 months after evacuation even when decreasing

 

Doctors will utilize the following tests and methods to diagnose choriocarcinoma, in addition to a thorough medical history and physical exam:

1. Pelvic exam: A visual and physical examination of the vagina, cervix, rectum, and adjacent regions. An enlarged uterus, which is frequent in choriocarcinoma, might be revealed by the exam.
2. Pap smear: Inserts a speculum into the vagina to examine the inner vaginal region and cervix. A physician will also extract a tiny tissue sample during the exam, which will be submitted to a lab and analyzed for malignant or abnormal cells.
3. Blood tests: Blood is drawn to acquire a complete blood count (CBC), to evaluate HCG levels, or to test for any chemicals often seen in cancer patients. It is crucial to remember that HCG levels will be elevated at the time of diagnosis, even in those who are not pregnant.
4. Pelvic ultrasound: This image depicts the interior of the pelvis. Ultrasounds can detect abnormalities in the uterine lining, as well as the organs and tissues around it.
5. Imaging tests: It is capable of detecting the existence of choriocarcinomas. A magnetic resonance imaging (MRI) scan, an X-ray, or a computerized tomography (CT) scan are a few examples. These tests help the healthcare professional to have a better look inside the body to see whether there are any tumors and how advanced they are.
6. The testicular architecture in males with choriocarcinoma is frequently quite modest or even retreated, leaving mainly metastatic disease and cells.

 

Management

The treatment approach may differ based on the individual's present state of health and the stage of the disease at the time of diagnosis. Other considerations to consider include the size of the tumor, the person's age at the time of diagnosis, and whether the cancer is localized to one part of the body or has spread.

A low-risk choriocarcinoma of stage I to III can be treated with a single drug, either methotrexate or actinomycin D chemotherapy. Multi-agent chemotherapy, adjuvant radiation, and surgery are used to treat high-risk and stage II to IV illness.

Following therapy and hCG normalization, quantitative hCG levels should be evaluated monthly for a year, along with a physical checkup twice during that period. Due to the modest but present risk of recurring choriocarcinoma, a first-trimester pelvic ultrasound should be conducted to establish uterine placement; the placenta should be sent for histologic testing for recurrence.

Low-risk and stage I to III choriocarcinoma is treated with methotrexate or actinomycin D treatment in the United States, with survival rates approaching 100%.

Multi-agent chemotherapy with etoposide, actinomycin D, methotrexate, folinic acid, cyclophosphamide, and vincristine is used as first-line treatment for individuals with high-risk choriocarcinoma in the United States and the United Kingdom.

In the United Kingdom, etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine are often used to treat pregnant choriocarcinoma. Induction treatment with etoposide and cisplatin has demonstrated good outcomes in patients with a significant tumor burden.

In roughly half of the patients with high-risk choriocarcinoma, surgical excision of the uterus or metastatic foci is used in combination with treatment.

 

Staging

The World Health Organization and the International Federation of Gynecology and Obstetrics devised the following choriocarcinoma stage system:

• Stage I: Disease confined to the uterus
• Stage II: Disease extending beyond the uterus, but confined to genital structures
• Stage III: Disease extending to the lungs
• Stage IV: Disease invading other metastatic sites

 

Criteria

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

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 hCG (mIU/ml)

• 0: Less than 10^3
• 1: 10^3 to 10^4
• 2: 10^4 to 10^5
• 4: Greater than 10^5

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: 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

 

Prognosis

The prognosis of prenatal choriocarcinoma differs from that of non-gestational choriocarcinoma, with non-gestational choriocarcinoma having a substantially poorer prognosis. The latter is also significantly less chemosensitive. The distinction between gestational and non-pregnant choriocarcinoma is highlighted by genotyping; gestational choriocarcinoma frequently contains a paternal chromosome complement, whereas non-gestational choriocarcinoma has DNA that matches the patient, with occasional karyotype anomalies.

In women treated with chemotherapy, low-risk pregnant choriocarcinoma has almost 100 percent survival, while high-risk gestational choriocarcinoma has 91 percent to 93 percent survival when using multi-agent chemotherapy with or without radiation and surgery. In women, adverse risk factors that increase the likelihood of mortality include stage IV illness or a cumulative score more than 12.

Increased quantities of choriocarcinoma in males with mixed germ cell tumors foreshadow a poorer prognosis, with pure choriocarcinomas having the poorest prognosis in testicular germ cell neoplasms. In men, hCG levels more than 50,000 mIU/ml are associated with a poor prognosis.

Intra-placental choriocarcinoma with neonatal metastases has an extremely dismal prognosis, with fewer than 20% survival.

 

Complications

Choriocarcinoma can be fatal if left untreated. Chemotherapy has enabled many people to attain remission and cure of their condition. Chemotherapy has a number of dangers, including the development of secondary cancers, nausea, vomiting, hair loss, diarrhea, fevers, infections, and the need for blood transfusions.

Potential complications that may impact the prognosis include:

• Metastasis refers to the spread of cancer to other regions of the body, most notably the liver or the brain.
• Pregnancy symptoms that appeared four months or more before therapy began.
• Following treatment, choriocarcinoma recurs.
• When a diagnosis is made after a woman has already given birth.
• When HCG hormone levels at the start of therapy are greater than 40,000 milli-international units per milliliter.

 

Choriocarcinoma in males (Testicular) 

Testicular choriocarcinoma is a histologic kind of nonseminomatous germ cell tumor, one of the two primary histologic categories of testicular malignancies, along with testicular seminoma. The exception to most of the guidelines outlined for testicular seminoma and all other kinds of nonseminomatous germ cell cancers is pure choriocarcinoma of the testis.

Unlike classic seminoma or mixed germ cell tumors (GCTs), pure choriocarcinoma of the testis is more likely to show with signs and symptoms of metastatic illness, particularly brain metastases. The likelihood of testicular choriocarcinoma should be considered in the differential diagnosis in male patients with metastatic foci from an unknown origin.

Metastases are most commonly seen in the lung, liver, brain, gastrointestinal system, spleen, and adrenal glands. Although uncommon, testicular choriocarcinoma cutaneous metastasis has been documented as angiomas, pyogenic granulomalike tumors, hemorrhagic nodules, or nontender subcutaneous nodules. In one case, a hemorrhagic lump on the lip was the first sign of pure testicular choriocarcinoma, and the diagnosis was discovered only after histologic testing.

Choriocarcinoma syndrome is an uncommon condition that arises in individuals with metastatic choriocarcinoma and significantly high beta–human chorionic gonadotropin levels (beta-hCG). The illness usually appears immediately after starting treatment, however examples of choriocarcinoma syndrome as the first sign of testicular cancer have been described.

The condition is distinguished by metastasis-related bleeding as well as acute hemorrhage from metastates. Any place can be affected, but lung metastases are the most common; patients may appear with a dry cough or hemoptysis, which can lead to severe respiratory failure. The condition is life-threatening and must be treated very away.

The workup for testicular choriocarcinoma should include assays of the following:

• Alpha-fetoprotein (AFP)
• Human chorionic gonadotropin, beta subunit (beta-hCG)
• Liver function

AFP is released by yolk sac components; increased AFP levels are associated with nonseminomatous germ cell cancers. Although choriocarcinoma may be a component of such a tumor, AFP levels in pure choriocarcinoma are within the normal range. AFP has a serum half-life of 5 to 7 days.

Testicular Choriocarcinoma is treated with orchidectomy, chemotherapy, and retroperitoneal lymph node dissection. Because the majority of choriocarcinoma patients have low risk characteristics, initial treatment is followed by radiographic evaluation and staging. The majority of radical orchiectomies are done on the same day or under 24-hour monitoring. This procedure is similar to an inguinal herniorrhaphy, and the patient can expect limited physical activity for a short time afterward. A brief course of pain medication may be necessary following orchiectomy.

In patients who did not respond to first therapy, high-dose chemotherapy with autologous stem cell rescue was employed. In the treatment of advanced nonseminomatous germ cell cancers, a multimodal strategy comprising the urologist and hematologist/oncologist is needed.

 

Prevention

Prior to diagnosis, monthly testicular self-examination should begin during puberty.

Following a diagnosis of testicular cancer, the patient and his treating physician must reach an agreement on stringent adherence to follow-up regimes. Early on, follow-up regimens are common, as malignancies can develop substantially in a short period of time.

 

Conclusion 

Women who have a molar pregnancy, whether whole or partial, should be advised about the risk of developing choriocarcinoma. These individuals should be regularly watched for the clearance of their hCG levels. Any woman who has given birth, but especially if she is at high risk, should be advised to return for more post-partum hemorrhage.

Clinicians caring for patients after molar pregnancy should be aware of the risk of heterophile (human anti-mouse) antibodies appearing in 3% to 4% of patients, leading in erroneously positive high hCG. Serial dilution of serum, which does not exhibit a similar decline with dilution, or sending serum and patient urine to a reference hCG laboratory can be used to ferret out the existence of heterophile antibodies. 

In women with hemoptysis with molar pregnancy, current or recent pregnancy, or irregular vaginal bleeding, choriocarcinoma should be suspected. An interprofessional treatment center staffed by nurses and doctors who specialize in gestational trophoblastic illness can help improve results.