Germ cell tumors (GCT) , the most common testicular cancer, are broadly categorized as seminomas and nonseminomatous GCT (NSGCT). The incidence of GCT has increased significantly during the last 40 years, predominantly in white men, in association with a simultaneous increase in cryptorchidism, hypospadia, and infertility [1].

Familial testicular GCT, defined as those diagnosed in at least two blood relatives, occurs in 1–2 % of all cases of testicular GCT. The evidence of the existence of a true familial form of GCT is mainly supported by several years of segregation studies, which suggest an autosomal recessive mode of inheritance [4], and more recently, linkage analyses have identified several genomic regions of modest interest on chromosomes 5, 6, and 12. However, no high-penetrance cancer susceptibility gene has been mapped yet [3–5] .

The Y chromosome, which cannot be analyzed by genetic linkage, carries a number of testis- and germ cell-specific genes. In 2005, the potential role of the Y chromosome gr/gr deletion as a familial testicular GCT risk factor was analyzed. This hypothesized association was based on the clear link between male infertility, whose most commonly identified genetic cause is the gr/gr deletion, and testicular GCT. The presence of gr/gr deletion was associated with a twofold increased risk of testicular GCT and more strongly with seminoma [4]. In 2008, a study of the gene DND1 in 263 patients showed that, whether it is disease-causing or not, mutations in DND1make, at most, a very small contribution to testicular GCT susceptibility in adults and adolescents [5]. More recently, germline mutations in phosphodiesterase 11A (PDE11A) were analyzed, concluding that a strong but not perfect concordance between the presence of a testicular tumor and the presence of a mutation existed [4, 5].

Although the genetic basis of familial GCT remains still unknown, two recent genomewide association studies (GWAS) have identified the 12q22 locus as a GCT susceptibility locus in both seminomas and NSGCTs [6, 7]. The 12q22 locus contains KITLG (also known as stem cell factor or steel), which encodes the ligand for the membrane-bound receptor tyrosine kinase, c-KIT. It has been postulated that KITLG may explain the association on chromosome 12, since intratubular germ cell neoplasia cells, seminoma cells, and primordial germ cells all are known to express c-KIT in a membranous pattern by immunohistochemistry techniques . A second association was identified at 5q31, downstream of SPRY4, a negative regulator of the RAS–ERK–MAPK pathway [8]. A functional association between KIT and SPRY4 has been suggested by tumor studies of imatinib-treated gastrointestinal stromal tumors [9] .

Peutz–Jeghers syndrome is a hereditary autosomal dominant disorder associated with considerable morbidity and decreased life expectancy. It is the most common form of hamartomatous polyposis with a reported prevalence of between 1 in 29,000 and 1 in 200,000. Peutz–Jeghers syndrome clinical hallmarks are intestinal hamartomatous polyposis and melanin pigmentation of skin and mucous membranes [1].

Genetically, Peutz–Jeghers syndrome is characterized by mutations in LKB1 (also known as STK11), a tumor suppressor gene located on the short arm of chromosome 19 (19p13.3). Patients are predisposed to multiple neoplasms. The most common malignancies are small intestinal, colorectal, stomach, and pancreatic adenocarcinomas. In the gynecologic tract, the best-known tumors are ovarian sex cord tumor with annular tubules and adenoma malignum of uterine cervix. In male patients, testicular lesions are less well characterized, but tend to develop during childhood and are associated with estrogenic manifestations, notably gynecomastia. An association with testicular tumors, particularly Sertoli cell tumors, sex cord tumors with annular tubules, and aromatase-producing sex cord tumors, is also reported [10] .

The main testicular sex cord stromal tumors described in Peutz–Jeghers syndrome are intratubular large cell hyalinizing Sertoli cell neoplasia and large cell calcifying Sertoli cell tumor . Intratubular large cell hyalinizing Sertoli cell neoplasia is a neoplastic process usually confined to the seminiferous tubules, although it may occasionally progress to invasive Sertoli cell tumor with or without associated calcification. Large cell calcifying Sertoli cell tumor is related to inherited genetic syndromes such as Peutz–Jeghers syndrome and Carney complex in up to 40 % of the cases; however, only a small fraction of syndromic patients (< 27 % of Peutz–Jeghers patients) develop invasive large cell calcifying Sertoli cell tumor[11] .

Carney complex is an autosomal dominant condition characterized by hyperpigmentation of the skin (lentiginosis), myxomas of the heart and skin, endocrine tumors or overactivity, and schwannomas. It is most commonly caused by inactivating mutations of the regulatory subunit 1A of the protein kinase A (PKA) or cAMP-dependent protein kinase (PRKAR1A). The PRKAR1A gene, on chromosome 17q22-q24, may function as a tumor-suppressor gene. Inactivating germline mutations of the PRKAR1A gene are found in 70 % of patients with Carney complex. Germline, protein-truncating mutations of phosphodiesterase type 11A (PDE11A) have been described to predispose to a variety of endocrine tumors, including adrenal and testicular tumors [12]. Less commonly, the molecular pathogenesis of Carney complex is a variety of genetic changes at chromosome 2p16. Despite dissimilar genetics, there appears to be no phenotypic difference between PRKAR1A and chromosome 2p16 mutations [13].

In the series described by Carney, nine patients presented with testicular tumors: large cell calcifying Sertoli cell tumor, Leydig cell tumor , adrenocortical rest tumor, or a combination of these. Large cell calcifying Sertoli tumors are the most common lesions and develop in approximately 30 % of patients within the first decade and in virtually all carriers by adulthood. Large cell calcifying Sertoli tumors may occur alone or may be associated with Leydig cell tumor, Leydig cell hyperplasia, or adrenal cortical rest components [14] .

Sex cord stromal tumors in Carney complex have an apparent indolent natural history with low metastatic potential. Orchiectomy has been standard treatment in the past; however, large cell calcifying Sertoli cell tumors of the testes are overwhelmingly clinically benign, and unless there are significant hormonal changes or complicating symptoms, surveillance may be a preferred management strategy [15]. In patients with Carney complex, enlargement of a solitary testicular tumor to greater than 4 cm is suspicious of malignancy and orchiectomy is typically pursued. Although most unilateral solitary large cell calcifying Sertoli tumors behave in a benign fashion, those exhibiting extratesticular growth and occurring in older patients (mean age 39 years) warrant orchiectomy because of the risk of malignancy [14]. Some authors have suggested that large cell calcifying Sertoli tumors in Carney complex have more benign clinical outcomes when compared with those in Peutz–Jeghers syndrome [15] .

Impaired fertility, defective sperm, and oligospermia have been reported in men with Carney complex. The pathway that leads to infertility seems independent of the presence of testicular sex cord neoplasms, but the presence of a relationship is still unclear [16]. Clinical testing is available for PRKAR1A, and sequencing detects approximately 55 % of mutations. Many different mutations have been reported in the PRKAR1A gene, and in almost all cases, the sequence change leads to a premature stop codon [17]. More than two thirds of patients with Carney complex inherit the mutation from a parent, but approximately 30 % of mutations occur de novo [18] .

Familial adenomatous polyposis (FAP) is a disease classically characterized by the development of hundreds to thousands of adenomatous polyps in rectum and colon during the second decade of life. Almost all patients will develop colorectal cancer. It can have different inheritance patterns and different genetic causes. Attenuated FAP is a less severe form of FAP, marked by the presence of < 100 polyps and a later onset of colorectal cancer. FAP is caused by autosomal dominantly inherited mutations in the APC (adenomatous polyposis coli) gene, a tumor suppressor gene that controls beta-catenin turnover in the Wnt pathway. The APC gene is localized on chromosome 5q21. De novo occurrence is reported in 30–40 % of the patients. Mutations are detected in 85 % of classical FAP families, while only 20–30 % of attenuated FAP cases will exhibit a germline APC mutation. MYH/MUTYH, on chromosome 1p, is the second FAP-related gene and is involved with base-excision repair of DNA damaged by oxidative stress. MUTYH mutations are inherited in an autosomal recessive fashion and account for 10–20 % of classical FAP cases without an APC mutation and for 30 % of attenuated FAP cases [19] .

The prevalence of concomitant testicular and colorectal cancer in the same patient is rare. Recent studies have suggested that the protein APC plays an important role in cell adhesion and migration, which is intricately linked with its tumor-promoting activities. Tanwar et al. have shown that APC is also essential for maintaining the integrity of the seminiferous epithelium [20]. Epigenetic studies suggest the involvement of the APC gene in testicular yolk sac tumor of infants. Loss of heterozygosity at 5q21, where the APC gene is localized, was detected in at least three of nine testicular yolk sac tumors. Promoter methylation was detected in seven of ten infantile yolk sac tumors; of the seven cases showing methylation, three also harbored loss of heterozygosity at 5q21. These data indicate that inactivation of the APC gene, by allelic loss and/or promoter methylation, is related to the occurrence of infantile yolk sac tumors [21] .

A case of bilateral Sertoli cell tumor in a FAP patient has been reported. The bilaterality and overexpression of beta-catenin in this tumor strongly suggests an association between these two events. Also, testicular germ cell tumors have been reported in two siblings in the context of an attenuated FAP linked to mutations in MUTYH[22].