Molecular and epigenetic pathogenesis of germ cell tumors

The development of germ cell tumors(GCTs)is a unique pathogenesis occurring at an early developmental stage during specification,migration or colonization of primordial germ cells(PGCs)in the genital ridge.Since driver mutations could not be identified so far,the involvement of the epigenetic machinery during the pathogenesis seems to play a crucial role.Currently,it is investigated whether epigenetic modifications occurring between the omnipotent two-cell stage and the pluripotent implanting PGCs might result in disturbances eventually leading to GCTs.Although progress in understanding epigenetic mechanisms during PGC development is ongoing,little is known about the complete picture of its involvement during GCT development and eventual classification into clinical subtypes.This review will shed light into the current knowledge of the complex epigenetic and molecular contribution during pathogenesis of GCTs by emphasizing on early developmental stages until arrival of late PGCs in the gonads.We questioned how misguided migrating and/or colonizing PGCs develop to either type Ⅰ or type Ⅱ GCTs.Additionally,we asked how pluripotency can be regulated during PGC development and which epigenetic changes contribute to GCT pathogenesis.We propose that SOX2 and SOX17 determine either embryonic stem cell-like(embryonal carcinoma)or PGC-like cell fate(seminoma).Finally,we suggest that factors secreted by the microenvironment,i.e.BMPs and BMP inhibiting molecules,dictate the fate decision of germ cell neoplasia in situ(into seminoma and embryonal carcinoma)and seminomas(into embryonal carcinoma or extraembryonic lineage),indicating an important role of the microenvironment on GCT plasticity.

Surgical treatment of metastatic germ cell cancer

Among young men between the ages of 15 and 40 years,germ cell cancer is the most common solid tumor[1].The worldwide incidence of germ cell cancer is 70000 cases.Compared to all solid tumors of men,germ cell cancer accounts for 1%of all male tumors.Nevertheless,the mortality of this rare tumor entity is about 13%since 9507 patients died worldwide of germ cell cancer.The improvement in survival of germ cell cancer patients is due to a multimodal treatment of germ cell cancer including cisplatin-based chemotherapy and surgery leading to higher cure-rates even in advanced stages[1],whereas the increasing incidence of germ cell cancers cannot be thoroughly explained.In this article we review the current indications for surgery in metastatic germ cell cancers,highlight the strength and weaknesses of techniques and indications and raise the question how to improve surgical treatment in metastatic germ cell cancer.

Testicular germ cell tumors

Optimal quality of cancer care is crucial for best outcomes.This is especially true for patients suffering from testicular germ cell tumors.These patients are very young,sometimes adolescent,usually healthy and cure rates independent of stage of the disease in industrialized countries approach 97%.With these figures,testicular germ cell tumors present a role model for a curable cancer.The life expectancy of patients in early stages with local treatment followed by active surveillance is not limited compared to the general population.In patients with metastatic disease tumor recurrences do not impact on the life expectancy either since most of the recurrences are curable as well.However,in metastatic patients,the long-term sequelae of the initial systemic treatment like secondary malignancies and life-threatening long-term toxicities due to cisplatin meanwhile represent the most frequent causes of death 30 and more years after end of treatment.

PSA screening-for whom and when?

Reasons for and against screening of,prostate cancer have been discussed widely over the last decade.In 2014,the European Randomized Trial for Screening of Prostate Cancer(ERSPC)has reported a relative reduction of the cancer-specific survival of 27%in participants who definitely followed the screeningprotocol.This relative advantage has proven to be stable from year 7 to year 13 after the beginning of screening.Still,the disadvantages of overdiagnosis and overtreatment are the downsides of a population-based screening approach.But given the overall advantage of screening,a risk-adapted prostate-specific antigen(PSA)screening using a baseline PSA value at ages 45-50 may significantly reduce the number needed to diagnose maintaining the benefits of screening.PROBASE is a randomized risk-adapted screening trial currently ongoing in Germany to answer this important question.