Testicular cancer

Most common cancer diagnosis in men age 15-35 years.

Accounts for less than 1% of all male cancers, and less than 0.1% of all cancer deaths.

The most common cancer among young men in developed nations.

The incidence has risen over the past several decades.

Estimated 9500 cases are diagnosed annually in the US.

Testicular germ cell tumors of the testicle account for the vast majority of cases of testicular cancer, with other testicular neoplasms occurring rarely.

Testicular germ cell tumors comprise 95% of malignant tumors arising in the testes and are divided into two main subtypes: seminoma and non-seminoma.

See nonseminomatous testicular cancer

Process is now curable even in patients with metastatic disease.

Testicular germ cell tumors are separated into two main groups: seminoma and nonseminomas, each accounting for approximately 50% of cases.

Factors include personal or family history of testicular cancer and cryptorchidism.

Cisplatin based chemotherapy associated with unprecedented survival rates, with cure rate of 80%.

5-year relative survival rates for all patients with TC is 95%.

1 in 600 men in the US is a testicular cancer survivor, with a gain of upwards of 40 years of life.

For patients with refractory disease standard does chemotherapy is rarely curative.

Survivors of testicular cancer treatments have up to a 7 fold increased long-term risk for cardiovascular disease compared with controls.

There is a high prevalence of metabolic abnormalities in testicular cancer survivors treated with chemotherapy at a relatively young age and shortly after completion of treatment.

Non-seminomas are less common but more aggressive and often include multiple cell types.

When both seminoma and elements of non-seminoma are present, management follows that of a non-seminoma.

The four types of non-seminomas are:embryonal carcinoma, choriocarcinoma, yolk sac tumor, and teratoma.

Most non seminomas are mixed tumors of these four subtypes.

Teratomas are sometimes classified as either mature or immature.

Teratomas rarely have sarcoma or adenocarcinoma elements and referred to as teratoma with somatic type malignancy.

Survivors of testicular cancer have a higher frequency of metabolic syndrome, and particularly is more prevalent in carriers of the minor allele of a single nucleotide polymorhism rs523349.

At a median age of only 38 years three of four testicular cancer survivors are overweight or obese, 43% had hypertension, and is significantly higher proportion have elevated LDL compared with matched controls.

Overall, one in five testicular cancer survivors had metabolic syndrome.

Testicular germ cell tumors (GCT) account for only 1% of male malignancies in the United States.

The most common malignancy in young men 15–35 years old.

A model of curable cancer.

Biochemical markers play a critical role in diagnosis, staging, risk assessment, evaluation of response to therapy and detection of relapse.

Current chemotherapy protocols and surgery yield cure rates exceeding 95%.

Median age at diagnosis of 34.

The age-adjusted incidence rate in the United States is 5.6 per 100,000 men per year based on data from the Surveillance, Epidemiology and End Results (SEER) program.

The lifetime risk of developing testis cancer is approximately 0.4%.

The incidence of GCT, particularly in Caucasian populations, is increasing globally.

The lifetime risk of GCT’s in U.S. Caucasian men is estimated to be 1 in 230.

Estimated that 1.4% of men with newly diagnosed GCT have a positive family history.

In countries with the highest rate of GCTs, such as Denmark, one of the countries with the highest lifetime risk, it exceeds 1%.

The rates of testicular cancer in industrialized nations are five times higher than those in less developed regions.

Significant differences can be noted between neighboring countries and even within regions of the same country.

Immigrant populations carry the risk of their country of birth in the first generation.

The risk of testicle cancers in second generation immigrants shifts toward that of the adoptive population.

While no specific etiological factors have yet been identified, the young age at presentation suggest an environmental risk factor acting in-utero or early in life.

The highest rates occur in Caucasian populations, with the incidence among white men has been five times that of African American men.

Rates of testicular cancer for African American and Hispanic young adults in the U.S. appear to be increasing.

Pacific Islanders, Asian, American Indian and Alaskan Natives have an intermediate risk.

The native Maori of New Zealand, however, has one of the highest incidence of testicular cancer in the world.

Life expectancy in the second year post-diagnosis is nearly identical to the general population.

The contralateral testis may produce a second primary GCT in 2–5% of cases.

Late relapse of GCT affects approximately 3% of patients. with non-seminomatous GCT.

Non-germ cell cancers are becoming an increasing problem following treatment of GCT, with a 40-year cumulative incidence of a second malignant neoplasm approximately one in three.

GCT survivors are at increased risk of developing delayed cardiovascular disease, neuropathy, nephro, oto, pulmonary toxicity, and sexual and fertility impairment.y

In GCT the most consistent chromosomal anomaly in a gain of the short arm of chromosome 12—i(12p).

GCTs are linked to genetic syndromes that include, Klinefelter syndrome which is associated with primary mediastinal GCT, and Down’s syndrome which has an increased rate of testicular seminoma.

Sons of men with testicular GCT have a four- to six-fold increased risk.

Siblings of men with testicular GCT have an increased risk of eight- to ten-fold.

Patients presenting with testicular cancer are divided into seminoma or nonseminomatous germ cell tumors (NSGCT).

Patients with testicular cancer most often present with a painless or painful testicular noldule, mass, enlargement, or induration. 
Often patients present with testicular discomfort or swelling suggestive of epididymitis or orchitis.
Testicular ultrasound can confirm the presence of a testicular mass.
Testicular germ cell tumors or heterogeneous, hypoechoic, and vascular on ultrasound.
Ultrasound finding suspicious for a mass with malignancy, is followed by an inguinal orchiectomy to make a diagnosis.
Transcrotal biopsies are not performed because of the risk of local or atypical regional recurrence and complicate management.
Serum tumor markers including LDH, AFP, beta hCG are assessed before and after orchiectomy.
Rarely, patients present with supraclavicular adenopathy, retroperitoneal mass, gynecomastia, venous thrombosis, or pulmonary embolism.

Management is based on volume of disease assessed using staging studies and tumor marker levels.

In low volume disease the goal is to decrease treatment related morbidity while maintaining a high cure rate.

In patients presenting with advanced disease,the goal of treatment is to improve response to chemotherapy with acceptable patient morbidity.

Seminoma represents approximately 60% of testicular GCTs.

The incidence of testis tumors has risen over the last decade mostly due to seminomas.

At presentation 80% of cases are stage I.

Seminoma cases have a comparatively better prognosis than non-seminoma.

Currently, stage I patients are typically managed by surveillance alone, and stage II by a balance of radiation and chemotherapy.

Radical inguinal orchiectomy is the primary treatment for most patients who present with the testicular mass that is concerning for malignancy on ultrasound.

Concurrent insertion of testicular prosthesis is considered during radical angle orchiectomy if desired by the patient.

Stage I. The main option is observation.

Patients are followed and treatment is opted for only in those who present with retroperitoneal or metastatic disease during follow-up.

With stage I there is almost a 100% survival.

Previously, radiation was given after diagnosis of stage I seminoma disease to prevent relapse.

Radiation for Stage I disease reported high survival rates and relapses were mainly outside of the radiation field.

Classical radiation fields follow areas of nodal involvement from surgical studies of modified retroperitoneal lymph node dissection (RPLND) templates, on the right in the peri-caval and interaorto caval areas down to the common iliac vessels, and on the left, periaortic from the renal vessels to the bifurcation of the common iliac.

Radiation fields go down to the lower border on both sides is placed at a level roughly mid pelvis covering the common iliac nodes yet sparing the bladder and prostate.

For  a patient to stage I non-seminoma, with LVI, invasion of the spermatic cord, or invasion of the scrotum treatment, options include surveillance, adjuvant, chemotherapy, with one cycle of BEP, or nerve sparing or PLND.

20 Gy in 2 Gy daily fractions is ideal, though, carboplatin has an equivalent curing effect.

The main side effects of radiation are sterility, cardiovascular disease and second malignancies.

Shielding of the contralateral testis has a protective effect.

The chance of second malignancies to be twice as high as healthy counterparts.

Surveillance of seminoma patients in stage I is now increasingly preformed.

Disease relapse while on surveillance is seen in 15–20%.

Relapse is confined mainly to the retroperitoneum.

There is high risk for relapse when the primary testis tumor >4 cm and rete testis involvement, and prophylactic treatment with radiation or carboplatin would mean 65% of patients would receive unnecessary treatment.

Most relapses appear in the first 2 to 3 years after diagnosis.

Most current guidelines recommend CT scanning every 6 months for the first 2 to 3 years.

Diagnosis of relapse at an earlier stage with a smaller size of nodal disease allows for cure by radiation alone, whereas a higher disease load or relapse outside of the retroperitoneum necessitates use of chemotherapy.

Single agent carboplatin is the accepted alternative to radiation and surveillance.

One or two cycles of carboplatin have reported relapse rates of 1.8–8.6%.

The Medical Research Council (MRC) compared one cycle of carboplatin to adjuvant radiotherapy in nearly 1,500 patients, showing a 5-year relapse rate of 4% for radiotherapy and 5.3% for chemotherapy.

Low volume retroperitoneal relapsed disease (i.e., less than 5 cm) may be cured by radiation.

Large bulky disease or involvement of other organs is better treated by chemotherapy.

Most cases may be cured by three courses of bleomycin, etoposide and cispatin (BEP) or four courses of EP.

Rare cases of failure of primary chemo may be salvaged by local radiation or second line chemo therapy.

In studies managing stage II seminoma show that for tumor size up to 5 cm radiation is an acceptable treatment modality with a 5-year relapse rate of up to 9%.

Bulkier disease is best treated by chemotherapy with relapse rates of 6–13.5%.

Recent studies have shown the superiority of chemotherapy also in lower stages—seminoma IIa/b.

In older age patients where radiation may have fewer side effects.

A residual mass after radiation or chemotherapy is a unique challenge.

In NSGCT post-chemotherapy residual disease teratoma or cancer may be frequently found.

In most residual seminoma masses harbor fibrosis or necrosis.

PET-CT may reliably indicate the presence of active tumor; therefore a negative PET-CT may allow observation.

Some advocate resection of all masses larger than 3 cm

NSGCT(Non-seminomatous Germ Cell Tumor

Clinical stage I accounts for 50–60% of non-seminomatous testicular tumors.

The risk of occult metastatic disease is dependent on the presence of lymphovascular invasion (LVI) in the tumor.

LVI is present in about 30% of cases and the risk of recurrence is about 50% with LVI versus 15–20% without LVI.

Histological embryonal predominance is a risk factor.

Predominance of embryonal carcinoma’s is an indicator of relapse in stage I non-seminoma, with a high proportion of embryonal carcinoma in the primary tumor of greater than 50% is associated with an increased risk of relapse: search patients are at higher risk and are considered for adjuvant therapy.

Recurrences occur most commonly in the retroperitoneum.

Majority of recurrences are diagnosed within 2 years of orchiectomy.

Stage I management options NSGCT include surveillance, retroperitoneal lymph node dissection, and adjuvant chemotherapy.

Surveillance among patients with clinical stage I NSGCT indicate that approximately one in four patients will recur and require salvage treatment.

Most patients with Stage I NSGCT disease do not benefit from adjuvant therapy, and surveillance is recommended.

50% of those with LVI and 15% of the patients without LVI will later need salvage treatment.

RPLND is not frequently employed today.

RPLND is a diagnostic and a therapeutic procedure.

RPLND is the most accurate means of staging patients with CSI NSGCT; roughly 50% to 70% will be pathologic stage I.

Retroperitoneal recurrence is rare with properly performed RPLND and abdominal CT scan may be omitted after negative RPLND.

In pathologic stage II disease RPLND is curative in 50% to 90% of patients, thus selected patients may avoid adjuvant chemotherapy

50% of LVI positive patients will relapse, therefore adjuvant treatment would spare half of this group from a recurrence requiring three to four courses of chemotherapy and possibly post-chemotherapy surgery (PCS) for a residual tumor.

One course of adjuvant BEP reduces the risk of relapse by 90–95% in all patients.

No recurrences occurred later than 3.3 years post-treatment and as such, follow-up can safely be reduced to 5 years.

Conversely, the other half would receive adjuvant chemotherapy unnecessarily.

Adjuvant chemotherapy is associated with long-term side effects including infertility, secondary malignancies, and increased risk for cardiovascular disease, impaired kidney function, hearing impairment, and peripheral neuropathy.

For CSI NSGCT there are no randomized trials that demonstrate superiority of surveillance or adjuvant treatment, as cure approaches 100% regardless of treatment strategy.

The SWENOTECA study show that adjuvant therapy can be safely reduced to just one course of BEP, resulting in a reduction in relapse rate of 90–95%.

In metastatic NSGCT, the degree of marker elevation before chemotherapy correlates with prognosis.

The International Germ Cell Cancer Collaborative Group has incorporated serum concentrations of human chorionic gonadotrophin (hCG), AFP, and lactic dehydrogenase (LDH) into a prognostic classification system with high, intermediate, and low risk disease.

The serum tumor markers alpha-fetoprotein and beta-human chorionic gonadotropin are critical in determining prognosis and assessing treatment outcomes.

These markers are determined before and after treatment and throughout the follow up period.

LDH is important for determining prognosis and helps stratified patients starting first line chemotherapy for disseminated non-seminomatous tumors.

Beta-hCG is the most commonly elevated serum tumor marker in testicular cancer.

Elevated levels of beta-hCG may be present in both seminomatous and non-seminomatous tumors.

In patients with seminoma and beta-hCG levels greater than 1000 international units/L the possibility of non-seminoma should be considered.

Individuals with post orchiectomy hCG levels of greater than 500,000 IU/L should undergo brain MRI as they are at an increased risk of having brain metastases.

Treatment is tailored according to the risk assignment.

Systemic therapy for metastatic GCT consists of cisplatin-based chemotherapy.

For good risk disease, the accepted standard is three courses of BEP or four courses of EP.

Standard therapy for intermediate and poor risk disease remains four courses of BEP.

Roughly 70% of patients treated with first line chemotherapy will have complete radiographic and biochemical response.

In the remaining 30% a residual mass will persist after chemotherapy, most commonly in the retroperitoneum.

Patients with residual masses larger than 1cm undergo post-chemotherapy retroperitoneal lymph node dissection because of possible residual teratoma (40%) or active cancer.

The management of patients achieving a complete radiographic response to systemic chemotherapy is usually observation.

A study from Indiana University analyzed 141 consecutive patients who achieved complete remission following first-line induction chemotherapy: After a median follow-up of 15.5 years, 12 patients experienced a relapse, of who four died of their disease, with an estimated 15-year cancer-specific survival rate was 97%.

Patients that relapse in the retroperitoneum on observation which is 4%, remain curable.


Leave a Reply

Your email address will not be published. Required fields are marked *