Malignant ovarian and testicular germ cell tumors: Common characteristics but different prognoses

Both ovarian and testicular germ cell tumors (GCTs) arise from the primordial germ cell and share many similarities. Both malignancies affect mainly young patients, show remarkable responsiveness to cisplatin‐based therapy, and have an excellent prognosis, which also highlights the importance of minimizing long‐term side effects. However, certain differences can be noted: The spreading of the disease differs, and the staging system and treatment recommendations are dissimilar. Moreover, the prognosis for ovarian GCTs is significantly inferior to that for testicular cancer, as exemplified in this review comparing the survival in Swedish patients diagnosed with testicular (1995–2022) and ovarian (1990–2018) GCTs. The 5‐year overall survival in ovarian GCTs was 85.2%, versus 98.2% for testicular GCTs. How can this be explained? One reason may be the difference in knowledge, experience, and evidence because the incidence rate of testicular cancer is more than 15 times that of ovarian GCTs. Given the rarity of the disease in women and the lack of established guidelines, a comprehensive understanding of the disease and treatment decisions is challenging. The main objective of this review is to derive insights from testicular GCTs (seminoma and non‐seminoma) by reviewing etiological, tumor biological, and clinical knowledge, and to thereafter suggest actions for ovarian GCTs based on this. We hypothesize that by adopting specific treatment strategies from testicular GCTs—including de‐escalating adjuvant chemotherapy for low‐risk patients and implementing more standardized and intensive treatment protocols in cases of relapse—we can improve the prognosis and minimize long‐term side effects in ovarian GCT patients.


Introduction
Both ovarian and testicular germ cell tumors (GCTs) develop from the primordial germ cells, which are pluripotent precursor cells to our eggs and sperms.Ovarian GCT accounts for only 3%-5% of all ovarian malignancies; however, in women younger than 30 years of age, ovarian GCTs account for 70% of the ovarian malignancies [1].
Likewise, testicular GCT is the most common malignancy in young men [2].
Little is known about the etiology and molecular origin of ovarian GCTs and about risk factors for getting the disease [3,4].The only established risk factor is gonadal dysgenesis, which is secondary to chromosomal disorders [5].For male GCTs, more risk factors are described, but the etiology is still unknown.The incidence of both ovarian and testicular GCTs differs depending on geographic region.The lack of knowledge in this field identifies an unmet need and led us to focus part of this review on etiological similarities and differences between testicular and ovarian GCTs.
The 5-year relative survival for women with GCTs is reported to be between 82% and 94% [6][7][8][9][10][11], generally lower in national population-based cohorts, and constantly reported to be clearly lower than the 98% for males with GCTs [12].Although GCTs are highly malignant, rapidly growing tumors, both women and men with GCTs are most often diagnosed with stage I disease.Advanced disease stage is the most important negative prognostic factor in ovarian GCTs, whereas markedly increased tumor markers [human chorionic gonadotropin (hCG) and alpha fetoprotein (AFP)] and metastasis to liver, bone, and brain are mostly considered for testicular GCTs [13,14].Very few prognostic factors besides high age and advanced stage actually exist for ovarian GCTs [4].However, incomplete surgical resection and yolk sac tumor (YST) histology seem to have a negative impact on prognosis [3].
The extremely good prognosis in testicular GCTs and the somewhat less excellent prognosis in ovarian GCTs raise concerns.The knowledge base for male GCTs is larger because more patients are affected by this disease; the incidence rate of testicular GCT is more than 15 times higher than that for ovarian GCT, and the fine-tuning of care programs has been ongoing for decades.The rarity of the disease in women implies that a clinician sees only a few cases per year, making it more difficult to establish an overall picture of the disease, and clinical studies are scarcer.This can lead to inequality and survival differences that are not intentional gender discrimination on an individual basis but caused by a lack of centralized care of ovarian GCT patients.
Our aim was to carry out a comprehensive review of the etiological, tumor biological, and clinical knowledge of ovarian GCTs (dysgerminoma and non-dysgerminoma) in adult women and to thereby obtain learning points from the male counterpart of testicular GCTs (seminoma and non-seminoma).Because survival data comparing ovarian and testicular GCTs by stage and age were difficult to find, we have used Swedish register data to illustrate survival differences in Swedish patients diagnosed with testicular (1995-2022) and ovarian (1990-2018) GCTs.

Incidence and age differences between ovarian and testicular germ cell tumors
Malignant ovarian GCTs are rare.Although data are diverse regarding incidence, it is most often reported to be approximately 0.3-0.4cases/100,000 [11,15], whereas the incidence for testicular GCTs in Sweden is 7.4/100,000 (Table 1).Were mature teratomas to be included in ovarian GCTs, the incidence of GCTs of the ovary would supersede that of GCTs of the testicle [15][16][17].
The incidence of testicular GCTs is highest in Europe, with the highest incidences recorded in Denmark and Norway.For ovarian GCTs, the incidence seems to be higher in Eastern Asia, Central America, and North America, with variations in different age groups [18].Peak incidence is around 35 years for seminomas and around 25 years for nonseminomas, whereas the peak incidence in ovarian GCTs is around 15-19 years [18,19].
The varying incidence and the young age of patients suggest that both genetic and environmental risk factors might be of relevance in getting the diseases.

Development of ovarian and testicular germ cell tumors
Testicular and ovarian GCTs have a common origin in the primordial germ cell and share similar embryological, pathological, and genetic features (Fig. 1).
The subtype of GCT is dependent on the degree of germ cell differentiation: Seminomas and dysgerminomas originate from pluripotent cells and represent more undifferentiated forms of GCTs.Embryonal carcinomas also arise from pluripotent cells, but they encompass a mixture of Non-seminoma 40%-45% [12] Immature teratoma 35% [10] to 48% [9] Teratoma b Teratoma with malignant transformation 0.2%-3% [10,52] Teratoma with malignant transformation 3%-6% differentiated cells and components that retain embryonic features.The other non-seminoma and non-dysgerminoma subtypes (YSTs, choriocarcinomas, and teratomas) display a higher degree of differentiation and mirror cells that have progressed further along the embryologic developmental pathway [20,21] (Table 1).
At birth, there are over two million oocytes.However, most of these primordial oocytes undergo apoptosis, resulting in only several hundred remaining and maturing cells.The first round of meiosis-meiosis I-will not start until a mature primary oocyte is released during ovulation, whereas the completion of meiosis II occurs upon fertilization.The initiation of spermatogene-sis begins at the onset of puberty.Within the testicles, diploid spermatogonia undergo the phases of meioses I and II, transforming into haploid spermatozoa.Throughout a lifetime, approximately 10 12 spermatozoa are produced, requiring several hundred successive mitoses.The path toward contracting a malignant GCT seems to align with the onset of puberty in both males and females.Notably, the discrepancy in GCT incidence between the two sexes may in part be explained by the lower count of germ cells residing in the ovaries compared to the testicles during adolescence [21,22].
Both ovarian and testicular GCTs have a low mutation rate and marked aneuploidy.The mutation rate ranges from 0.05 to 0.5 mutations per megabase [23][24][25], which is consistent with their embryonal origin.The low mutation rate might also explain the chemo-sensitivity even in advanced or recurrent disease.The mutation rate does not seem to differ between pediatric and adult patients, nor between dysgerminomas and non-dysgerminomas, or seminomas versus non-seminomas.Instead of being of mutational origin, both ovarian and testicular GCTs are hypothesized to result from dysregulation of the mitosis/meiosis, leading to chromosomal abnormalities.The majority of both ovarian and testicular GCTs have gains in chromosome arm 12p and aneuploidy [26,27].

Common risk factors for testicular and ovarian germ cell tumors
To date, evidence of exposures presents early in life, during embryonic development, is the most well-described risk factor for both ovarian and testicular GCTs (Table 2).For testicular GCTs, a family history, cryptorchidism, and previous GCT are the most well-known risk factors.In women, the only established risk factor for GCTs is gonadal dysgenesis, secondary to chromosomal disorders [28].However, the evidence burden in women is much lower than in men.The family history of male GCT, especially in fathers and brothers, is well known [29].For women, one case report describes two patients with a clear family history of GCT in which one son developed testicular cancer and one daughter had an ovarian GCT, indicating this as an interesting area for future investigation also in women [21].Other risk factors in males that would be interesting to investigate for their presence in females include previous GCT in the contralateral gonad (testicle or ovarium) [30], inguinal hernia [31][32][33], other urogenital malformations [31], low birth weight, short gestational age, twinning [34,35], or presence of concomitant neurodevelopmental disorders [36].

Risk factors related to perinatal and pregnancy-related factors
Risk factors that would be unique for women include various features related to pregnancy or childbearing.The impact of number of births and age at childbirth on risk of ovarian GCTs remains unclear.Studies evaluating reproductive factors have been small (typically including fewer than 80 cases) [37][38][39].The two largest studies published to date-including 345 [40] and 188 [41] ovarian GCTs, respectively-reported no association with childbirths in the first study and a trend indicating an increased risk in the second.It has been suggested that intrauterine factors have an impact on the risk of GCTs in the offspring for both ovarian [35,42] and testicular GCTs [43].

Learning objectives in etiological differences
One clinical implication of the increased risk for a new second GCT in men is that a contralateral biopsy is performed at the time of orchiectomy in patients with high-risk characteristics (i.e., age >40 years, cryptorchidism, low sperm count, atrophic testicle, heredity, or microlithiasis) [12].If signs of germ cell neoplasia in situ are present, preventive radiotherapy is indicated.Bilateral ovarian GCTs are rare but can be seen in patients with dysgerminomas (10%-15%) [44].Contralateral biopsies are performed only if obvious signs of pathology are seen on the ovarium during surgery, but not routinely as for males [3].Few studies have investigated the risk of a second primary GCT in the contralateral ovary; however, Liao et al. found that women who received treatment for an ovarian GCT did not have an increased risk of a second ovarian GCT, in contrast to the increased risk of a second testicular GCT in men [45].Nevertheless, further studies would be of interest to determine whether there is an increased risk of a second primary GCT in women and, if not, why this is only a risk factor in men.

Future research
We hypothesize that the field of etiological risk factors would benefit from looking in other or newer directions and conducting large multinational studies with a representative comparator group.The aim would be to study early as well as late exposures, and potential clues might be identified in studies of • differences in embryogenesis, as, for example, the number of maturing germ cells; • differences in environmental exposures, that is, hormone disruptors that are different for males and females; • differences in incidence patterns in different ethnicities; or • differences in tumor biology in patients with rare chromosomal or nonchromosomal aberrations.

Clinical and histological classification
Testicular GCTs are staged according to Royal Marsden, and modified [46] and ovarian GCTs according to the International Federation of Gynecology and Obstetrics (FIGO), which is also used for epithelial ovarian cancer [3] (Table 3).
For prognosis and treatment decisions, prognostic risk groups, according to the International Germ Cell Cancer Collaborative Group (IGCCCG), are used in testicular GCTs, based on histology (seminoma/non-seminoma), localization of the primary tumor (testicular/retroperitoneal versus mediastinal), and/or metastases and levels of tumor markers [47].There is no equivalent prognostic risk group classification for ovarian GCTs.
Although testicular GCTs are only divided into seminomas/non-seminomas, the subtype of ovarian GCTs is most often specified (and not only described as "non-dysgerminomas").
In the latest version of the WHO classification system from 2020, some changes concerning ovarian GCTs can be found.In previous versions, small foci (up to 3 mm) of YST were allowed in immature teratomas (ITs).In the latest update, however, it is specified that any presence of YST in an IT will now reclassify it as a mixed GCT [48].This is in line with classification in testicular GCTs, where a tumor with any number of secondary elements in a seminoma will convert the tumor to a non-seminoma (mixed GCT).However, a dysgerminoma with raised AFP will still be classified as a dysgerminoma, whereas a testicular seminoma with raised AFP will always be considered a non-seminoma [49].It might be of value to add a comment to the diagnosis stating that a nondysgerminoma element may be present and highlight the need for an intensified treatment strategy.Table 1 summarizes the classification of ovarian and testicular GCTs.

Teratomas
Teratomas represent a field where large differences are seen between men and women.Ovarian and prepubertal testicular teratomas seem to be derived from benign germ cells, whereas postpubertal testicular teratomas derive from malignant germ cells [50].Although ovarian mature teratomas and prepubertal testicular teratomas are considered benign, postpubertal testicular teratomas are almost always considered malignant and have the potential to metastasize, regardless of their degree of immaturity [50,51].

Ovarian teratomas
Ovarian mature teratomas-better known as dermoid cysts-are by far the most common ovarian tumor.They contain mature tissue of all three embryonal layers (endoderm, ectoderm, and mesoderm) and are benign.Malignant transformation is rare-0.2%-2% of all mature teratomas [10,52]-and is more common in women older than 50 years of age [17].Squamous cell carcinoma is the most common secondary malignancy [17,53], and treatment is directed toward the transformed histology.In contrast to the benign ovarian mature teratomas, ITs are malignant and account for <1% of all teratomas [54] and represent 35%-48% of all malignant ovarian GCTs [9,10,54].
The diagnosis and grading are based on the presence of immature neuroepithelium (grade 1: The total amount of immature neuroepithelial tissue does not exceed one low-power field in any one slide; grade 2: >1-3 low-power fields on any one slide; grade 3: >3 low-power fields of immature neuroepithelial tissue on any one slide).Berney et al. [49] proposed that ITs would be better termed "teratoma with primitive neuroepithelium" to better describe the malignancy.The grading of ovarian ITs is of importance both for prognosis in children, and-more importantly-for treatment decisions in women.Patients with stage IA-B grade 1 tumors are treated with surgery alone, whereas patients with grade 2 and 3 tumors are recommended adjuvant chemotherapy in international guidelines comprising three to four courses of bleomycin, etoposide, and cisplatin (BEP) [3].In contrast to their male counterparts, ovarian ITs have been considered highly chemosensitive [3,4].However, this has more recently been questioned [15,49], and although randomized clinical trials are lacking, the clinical trial AGCT1531 will evaluate the outcome of recommending surgery alone to patients with stage IA and IB ovarian IT of any grade.A possible explanation behind the difference in chemo-sensitivity between testicular and ovarian teratomas might be that of the misclassification of ovarian mixed GCT to ITs (as mentioned above).

Growing teratoma syndrome
Growing teratoma syndrome is characterized by a transformation of IT deposits into mature teratoma during or after chemotherapy.Previously elevated tumor markers should be normalized, and only mature elements should be present upon histologic examination.In testicular GCTs, the incidence of growing teratoma syndrome ranges from 2% to 8%.The incidence rate is unclear in ovarian GCTs [55] but has been reported to be as high as 20% in IT patients [58].The recommended treatment approach is to perform as complete surgery as possible because it might otherwise cause severe local problems.To avoid growing teratoma syndrome, careful resection of all remaining tumors after the completion of chemotherapy is strongly recommended in testicular non-seminoma patients, as well as in ovarian ITs/mixed GCTs with teratomatous elements.

Prognostic factors and treatment
Do we care too much about histology and too little about other risk factors-such as tumor marker decline, tumor vascular invasion, or tumor sizefor our patients with ovarian GCT?

Stage I disease
Lymphovascular infiltration in the ovarium is not considered in treatment stratification for ovarian GCTs (Table 3).For testicular GCTs, it is the strongest prognostic factor for non-seminoma stage I, where those with lymphovascular infiltration have a relapse risk of ∼50% without treatment.Without lymphovascular infiltration, the risk is much lower-approximately 15% [59][60][61].Larger tumor size is associated with an increasing risk of relapse in testicular GCTs [62], and tumor size is a prognostic factor for relapse in stage I seminomas [63] as well as rete testis invasion.Tumor size is not associated with overall survival in ovarian GCTs [64,65], but its effect on risk for relapse or association with metastatic disease has not been investigated.Ovarian GCTs are seemingly larger at diagnosis (median 15 vs. 3-5 cm in testicular GCTs [62,66,67]), probably due to the localization in the abdomen and lack of symptoms from small ovarian GCT tumors, whereas even small testicular GCTs can give distinct symptoms with a palpable lump in the testicle.Hence, testicular GCTs are potentially easier to detect early.
Patients with testicular non-seminomas with lymphovascular infiltration are recommended postoperative chemotherapy with one course of BEP, whereas patients without this risk factor are recommended surveillance only, although one course of BEP could also be an option [59][60][61]68].However, adjuvant chemotherapy should not be given in the case of teratoma only in the testicular tumor (i.e., no YSTs, choriocarcinoma, embryonal carcinoma, or seminoma).Seminomas with risk factors, that is, tumor size >4 cm or rete testis involvement (15%-20% risk of relapse) are recommended postoperative chemotherapy with one cycle of carboplatin, but surveillance only is also an alternative [12,68].Seminoma patients without these risk factors are recommended for surveillance only.
For ovarian GCT stage I tumors, recommendations regarding postoperative treatment vary in guidelines, but patients are recommended either surveillance or treatment with between two and four cycles of postoperative BEP based on histology and FIGO stage IA-C [3,69].Overall, ovarian GCT patients in stage I tend to receive higher accumulated doses of postoperative chemotherapy (two to three courses of BEP vs. one course of BEP for testicular GCT patients).Studies have shown a low relapse rate and excellent survival with one cycle of adjuvant BEP in stage I testicular non-seminoma, with low toxicity [70,71].Previous studies have also proposed possible overtreatment of adult patients with ovarian GCTs compared to pediatric and male GCTs, with potentially chronic toxicity as a consequence [72].It would be of great value to identify additional risk factors for recurrence of ovarian GCT to thus further identify those patients who would benefit the most from postoperative chemotherapy and those who might benefit from de-escalation of treatment.

Stage II-IV disease
Greatly increased tumor markers and metastasis to liver, bone, and brain are other negative prognostic risk factors in testicular GCTs, and early on, patients are selected for very intensive chemotherapy among men [13] ( In women, only FIGO stage is considered, and no distinguished risk differences exist based on different metastatic regions.In advanced-stage ovarian GCT, cytoreductive surgery is recommended, even though consideration should be taken to avoid delays in postoperative chemotherapy.Four cycles of BEP are recommended for those with advancedstage disease (i.e., not completely resected stages I and II-IV) [3].Adjustments of the treatment according to tumor marker decline are not standardized in ovarian GCT, and the recommendations on intensification/salvage treatment are not as well defined as in testicular GCT.Early intensification to high-dose chemotherapy and autologous stem cell transplant is usually not performed in women.Furthermore, ovarian GCT patients are not divided into risk groups, and all patients receive four cycles of BEP, regardless of tumor burden, which might result in over-treatment for some patient groups.
Knowledge regarding female patients with GCTs could potentially be increased by testing established risk factors from the male counterpart (preferably the level of the tumor markers hCG and AFP) in structured population-based investigations or randomized trials, to see where treatment for women could potentially be improved.Moreover, for newer tumor markers for seminomasuch as placental alkaline phosphatase [75] and miRNA-371a-3p-more evidence is present in male GCT patients [76] than in female GCT patients.Although these markers have not led to any change in clinical practice in male GCTs as yet, their use is upcoming.Hopefully, the future will teach us more, and the markers will be more fully incorporated into treatment guidelines.

Relapse treatment
Men who relapse after primary chemotherapy for a testicular GCT are grouped into prognostic risk score groups according to the International Prognostic Factors Study Group (IPFSG) score, with a more or less favorable prognosis (Table 3) [77].Conventional dose chemotherapy or high-dose chemotherapy are acceptable options for first-salvage chemotherapy in testicular GCTs [63], but in SWENOTECA guidelines, patients with a favorable risk score according to the IPFSG-score will most likely be cured by conventional dose TIP.Patients with an intermediate or worse risk score are recommended for high-dose chemotherapy [12].
In contrast, women with relapse after primary chemotherapy for ovarian GCT are considered having a poor prognosis [3].There are no standardized recommendations for relapse treatment for ovarian GCT, though (T)IP is recommended as a second-line treatment in patients who are considered platinum-sensitive.Although reports have shown that high-dose chemotherapy for recurrent ovarian GCT may result in durable and prolonged remissions, this is not standard treatment, and the role of high-dose chemotherapy is still unclear.Reddy Ammakkanavar et al. [78] concluded in a study of high-dose chemotherapy-treated ovarian GCT patients that the use of high-dose chemotherapy treatment as initial salvage resulted in a higher probability of achieving long-term disease-free survival.Several patients in the series had received what they considered to be inappropriate salvage therapy, such as non-platinum-based regimens or repeated cycles of the same chemotherapy before referral for high-dose chemotherapy.
Due to the rarity and lack of explicit guidelines in recurrent or advanced ovarian GCT, it has been suggested that centralization of care may improve clinical outcomes [79].Better prognosis among patients treated at larger centers has been shown previously in both women [9] and men [80] with GCTs.A European reference network of healthcare providers was formed in 2017 to improve the management of rare gynecological tumors, including ovarian GCTs, and an evaluation of this collaboration was recently published [73].
The international network Malignant Germ Cell International Consortium (MaGIC) collaborates to enable trials for adolescents and young adults with GCTs of both sexes.Treatment strategies for these age groups and ongoing trials are summarized in a recently published review [81].

Survival
The prognosis in both ovarian and testicular GCT is generally good; however, the outcome is constantly reported to be notably better in men than in women.The 5-year cause-specific survival in 2541 ovarian GCTs identified in the Surveillance, Epidemiology and End Results program (SEER) 1978-2020 was approximately 94% (97% in dysgerminoma and 92% in non-dysgerminoma) [6].
In national population-based cohorts, the reported survival has generally been lower; for example, the 5-year net survival among patients diagnosed with ovarian GCTs in France 1989-2010 was 82% [8]; 5-year overall survival for GCT patients diagnosed in the Netherlands 1989-2015 was 73%-88% (with improved survival during the study period) [7], and the 20-year cancer-specific survival in Norwegian patients diagnosed 1980-2009 was 88% [9].
The 5-year overall survival among patients with testicular GCT between 2009 and 2018 was 98% in Sweden.Among patients with seminoma and non-seminoma clinical stage I, the 5-year overall survival was 99.3% and 99.4%, respectively, and among patients with metastases at diagnosis, the overall 5-year survival was 95.3% among seminoma patients and 94.1% among nonseminoma patients [82].Because survival data comparing ovarian and testicular GCTs by stage and age were difficult to find, we analyzed the survival in population-based cohorts with data used in previous studies (testicular [36,83]; ovarian GCTs [84]).In these cohorts of Swedish patients with testicular (4150 with seminomas and 3513 with non-seminomas, 1995-2022) and ovarian (67 with dysgerminomas and 226 with non-dysgerminomas, 1990-2018) GCTs, 10-year overall survival in seminoma patients was 99.1%, compared with 92.8% in dysgerminoma patients (Fig. 2a,b).In non-seminoma patients, 10-year overall survival was 96.6%, compared with 79.3% in non-dysgerminoma patients.Higher age at diagnosis was associated with shorter survival in both men and women (Fig. 2c, p = <0.001:and 1D, p = <0.001).Combined, the 5-year overall survival in ovarian GCTs was 85.2%, which is clearly lower than the 98.2% for testicular GCTs.

Late complications
Because the majority of GCT patients are cured, both acute and long-term side effects of the cancer treatment are of significant importance.Reassuringly, most patients have a general health-related quality of life comparable to people who have not undergone treatment for GCTs [85].However, there is an increased risk of some conditions due to late effects of treatment, such as cardiovascular disease and neuropathy.Because the treatmentparticularly chemotherapy-used in ovarian and testicular GCTs is very similar, learning objectives from studies conducted on the other gender are possible (Table 4).It is relevant to bear in mind that surgically related complications might, of course, differ, as well as complications related to hormonal changes.

Cardiovascular disease and metabolic syndrome
Cardiovascular mortality is higher in testicular cancer survivors than in the general population [86,87], which might be related to treatment toxicity or low testosterone levels with increased risk for metabolic syndrome [88,89].Cisplatin-based chemotherapy increases the risk for cardiovascular disease two-to threefold in comparison to men treated with surgery alone or compared to the general population and may also increase after infradiaphragmatic irradiation [88][89][90].A combination of both chemotherapy and radiotherapy is particularly harmful, with an absolute risk for cardiovascular disease of 20% several years after treatment [89].Cisplatin-based chemotherapy is also associated with an increased prevalence of hypertension and metabolic syndrome, whereas radiotherapy is associated with an increased prevalence of diabetes [89,91,92].
The risk of long-time side effects has been less studied in ovarian GCT patients, and the risk of cardiovascular disease or metabolic syndrome compared to the general population has not been investigated.Long-term follow-up studies of ovarian GCT patients indicate an increased risk of hypertension [93].There are some indications that chemotherapy might have a dose-dependent adverse effect on heart function in women.Mur-braech et al. [93] found an increased risk of impaired right ventricle function and left ventricle diastolic function in ovarian GCT patients treated with high-dose cisplatin-based chemotherapy, but not in women treated with lower doses.
Differences in cardiovascular effects might be related more to the historical use of radiotherapy in testicular GCT patients.Chemotherapy and/or radiotherapy might also have a greater impact on hormonal levels in men than women, with a secondary effect on cardiovascular risk.

Neuropathy
The risk of peripheral sensory neuropathy increases with an increasing number of BEP cycles, from 5% of patients after one cycle of BEP [94] to 25%-35% after three to four cycles of BEP [95].Both cisplatin and bleomycin are associated with the risk of Raynaud's phenomenon [96].
Neuropathy-including Raynaud's phenomenonhas been less studied among ovarian GCT patients, but it seems to be similarly increased [85].A Norwegian study found that although more than half of the ovarian GCT patients treated with cisplatin-based chemotherapy reported neuropathic symptoms, more severe pathological neurological findings were seen in only 10%, and especially in patients treated with more than three cycles of BEP [97].

Tinnitus
Posttreatment of metastatic disease with BEP, 20%-25% of patients report long-term hearing impairment and tinnitus [98], in particular at higher frequencies.Increasing age is an important factor for hearing loss regardless of treatment [99].
Factors that can increase this risk include severe noise exposure prior to treatment, co-treatment with other ototoxic agents (such as aminoglycosides), and abnormal renal function.Compared with age-matched controls, ovarian GCT patients seem to have an increased risk of tinnitus [85], as well as hearing impairment [100].

Secondary malignancies
The risk of secondary malignancy is increased in testicular GCT patients, but not as clearly in ovarian GCT patients.As with cardiovascular disease, this might be explained by the more historical use of radiotherapy in testicular GCT patients.The excess risk of second cancers after cisplatinbased chemotherapy or radiotherapy has been reported to be 40%-80% in testicular GCT patients [101][102][103][104].In a large Norwegian study among 5600 testicular cancer survivors, a 28% excess risk of second cancer after surgery alone compared with the general population was reported, with a significantly increased risk of thyroid cancer and melanoma, which could in part be explained by surveillance bias.However, genetic susceptibility and/or environmental factors predisposing for testicular cancer, as well as other malignancies are likely to be contributing factors [105].
The risk of developing secondary cancer in ovarian GCT patients compared to the general population has not been studied; however, there are two large cohort studies reporting the incidence of secondary malignancies.In a Norwegian populationbased cohort of ovarian GCT patients who were alive 10 years after diagnosis, 23 out of 170 women developed a secondary cancer during follow-up.
Of the 31 patients treated with surgery alone, no one was diagnosed with a secondary cancer, compared with 5 of 41 patients (12%) treated with chemotherapy, and 18 of 98 patients (18%) receiving radiotherapy and/or chemotherapy.Among 10year ovarian GCT survivors treated in the United States in 1978-2010, a second malignancy was diagnosed in 7 of 70 patients (10%) treated with radiotherapy, and 22 of 967 patients (2%) treated with surgery and/or chemotherapy [6].

Fertility
A major concern among young cancer patients is the possibility of being a parent in the future; here, equal understanding between male and female GCT patients seems to be considered.All men aged <56 years in Sweden who are interested in future parenthood should be offered cryopreservation of sperm, as subfertility is common among men diagnosed with testicular cancer and rises with increasing treatment intensity [106].Carboplatin does not seem to affect sex hormones or spermatogenesis [107], nor does one cycle of BEP [108].It is considered safe to conceive 6 months after completing chemotherapy, and neither chemotherapy treatment nor radiotherapy seem to increase the risk of malformations in offspring-although a testicular cancer diagnosis per se is associated with a moderately increased risk of offspring malformations [109].Retrograde ejaculation occurs in 32% of patients after unilateral and 59% after bilateral retroperitoneal lymph node dissection [110].
In all women with a desire to preserve fertility, fertility-sparing surgery is recommended regardless of subtype and disease stage.Cisplatin is generally considered moderately gonadotoxic; however, chemotherapy regimens used for ovarian GCTs have been found to be safe from a fertility perspective in women.In women with GCTs, many lose their menstruation during chemotherapy treatment, but ovulations reoccur in 85%-95%, with a higher risk of amenorrhea with increasing age [111].To reduce the gonadotoxicity during chemotherapy, ovarian suppression with gonadotropin-releasing hormone (GnRH) agonists/luteinizing hormone-releasing hormone analogs (LNRHa) can be considered [112], but it is unclear if this has an impact on fertility rate.Level of serum anti-Müllerian hormone seems to be the most accurate method to evaluate ovarian reserve after cancer treatment [113].Women are encouraged to avoid pregnancy the first 2 years after diagnosis because most relapses occur during this time period.Before attempting a pregnancy, a karyotype examination of the patient should be considered-especially in women with dysgerminomas-to exclude genetic disorder [113].
The chance of conceiving and having a healthy child is good, with pregnancy-rates of at least 75% in patients attempting pregnancy [111,114], and an infertility rate comparable with that of age-matched women [85].Although fertility rates are good, oocyte cryopreservation is an option if chemotherapy treatment can be safely postponed, as hormonal stimulation for oocyte and embryo cryopreservation would delay time to treatment.Further, reimplantation of ovarian tissue after cryopreservation could be associated with a risk of reimplantation of cancer cells.

Hypogonadism/low levels of sex hormones
Late effects after treatment may, to some extent, be caused by lower levels of sex hormones after orchiectomy or oophorectomy as well as being caused by the chemotherapy given.In testicular cancer patients, endocrine hypogonadism is prevalent in 5%-13% of patients after orchiectomy, increasing to 11%-27% after chemotherapy [115,116].Patients treated for testicular GCT should be followed with regular hormonal assessments according to guidelines, and testosterone replacement therapy is recommended for patients with low testosterone levels and clinical symptoms of hypogonadism [68].The effect of unilateral oophorectomy on hormone levels has been less studied.A review from 2021 states that women have a similar age at menopause and chance of pregnancy after unilateral oophorectomy, whereas a decrease in quantity of ovarian pool and an increased risk of both neurological and overall mortality have been observed [117].These data indicate the need to further study the long-term effects after unilateral oophorectomy in GCT patients and possibly substitute decreased hormone levels.Because this is a standard concept in men but not applied in women, it implies unjust biases in surveillance concepts for men and women.

Socio-economic factors
Although rare, being diagnosed with cancer as a young adult at the outset of starting a career, family, or in the midst of an education disrupts not only everyday life but also the anticipated social trajectory.In testicular cancer patients, the longterm impact on work loss varied with the extensiveness of treatment, and a pre-diagnostic history of work loss played a role [118].A recent Norwegian study reported that testicular cancer patients in high-risk groups had a significantly enhanced risk of advanced health outcomes (measured as partnership, educational level, workforce participation, and financial household problems) compared to low-risk groups [119].The study stressed that extensive treatment corresponds to a large proportion of the negative aspects perceived in the future for these patients.Male cancer survivors were also less likely to marry than cancer-free male comparators [120].However, in studies of healthrelated quality of life, testicular cancer patients overall provided similar scores as matched comparators from the general population [121], but a reduced quality of life was seen in testicular cancer patients in need of extensive platinum-based chemotherapy [122].
A case-control study found that fewer of the women treated for ovarian GCT were married or in a relationship and had a lower income than age-matched controls [85].Quality of life as well as psychological health have been good in follow-up studies of ovarian GCT patients [123,124].

Conclusions
Ovarian and testicular GCTs share many characteristics, including young age at diagnosis, shared cell of origin, low mutation rate, and marked aneuploidy.The cisplatin-based therapy and the good prognosis of both ovarian and testicular GCTs underscore the importance of focusing on the longterm effects of the cancer treatment.Considerations about late effects share similarities between men and women with GCTs, but the long-term effects after unilateral oophorectomy in female GCT patients are, in our view, neglected, and possibilities to substitute decreased hormone levels should be considered as is done for males.
The significantly lower incidence of ovarian GCTs, and hence the limited body of evidence, suggests that valuable insights also in treatment concepts and research about etiology could be obtained from the male counterpart of testicular GCTs.Given the notably better prognosis in testicular GCTs, there lies an opportunity to enhance the prognosis in ovarian GCTs by incorporating certain treatment approaches of testicular GCTs.We suggest six action points that aim to improve outcomes in ovarian GCTs: 1. Establish country-based centralized care for ovarian GCT patients to increase knowledge and facilitate both prospective and retrospective trials of different treatment strategies (e.g., trials for young patients initiated by international groups, i.e., the MaGIC consortium).
2. Further investigate prognostic factors to better define risk groups of ovarian GCTs, potentially focusing less on histological subtype and more on factors, such as tumor marker decline, tumor vascular invasion, tumor size, and age at diagnosis.
3. Consider de-escalating adjuvant chemotherapy treatment for low-risk ovarian GCT patients.
4. Define escalation treatment in care programs for ovarian GCT patients with poor tumor marker decline (AFP, hCG) during BEP treatment.
5. Implement more standardized and intensive treatment protocols in the event of relapse of ovarian GCTs and define intensification/salvage treatments in care programs, also considering high-dose treatment with autologous stem cell transplantation in selected patients.
6. Conduct a thorough investigation of late side effects in ovarian GCT patients and include monitoring of hormones during follow-up, as is done for males.
Although the prognosis for patients with testicular GCTs is already good, the fine-tuning of care must continue.Learning points are also possible here.There is a long tradition of performing cytoreductive surgery in advanced stage ovarian GCT patients, and there might be an opportunity to learn from this approach in selected groups of testicular GCT patients.Knowledge of and findings relating to similar etiological factors-such as chromosomal abnormalities-are also of interest because there is an increased risk for men who have a father and a brother with testicular cancer.The novel findings of a slightly increased risk for patients with neurodevelopmental disorders to get seminoma [36] could potentially also be investigated with a closer genetic characterization.Similarities, differences, and suggested learning points are summarized in Fig. 3.
This review has offered a comprehensive evaluation of etiology, tumor biology, and clinical insights about ovarian GCTs (dysgerminoma and nondysgerminoma) in adults and has amassed valuable learning points from the much more prevalent testicular GCTs (seminoma and non-seminoma).We believe that the reasons for the differences in prognosis between men and women with GCTs are multifactorial as described above, but the lack of research and knowledge in women with GCTs due to this being a rarer disease likely contributes.Therefore, centralization of care is important both from a care and research perspective.Hopefully, this will contribute to a deeper understanding of these intriguing malignancies in both men and women.funding to the department.CS and AJ declare they have no conflicts of interest.
Abbreviations: AFP, alpha fetoprotein; N/A, not available; NS, not specified.a Very diverse data regarding age in the literature leading us to calculate this in Swedish data, n = 293 patients diagnosed 1990-2018 in Swedish register data.b Sparse data.

Fig. 1
Fig. 1 The cell of origin, the normal development of sperm and oocytes, and the corresponding tumor development of malignant ovarian and testicular germ cell tumors.The soluble tumor markers present today, alpha fetoprotein (AFP), human chorionic gonadotropin (hCG), lactate dehydrogenase (LDH), placental alkaline phosphatase (PLAP), and micro RNA 371-374 can be used in both males and females.GCNIS: germ cell neoplasia in situ.

Fig. 2
Fig. 2 (a) Overall survival for testicular germ cell tumors (seminoma) in panel (a) is clearly superior to the overall survival for ovarian germ cell tumors (dysgerminoma) shown in panel (b).(c) Overall survival for testicular germ cell tumors (nonseminoma) stratified by age group is clearly superior to (d) figure showing overall survival for ovarian germ cell tumors (non-dysgerminoma), stratified by age group.

Fig. 3
Fig.3Summary of similarities, differences, and learning points in ovarian and testicular germ cell tumors.

Table 1 .
Classification of ovarian and testicular germ cell tumors.

Table 2 .
Factors increasing the risk of ovarian and testicular germ cell tumors.

Table 3 .
Stage and prognostic factors.

Table 4 .
Risk of long-term side effects after cisplatin-based chemotherapy.