Testicular choriocarcinoma: Rare and Life-threatening

  Introduction:

Choriocarcinoma is malignant, gestational trophoblastic cancer. Group of pregnancy related conditions that are developed inside women's womb is known as gestational trophoblastic disease (GTD). This is a rare type of tumor that mostly affects pregnant women.The cancer which is initially is present in uterus can spread to other parts of body like lungs, kidney and liver. But the cancer is characterized by early hematogenous spread to lungs.

    This type of cancer is classified as germ cell tumor and me a rise in testis also.We will be mainly focusing on choriocarcinoma in testis.

    Testicular choriocarcinoma is the rarest and most aggressive form of all testicular cancers. Testicular choriocarcinoma is non-seminomtous germ cell tumor (NSGCT). Almost all choriocarcinoma can be classified as pure choriocarcinoma or component of mixed germ cell tumor. Germ cell tumors can be classified as either seminomatous or non-seminomatous histologic types, whereas choriocarcinoma is the most aggressive subtype of non-seminomas due to their biologic characteristics.

    International Germ Cell Cancer Collaborative Group (IGCCCG) developed a clinically based prognostic classification for germ cell tumors, which has been used since 1997. The IGCCCG classification stratifies patients into good, intermediate, and poor prognosis subgroups on the basis of three criteria:

•         the primary tumor site,
•         the levels of serum tumor markers,
•      and whether extra-pulmonary visceral metastases are present.

    The majority of the patients with metastatic disease are allocated in the good-risk group, representing 56% of patients with a non-seminomatous germ cell tumor (NSGCT) with a high curability rate >90%, while patients in the intermediate risk (representing 28% of patients with NSCGTs) and poor prognosis groups (representing 16% of patients with NSCGTs) have 5-years survival rates of only 80 and 48%, respectively. The poor-risk NSGCT is defined by the presence of a mediastinal primary tumor, non-pulmonary visceral metastases, or any of the following serum tumor marker elevations:

•         alpha-fetoprotein (AFP) >10,000 ng/mL,
•         human choriogonadotropin (hCG) >50,000 IU/L and/or
•        lactate dehydrogenase (LDH) >10 times the upper limit of normal rely on IGCCCG classification.

    Choriocarcinoma affects younger men between the age of 15 to 30. Choriocarcinoma metastasizes hematogenously with testicular primary tumor. Due to early spread and inherent resistance to anticancer drugs patients have poor prognosis. Patient with testicle choriocarcinoma will have markedly elevated beta HCG level in their blood serum. Since it is a metastatic disease it is most commonly spread to kidney lungs and liver. In severe cases widespread metastases main occur which include skin, gastrointestinal tract and brain. Choriocarcinoma is one of the rarest germ cell tumors and malignancies and have almost less than 1% of the total number of patients to examine.


    Pathological examination:

    Pathological examination show that choriocarcinoma is composed of cytotrophoblasts, intermediate trophoblast and syncytiotrophoblast cells. Cytotrophoblast or layer of langans is the inner layer of trophoblast.

    Trophoblast are the cells that form outer layer of blastocyst  and are present 4 days post fertilization in humans. Blastocyst is distinctive stage of embryo mainly within 5 to 9 days after fertilization. Intermediate trophoblast is a distinct subtypes of trophoblastic tissue that arises from cytotrophoblast.

    Syncytiotrophoblast is it area covering of vascular embryonic placental villi. Syncytiotrophoblast invades the wall of uterus to gain nutrients circulation between embryo and mother.

    Cytotrophoblast mainly resembles trophoblastic stem cells whereas syncytiotrophoblast resembles terminally differentiated cells. Syncytiotrophoblast is seen in plexiform arrangement which often show bizarre, and typical nuclei. Cytotrophoblast cells are mainly found around the foci of hemorrhage.

    In embryo development, syncytiotrophoblast secrets human chorionic gonadotropin hormone (HCG). The patient also contains the same cells in tumor hence high beta HCG is a marker of choriocarcinoma. Choriocarcinoma is also characterized by rapid proliferation, invasiveness, vascularity and tendency to outgrow its blood supply with subsequent necrosis of tumor.

    At early stage of choriocarcinoma the cancer is metastasize to nearest regional lymph nodes along with hematogenous spread to lung liver and brain. In autopsy report, the cause of death in almost 45 percentage patients, suffering from testicular choriocarcinoma is found out to be hemorrhage. The tumour cell directly invade and erode the blood vessels.

    It is supposed to be believed that some products of tumor cells attack blood vessels without  direct invasion. Basically choriocarcinoma is probably massive tumor lysis, which is the result of chemotherapy. But subsequent cytokinin release, aggravated with alveolar hemorrhage can lead to acute respiratory failure and death. Whereas the pathogenesis of acute respiratory failure with testicular choriocarcinoma is multifactorial and involved massive lung metastasis, intra alveolar tumor lysis, early necrosis of tumor and  consecutive super infection which is add on after chemotherapy with neutropenia. Elevated level of cytokines is probably raising the systemic inflammatory response which is directing to multiorgan failure.

    Paraneoplastic hyperthyroidism is induced by high level of HCG in serum. Paraneoplastic hyperthyroidism plays an additional role in pathogenesis of choriocarcinoma. HCG level higher than 50000 U/L is a sign of presence of incidence of hyperthyroidism. HCG is dimeric molecule composed of two subunits, one of the subunit which is identical alpha subunit of TSH. Due to the structural similarity of alpha subunit of TSH and HCG the stimulation of TSH receptor by HCG, lead to thyrotoxicosis and make the patient's condition worse.

    High risk factor: 

    Choriocarcinoma syndrome is a rare but life-threatening condition in “super high-risk” patients with testicular germ cell tumors. Mainly in the patients which are characterized with widespread lung metastases, choriocarcinoma histology, and a high HCG level. Such patients may be not eligible for prospective clinical trials. Their eventual inclusion in reports as early deaths is recommended when interpreting the results of clinical trials in patients with poor-risk TGCTs. 

The optimal therapeutic approach for this group of patients is still incomplete to define. Patients with widespread lung metastases, pure choriocarcinoma, and high hCG should be treated by 2–3 days of full-dose cisplatin and etoposide with the continuation of chemotherapy after the patient′s recovery. Bleomycin should be avoided during induction chemotherapy because it may induce pulmonary fibrosis. However, it should be re-introduced once the patient's condition get better, because its complete omission in the treatment was demonstrated to be detrimental in a prospective randomized trial. 

Prospective translational trials that will lead to a better understanding of the pathophysiology of the choriocarcinoma syndrome and development of new biomarkers for better stratification of super-high-risk patients are warranted. Due to its low prevalence, international collaboration and clinical trials utilizing new treatment strategies are needed to decrease the mortality rate caused by this rare but highly fatal condition.