Testicular Cancer Papers
Testicular cancer involves the malignant transformation of normal gonocytes into germ cell tumours. It is the most common malignancy amongst men aged 15-35 years, and has a current cure rate of 90%, however incidence amongst Caucasian males is steadily rising.1 There are three main types: teratoma, usually neonates and children; seminoma/nonseminoma, occurs in men >15 years old; and spermatocytic seminoma which occurs in men >50 years old. Seminoma/nonseminoma are the most common, and only malignant type so for relevance it will be the main focus of the essay.
Signs/Symptoms
Testicular cancer, in 95% of cases, is a solid neoplastic mass. It typically presents as a nodule, or a painless swelling in one testicle.1 The next most common symptom …show more content…
is a painful testes, however this pain at presentation is possibly secondary to a haemorrhage or a mass effect linked to the rapid growth of the tumour. Trauma is only observed in one out of ten patients,1 and initially it was regarded as a risk factor but it is now classified as secondary. The enlarged gonad is more prone to injury, and therefore possible detection of the pre-existing tumour is increased. Nearly two thirds of patients with the cancer have abnormal semen analysis,1 however infertility is uncommon as an initial complaint, at less than five percent. In approximately 90% of cases, there is widespread testicular atrophy with impaired to absent spermatogenesis. Despite the external location of the testes, there is normally a delay in diagnosis. The mean delay time is approximately 5 weeks.2 This is important as germ cell tumours show rapid growth, therefore a delay in diagnosis would theoretically allow a possible tumour spread. A delay in diagnosis more than 16 weeks showed a decrease in survival rate.
Risk factors
Genetic predisposition plays a major role in the risk of getting testicular cancer. The risk is eight to ten times higher in a brother of a person with testicular cancer, and is four to six times as high in a son of a sufferer1. Other genetic disorders, including Down’s Syndrome, are also associated with an increased risk. The main risk factors is cryptorchidism, a condition that occurs in 2-5% of boys and involves the patient only having one testicle.1
Pathogenesis
The genetic loci that confer predisposition have been identified, and include embryonic transcription factor Blimp1,1 the genes encoding proteins for KITGL-KIT signalling and abberations on chromosome 12p. The overexpression of embryonic transcription factors, as mentioned above, lead to the suppression of apoptosis, accumulation of mutants and increased proliferation in gonocytes. Other non genetic factors such as exposure to oestrogens and anti-androgens are involved in the increased risk in Northern European populations.2 Epidemiological observations indicate that the effected population of cells leading eventually to the invasive cancer are present only during a limited time window, during foetal development. The embryonic primordial germ cells are discriminated from the regular somatic cells in a process known as specification. If the transcription factor Blimp1 malfunctions, the germ cells are lost.
Clinical behaviours of germ cell tumours depend on the sex and age of the patient, and also the anatomical localisation and the tumours histological composition.3 Testicular cancer is aneuploidy, which refers to the presence of an abnormal number of chromosomes. Increased copy numbers of iso-chromosome 12p are found.1 Seminoma/nonseminoma testicular germ cell tumours are the only malignant type, and the seminomas have a slower growth rate. 60% of all testicular germ cell tumours are a combination of the two types, including some tissues of each kind. Germ cell tumours appear to develop as a result of a tumorigenic event in utero that lead to a precursor lesion, classified as an intratubular germ-cell neoplasia. Seminomas make up 40% and generally spread through regional lymph nodes to other organs, while the other 60%, non-seminomas, tend to metastasize through the lymph nodes particularly to the liver and lungs. Nonseminoma tumours are made up of teratomas, yolk sac, embryonal or choricarcinoma tumours.
The precursor of all testicular germ cell tumours is carcinoma in situ of the testes. The hypothesis for the carcinoma is that the undifferentiated gonocytes persist until adulthood, and then they transform until to neoplastic germ cells. Carcinoma in situ show similarities to the primordial germ cells and gonocytes, such as the erasing of parental imprinting, hypomethylatino and their patterns of gene expression. The development of these tumours is associated with spermatogenesis, but tumour development starts very early, likely in prenatal life.4
The carcinoma in situ cells are located in the inner side of the seminiferious tubules, most often in a single row along the basement membrane in close connection with the Sertoli cells of the adult testes. They are atypical germ cells with distinct borders, separated by delicate septa and lymphoid infiltrate when looked at under the microscope. It is often detected in the adjacent parenchyma of invasive malignant testicular germ cell tumours. No spontaneous regression occurs in these carcinomas, therefore all patients with this lesion will eventually develop an invasive TGCT.4 The primary ‘landing zone’ for metastatic spread in testicular cancer in the retroperitonium
Staging/Detection
Most testicular malignant germ cell tumours in adults are type II tumours, and only a small percentage are type III.3 Stage I testicular cancer means it is is only found in the testes, stage II refers to the progression of the disease to the lymph nodes in the abdonmen and pelvis, and stage III is a spread of the disease to other organs such as the lungs and liver. Accurate staging of the tumour is important and is determined with the use of computed tomography (imaging using waves) of the chest, pelvis and abdomen,4 or biopsy. All patients should undergo pre-orchidectomy ultrasound, and only high-risk patients undergo biopsy.1 In patients where a hypoechoic mass is shown, a testicular biopsy should never be performed. This may contaminate the scrotum, or alter the lymphatic drainage of the tumour.1
Other factors need to be taken into account when staging, such as the degree to which the tumour has metastatised, elevation of tumour markers and histology; such as intraepithelial neoplasias, vascular invasion or syncitiotrophoblasts. Most patients with testicular cancer receive a diagnosis when their disease is in stage one, and they present with a testicular mass. Less frequently however, patients may report with back pain or enlarged retroperitoneal nodes, or symptoms of medastatic disease which include cough, hemoptysis, pain and headaches.
Levels of tumour markers in the blood is an important indicator.
Levels of beta subunit of human corionic gonadotropin and alpha fetoprotein are taken. Levels of lactase dehydrogenase are also measured, but despite it being non specific for testicular cancer it is used as a indicator for the bulk of the disease.
Alpha fetoprotein is a 70 kilodalton single-chain glycoprotein, which in the fetus is synthesised in the liver, GI tract and yolk sac for its role as a major serum binding protein.5 It is related to germ cell tumours as it is produced by yolk sac components, and to a lesser extent embryonal carcinomas and teratomas. It is found in 20%-25% of teratomas, and over 60% of nonseratoma germ cell tumour patients show elevated levels of the protein. It is the most commonly elevated tumour marker for testicular cancer. However, in pure seminoma tumours it is not produced, so it can be an indicator of a mixed tissue tumour.
Human chorionic gonadotropin is a 38 kilodalton protein normally secreted by placental syncytiotrophoblasts that is produced by germ cell tumours. It has two subunits, α and β, but only the β unit is identified by radioimmunoassay techniques.5 Normalisation of the hCG levels after orchiectomy for patients with stage I disease shows evidence that the tumour has been eliminated, but if the levels remain elevated it is a sign there may be a residual disease. It is often only elevated in conjunction with choricarcinomas, embryonal carcinomas or mixed tissue germ cell tumours; and stage I
seminoma.
Finally, lactase dehydrogenase is a cellular enzyme produces by muscles. It has a relatively low specifity for germ cell tumours, so it is taken in the context of the other tumour markers. It is usually elevated in 40-60% of men with testicular cancer.5 It has a limited sensitivity for seminoma, but rising levels are an accurate indicator of recurrence. Lactase dehydrogenase is directly related to tumour burden in nonseminomas.
The tumour markers are important in detection, however they lack sensitivity and specificity. They cannot replace tissue diagnosis and should be taken as a component of the standard surveillance protocol, rather than the basis.
Treatment
Treatment of testicular cancer has a high success rate, currently at 85-90%. There are three main options; orchiectomy, lymph node dissection and chemotherapy. Oriechtomy involves the removal of the testicle, and is the first step in treating the cancer. The tissue from the removal can be helpful in determining pathological diagnosis. Teratomas are not malignant, however they must be surgically removed because they do not respond to radiation or chemotherapy.
Retroperitoneal lymph node dissection is surgically resecting lymph nodes in the retroperitoneum. It can be done bilaterally or unilaterally, as unilaterally is nerve sparing and increases the likelihood that a patient will be able to maintain normal ejaculatory function.7
Chemotherapy before surgical intervention increases the risk of complication. When choosing chemotherapy dosage and repeats, the tumour size, location and performance status of the patient following treatment are all factors. Vascular injury, uretal injury and neurological complications are some of the risks that increase when chemotherapy is undergone before surgery. Time should be allowed for blood counts to recover following chemotherapy, so infection can be prevented and lowered risk of bleeding. The chemotherapy commonly used to treat testicular tumours contains bleomycin, etoposide and cisplatin (BEP) and has been used since the 1970s. It is most efficient at treating patients with stage II or III seminoma and for all stages of seminoma. However, it is not effective for stage I seminoma, in which case radiation therapy to para-aortic lymph nodes is used.
Signs/Symptoms
Testicular cancer, in 95% of cases, is a solid neoplastic mass. It typically presents as a nodule, or a painless swelling in one testicle.1 The next most common symptom …show more content…
is a painful testes, however this pain at presentation is possibly secondary to a haemorrhage or a mass effect linked to the rapid growth of the tumour. Trauma is only observed in one out of ten patients,1 and initially it was regarded as a risk factor but it is now classified as secondary. The enlarged gonad is more prone to injury, and therefore possible detection of the pre-existing tumour is increased. Nearly two thirds of patients with the cancer have abnormal semen analysis,1 however infertility is uncommon as an initial complaint, at less than five percent. In approximately 90% of cases, there is widespread testicular atrophy with impaired to absent spermatogenesis. Despite the external location of the testes, there is normally a delay in diagnosis. The mean delay time is approximately 5 weeks.2 This is important as germ cell tumours show rapid growth, therefore a delay in diagnosis would theoretically allow a possible tumour spread. A delay in diagnosis more than 16 weeks showed a decrease in survival rate.
Risk factors
Genetic predisposition plays a major role in the risk of getting testicular cancer. The risk is eight to ten times higher in a brother of a person with testicular cancer, and is four to six times as high in a son of a sufferer1. Other genetic disorders, including Down’s Syndrome, are also associated with an increased risk. The main risk factors is cryptorchidism, a condition that occurs in 2-5% of boys and involves the patient only having one testicle.1
Pathogenesis
The genetic loci that confer predisposition have been identified, and include embryonic transcription factor Blimp1,1 the genes encoding proteins for KITGL-KIT signalling and abberations on chromosome 12p. The overexpression of embryonic transcription factors, as mentioned above, lead to the suppression of apoptosis, accumulation of mutants and increased proliferation in gonocytes. Other non genetic factors such as exposure to oestrogens and anti-androgens are involved in the increased risk in Northern European populations.2 Epidemiological observations indicate that the effected population of cells leading eventually to the invasive cancer are present only during a limited time window, during foetal development. The embryonic primordial germ cells are discriminated from the regular somatic cells in a process known as specification. If the transcription factor Blimp1 malfunctions, the germ cells are lost.
Clinical behaviours of germ cell tumours depend on the sex and age of the patient, and also the anatomical localisation and the tumours histological composition.3 Testicular cancer is aneuploidy, which refers to the presence of an abnormal number of chromosomes. Increased copy numbers of iso-chromosome 12p are found.1 Seminoma/nonseminoma testicular germ cell tumours are the only malignant type, and the seminomas have a slower growth rate. 60% of all testicular germ cell tumours are a combination of the two types, including some tissues of each kind. Germ cell tumours appear to develop as a result of a tumorigenic event in utero that lead to a precursor lesion, classified as an intratubular germ-cell neoplasia. Seminomas make up 40% and generally spread through regional lymph nodes to other organs, while the other 60%, non-seminomas, tend to metastasize through the lymph nodes particularly to the liver and lungs. Nonseminoma tumours are made up of teratomas, yolk sac, embryonal or choricarcinoma tumours.
The precursor of all testicular germ cell tumours is carcinoma in situ of the testes. The hypothesis for the carcinoma is that the undifferentiated gonocytes persist until adulthood, and then they transform until to neoplastic germ cells. Carcinoma in situ show similarities to the primordial germ cells and gonocytes, such as the erasing of parental imprinting, hypomethylatino and their patterns of gene expression. The development of these tumours is associated with spermatogenesis, but tumour development starts very early, likely in prenatal life.4
The carcinoma in situ cells are located in the inner side of the seminiferious tubules, most often in a single row along the basement membrane in close connection with the Sertoli cells of the adult testes. They are atypical germ cells with distinct borders, separated by delicate septa and lymphoid infiltrate when looked at under the microscope. It is often detected in the adjacent parenchyma of invasive malignant testicular germ cell tumours. No spontaneous regression occurs in these carcinomas, therefore all patients with this lesion will eventually develop an invasive TGCT.4 The primary ‘landing zone’ for metastatic spread in testicular cancer in the retroperitonium
Staging/Detection
Most testicular malignant germ cell tumours in adults are type II tumours, and only a small percentage are type III.3 Stage I testicular cancer means it is is only found in the testes, stage II refers to the progression of the disease to the lymph nodes in the abdonmen and pelvis, and stage III is a spread of the disease to other organs such as the lungs and liver. Accurate staging of the tumour is important and is determined with the use of computed tomography (imaging using waves) of the chest, pelvis and abdomen,4 or biopsy. All patients should undergo pre-orchidectomy ultrasound, and only high-risk patients undergo biopsy.1 In patients where a hypoechoic mass is shown, a testicular biopsy should never be performed. This may contaminate the scrotum, or alter the lymphatic drainage of the tumour.1
Other factors need to be taken into account when staging, such as the degree to which the tumour has metastatised, elevation of tumour markers and histology; such as intraepithelial neoplasias, vascular invasion or syncitiotrophoblasts. Most patients with testicular cancer receive a diagnosis when their disease is in stage one, and they present with a testicular mass. Less frequently however, patients may report with back pain or enlarged retroperitoneal nodes, or symptoms of medastatic disease which include cough, hemoptysis, pain and headaches.
Levels of tumour markers in the blood is an important indicator.
Levels of beta subunit of human corionic gonadotropin and alpha fetoprotein are taken. Levels of lactase dehydrogenase are also measured, but despite it being non specific for testicular cancer it is used as a indicator for the bulk of the disease.
Alpha fetoprotein is a 70 kilodalton single-chain glycoprotein, which in the fetus is synthesised in the liver, GI tract and yolk sac for its role as a major serum binding protein.5 It is related to germ cell tumours as it is produced by yolk sac components, and to a lesser extent embryonal carcinomas and teratomas. It is found in 20%-25% of teratomas, and over 60% of nonseratoma germ cell tumour patients show elevated levels of the protein. It is the most commonly elevated tumour marker for testicular cancer. However, in pure seminoma tumours it is not produced, so it can be an indicator of a mixed tissue tumour.
Human chorionic gonadotropin is a 38 kilodalton protein normally secreted by placental syncytiotrophoblasts that is produced by germ cell tumours. It has two subunits, α and β, but only the β unit is identified by radioimmunoassay techniques.5 Normalisation of the hCG levels after orchiectomy for patients with stage I disease shows evidence that the tumour has been eliminated, but if the levels remain elevated it is a sign there may be a residual disease. It is often only elevated in conjunction with choricarcinomas, embryonal carcinomas or mixed tissue germ cell tumours; and stage I
seminoma.
Finally, lactase dehydrogenase is a cellular enzyme produces by muscles. It has a relatively low specifity for germ cell tumours, so it is taken in the context of the other tumour markers. It is usually elevated in 40-60% of men with testicular cancer.5 It has a limited sensitivity for seminoma, but rising levels are an accurate indicator of recurrence. Lactase dehydrogenase is directly related to tumour burden in nonseminomas.
The tumour markers are important in detection, however they lack sensitivity and specificity. They cannot replace tissue diagnosis and should be taken as a component of the standard surveillance protocol, rather than the basis.
Treatment
Treatment of testicular cancer has a high success rate, currently at 85-90%. There are three main options; orchiectomy, lymph node dissection and chemotherapy. Oriechtomy involves the removal of the testicle, and is the first step in treating the cancer. The tissue from the removal can be helpful in determining pathological diagnosis. Teratomas are not malignant, however they must be surgically removed because they do not respond to radiation or chemotherapy.
Retroperitoneal lymph node dissection is surgically resecting lymph nodes in the retroperitoneum. It can be done bilaterally or unilaterally, as unilaterally is nerve sparing and increases the likelihood that a patient will be able to maintain normal ejaculatory function.7
Chemotherapy before surgical intervention increases the risk of complication. When choosing chemotherapy dosage and repeats, the tumour size, location and performance status of the patient following treatment are all factors. Vascular injury, uretal injury and neurological complications are some of the risks that increase when chemotherapy is undergone before surgery. Time should be allowed for blood counts to recover following chemotherapy, so infection can be prevented and lowered risk of bleeding. The chemotherapy commonly used to treat testicular tumours contains bleomycin, etoposide and cisplatin (BEP) and has been used since the 1970s. It is most efficient at treating patients with stage II or III seminoma and for all stages of seminoma. However, it is not effective for stage I seminoma, in which case radiation therapy to para-aortic lymph nodes is used.