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Testicular Cancer

Testicular Cancer

Overview

Testicular cancer, although an uncommon malignancy, is the most frequently occurring cancer in young men. It is estimated that 8,820 new testicular cancers were diagnosed in the United States in 2014, with approximately 380 deaths. For unknown reasons, the incidence of this cancer has increased since the turn of the century, from 2 cases per 100,000 population in the 1930s, to 3.7 cases per 100,000 population from 1969 to 1971, to 5.4 cases per 100,000 population from 1995 to 1999.

Most testicular tumors are of germ cell origin. Approximately 5% of testicular cancers are of Sertoli cell or Leydig cell (non–germ cell) origin. Testicular germ cell cancers are uniquely sensitive to chemotherapy and are considered the model for the treatment of solid tumors. Overall, cure rates exceed 95%, including 80% for patients with metastatic disease.

Epidemiology

Age

Testicular cancer can occur at any age, but it is most common between the ages of 15 and 35 years. Testicular germ cell tumors are the most common solid tumor in this age group. There is a secondary peak in incidence after age 60. Seminoma is the most common histology in the older population.

Race

Testicular cancer is rare among blacks (1.6/100,000 population), yet black men present with higher-grade disease and have significantly worse survival at 5 and 10 years. The incidence of testicular cancer has increased in whites in the United States and Europe during the past 80 years, whereas the incidence of testicular cancer in African Americans began to increase in the 1990s. Non-Hispanic white patients typically present with disease at early stages when compared with black, Native American, Hawaiian, and Hispanic patients.

Body Size

A recent systematic review and meta-analysis of North American studies showed that testicular cancer was positively associated with adult height and a trend of inverse association with body mass index.

Geography

Denmark has the highest reported incidence of testicular cancer with 1% of the male population affected; East Asia has the lowest incidence of this disease.

Primary Site

Germ cell tumors present most commonly in the testes (90%) and only infrequently in extragonadal sites (10%). The most common extragonadal sites (in decreasing order of frequency) are the retroperitoneum, mediastinum, and pineal gland. Many patients presumed to have a primary retroperitoneal germ cell tumor may have an occult germ cell tumor of the testicle. This possibility should be evaluated with testicular ultrasonography, especially when the retroperitoneal tumor is predominantly one-sided.


TABLE 1: Anticipated cure rates in patients with germ cell tumors, according to disease stage

Survival

rThe 5-year survival rate for all patients with testicular cancer is approximately 95%. Cure rates are highest for early-stage disease, which is treated primarily with surgery or radiation therapy (early seminoma), and lower for advanced disease, for which chemotherapy is the primary therapy (Table 1).

Etiology and Risk Factors

The specific cause of germ cell tumors is unknown, but various factors have been associated with an increased risk of this malignancy.

Prior Testicular Cancer

Perhaps the strongest risk factor for germ cell tumors is a history of testicular cancer. Approximately 1% to 2% of patients with testicular cancer will develop a second primary tumor in the contralateral testis over time. This represents a 500-fold increase in incidence over that noted among the normal male population. In addition, there is a 50% risk of developing testicular cancer over 5 years in men with a diagnosis of testicular carcinoma in situ (CIS), otherwise known as intratubular germ cell neoplasia (ITGCN).

The risk of contralateral testicular cancer was studied in a large population-based cohort of men with testicular cancer diagnosed before the age of 55. For 29,515 cases reported from 1973 through 2001 to the National Cancer Institute’s (NCI) Surveillance, Epidemiology and End Results (SEER) Program, the 15-year cumulative risk of developing metachronous contralateral testicular cancer was 1.9%, reaffirming the practice of not performing a biopsy on the contralateral testis at initial presentation.

Cryptorchidism

Patients with cryptorchidism, which occurs in 2% to 5% of boys born at term, have a fourfold to eightfold increased risk of developing germ cell tumors when compared with their normal counterparts. Orchiopexy, even at an early age, appears to reduce the incidence of germ cell tumor. Wood and Elder conducted an extensive review of the data about cryptorchidism as it related to testicular cancer. The relative risk of testicular cancer in cryptorchidism is 2.75 to 8. A relative risk of 2 to 3 has been noted in patients who undergo orchiopexy by age 10 to 12 years. Patients who undergo orchiopexy after age 12 or who have not had orchiopexy are 2 to 6 times as likely to have testicular cancer.

For an undescended testis, the most common malignant histology is seminoma. For those who undergo early orchiopexy, the most common malignancy is non-seminoma. Of note, in approximately 10% of patients with cryptorchidism who develop germ cell tumors, the cancer is found in the normally descended testis. Biopsies of nonenlarged cryptorchid testes demonstrate an increased incidence of intratubal germ cell neoplasm, a presumed precursor lesion.

Genetics

Klinefelter syndrome (47XXY) is associated with a higher incidence of germ cell tumors, particularly primary mediastinal germ cell tumors. For first-degree relatives of individuals affected with 47XXY, approximately a 6- to 10-fold increased risk of germ cell tumors has been observed. In addition, patients with Down syndrome have been reported to be at increased risk for germ cell tumors. Also thought to be at greater risk are patients with testicular feminization, true hermaphroditism, persistent Müllerian syndrome, and cutaneous ichthyosis. Virtually all adult patients with germ cell tumors have increased copies of isochromosome 12p, usually as i(12p). This is a useful marker in patients with undifferentiated tumors who fit the clinical profile of patients with germ cell malignancy. Although the i12p target genes have not been clearly defined, several candidate genes have been mapped to an amplified region at 12p11 and 12p13. Several other regions of the genome are also imbalanced, at a lower frequency than i12p. 12p is the location of the genes encoding the proteins involved in KITLG-KIT signaling. After KITLG-KIT is aberrantly activated in utero, additional genetic events, including overexpression of transcription factors such as NANOG, SOX17, and OCT3/4, lead to increased proliferation and accumulation of additional mutations. Epigenetic dysregulation also appears to play an important role in subsequent steps leading to the cancer phenotype.Whole-genome sequencing has identified mutations in the tumor suppressor gene CDC27, as well as recurring amplifications at the fibrous sheath interacting protein gene FSIP2, at 2q32.1 and region ar Xq28. A small number of patients may harbor the gene implicated in cisplatin resistance, XRCC2.

 

Family History

Of patients with newly diagnosed testicular cancer, approximately 1.4% have a family history of the disease. The risk of testicular cancer is increased 4- to 6-fold and 8- to 10-fold in sons and siblings of patients with testicular cancer, respectively.

Environment

Numerous industrial occupations and drug exposures have been implicated in the development of testicular cancer. Although exposure to diethylstilbestrol (DES) in utero is associated with cryptorchidism, a direct association between DES and germ cell neoplasm is weak at best.

Reports have suggested an increased risk of testicular cancer among individuals exposed to exogenous toxins, such as Agent Orange and solvents used to clean jets. One author has suggested that on the basis of epidemiologic evidence, exposure to ochratoxin A correlated with incidence data for testicular cancer.

Prior trauma, elevated scrotal temperature (secondary to the use of thermal underwear, jockey shorts, and electric blankets), and recurrent activities such as horseback riding and motorcycle riding do not appear to be related to the development of testicular cancer.

No supporting findings substantiate a viral etiology.

Fertility

An increased risk of infertility exists for men with unilateral testicular cancer successfully treated with orchiectomy. For example, 40% of patients have subnormal sperm counts, and by 1 year, 25% continue to have subnormal sperm counts.

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