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Table of Contents
CASE REPORT
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 89-95

Fertility preservation in testicular seminoma


1 Clinical Director, Dr. Patil's Fertility and Endoscopy Clinic, Bengaluru, Karnataka, India
2 Fellow in Reproductive Medicine, Dr. Patil's Fertility and Endoscopy Clinic, Bengaluru, Karnataka, India

Date of Web Publication22-Feb-2019

Correspondence Address:
Madhuri Patil
Dr. Patil's Fertility and Endoscopy Clinic, Bannerghatta Road, Bengaluru - 560 029, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tofj.tofj_3_18

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  Abstract 


Testicular cancer is the most common solid malignancy affecting males between the ages of 15 and 35, although it accounts for only 1% of all cancers in men. Germ cell tumors (GCTs) account for 95% of testicular cancers. Two broad categories of testicular tumors have been described, one pure seminoma (no nonseminomatous elements present) and the other is nonseminomatous GCTs. It is one the most curable neoplasm with 5 years survival rate of 98%–99% when diagnosed at an early stage. We present here one such case of metastatic seminoma, where the semen was cryopreserved for fertility preservation. Although the sample was oligoasthenospermic, a successful pregnancy and live birth was obtained with intrauterine insemination of the frozen sample in an controlled ovarian stimulation cycle. Testicular tumors can impair fertility after treatment in majority of patients. Fertility preservation methods such as semen freezing, sperm freezing using epididymal or testicular sperm extraction (TESE) or testicular tissue freezing provides hope for those who wish to father a child latter.

Keywords: Fertility preservation, metastatic, seminoma, testicular tumors


How to cite this article:
Patil M, Reddy P. Fertility preservation in testicular seminoma. Onco Fertil J 2018;1:89-95

How to cite this URL:
Patil M, Reddy P. Fertility preservation in testicular seminoma. Onco Fertil J [serial online] 2018 [cited 2019 Mar 23];1:89-95. Available from: http://www.tofjonline.org/text.asp?2018/1/2/89/252688




  Introduction Top


Overall incidence of testicular germ cell tumors (GCTs) is low, at only 1%–2% of all male malignancies,[1] but it remains the most common cancer in the 15–35 years age group.[2] 95% are GCTs and are bilateral in 3% of the cases.[3] The incidence varies across the globe with reportedly higher occurrence in the developed and Western countries. India has the lowest age-standardized incidence of 0.5/100,000 men.[4] Seminoma accounts for about a third of all testicular germ cell malignancies and is one of the most treatable cancers with a survival rate of 98% to 99% in early-stage disease.[5] It has high cure rates due to its extreme sensitivity to chemotherapy and radiotherapy.

Testicular GCT (TGCT) accounts for the vast majority (98%) of testicular cancers. For treatment purposes, TGCTs are grouped into two broad categories. These are seminomas and nonseminomas.[6] Seminoma is a slow-growing form of testicular cancer found in men in their 30s and 40s and can spread to the lymph nodes (LNs). These tumors are very sensitive to radiation therapy and chemotherapy.

Below is the list of different types of nonseminomatous GCTs (NSGCTs).

  • NSGCTs could be:


    • Choriocarcinoma
    • Embryonal carcinoma
    • Teratoma
    • Yolk sac tumor
    • Stromal tumors
    • Leydig cell Sertoli cell tumors.


Pure seminoma may be associated with raised blood levels of human chorionic gonadotrophin (HCG), which may also be raised in NSGCTs; however, raised alfa-fetoprotein (AFP) would suggest a nonseminomatous origin.

Testicular tumors usually present as a nodule or painless swelling of one testicle, which may be noted incidentally by the patient or by his sexual partner.[7] Occasionally, a man with a previously small atrophic testis will note enlargement. Approximately 30%–40% of patients complain of a dull ache or heavy sensation in the lower abdomen, perianal area, or scrotum, whereas acute pain is the presenting symptom in 10%. GCT may present extragonadally in the retroperitoneum or mediastinum in a small percentage of cases. The first symptom may be due to metastatic disease in approximately 10% of patients. Symptoms vary with the site of metastasis and can present with a neck mass (supraclavicular LN metastasis), cough or dyspnea (pulmonary metastasis), anorexia, nausea, vomiting, or gastrointestinal hemorrhage (retroduodenal metastasis), lumbar back pain (bulky retroperitoneal disease involving the psoas muscle or nerve roots), bone pain (skeletal metastasis), central or peripheral nervous system symptoms (cerebral, spinal cord, or peripheral root involvement), and unilateral or bilateral lower extremity swelling (iliac or caval venous obstruction or thrombosis). Gynecomastia may be a systemic endocrine manifestation seen in about 5% of men with TGCTs.[8]

Tumor markers (AFP, β-HCG, and lactate dehydrogenase [LDH]) are needed to differentiate between seminomas and NSGCTs and also for risk assessment and prognosis. Nonseminomas often raise AFP and/or HCG levels. Pure seminomas occasionally raise HCG levels but never AFP levels. A high-LDH level often indicates widespread disease. Patients with raised AFP should be managed as for nonseminoma, even if histology is pure seminoma. These tumor markers are done before orchiectomy and repeated after 7 days after orchiectomy. Testicular sonography (7.5 MHz transducer) of the affected testis and the contralateral testis should be conducted to rule out bilateral disease. Abdominal computed tomography (CT) should be done to look for retroperitoneal and pelvic LN enlargement. Thoracic CT scan is indicated only in advanced disease. Magnetic resonance imaging (MRI) of the central nervous system is needed only in advanced stages or with symptoms. Bone scan should be conducted in case of indirect indicators for involvement (e.g., symptoms). Positron emission tomography scanning again should be done on in Stage II/III disease so that the correct treatment strategy is chosen, especially in case of a residual tumor. In case of a borderline LN enlargement during the evaluation is observed (normal <1 cm), the CT scan should be repeated 6 weeks later before deciding on the definitive treatment strategy (radio/chemotherapy). If imaging is normal, the patient should be monitored for the decline of tumor marker until normalization. If the tumor markers remain high or plateau one could make a diagnosis of disseminated disease. The investigations that are done in men with GCTs is shown in [Figure 1].
Figure 1: Investigations in men with germ cell tumors

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If the man has not yet fathered children and/or desires fertility preservation, a semen analysis with ejaculate or testicular sperm/testicular tissue cryopreservation should be advised before surgery and radio/chemotherapy. In case of any sperm pathology (oligo/astheno/terato zoospermia) one should advise evaluation of total testosterone, lutenizing hormone, and follicle-stimulating hormone (FSH).

Today the 5-year survival rate for testicular tumors is 95%[9] as against 64%[10] four decades ago. As young patients dominate, it is important to consider the consequences of treatment that may affect the quality of life, for example, fertility, before cancer treatment is initiated. Chemotherapy and radiotherapy damage germ cells. Surgical treatment impairs the capability to ejaculate and it has been observed that 80% of cases develop retrograde ejaculation.[11]

Treatment for testicular cancer is based mainly on the type and stage of cancer. Among the different stages of GCTs, pure seminomas tend to be treated one way, and nonseminomas and mixed GCTs are treated another way. Usually, high inguinal orchidectomy with LN dissection is the primary treatment. Postsurgery either radiotherapy or chemotherapy is offered in patients with advanced disease.


  Case Report Top


A 33-year-old married man was referred to our center for semen cryopreservation in 2013 for metastatic seminoma. There was no significant family or history. The patient presented with an abdominal mass for which MRI abdomen was done. At MRI, a large retroperitoneal mass with a superior heterogeneously enhanced solid component with a larger peripherally cystic component in the left paraaortic region was detected. The mass was abutting and elevating pancreas, splenic veins, and renal angles. It was also abutting aorta and left psoas suggestive of probably a retroperitoneal gastrointestinal stromal tumors or a paraganglioma.

He underwent laparotomy with excision of a retroperitoneal tumor and left paravertebral LNs. Immunohistochemistry of the tumor was suggestive of placental like alkaline phosphatase and CD117 positive cells. These finding were suggestive of metastatic seminoma. Ultrasound (USG) of the scrotum after surgery was done as immunochemistry was suggestive of metastatic seminoma. On clinical examination, both the testes were of normal size and consistency and were freely movable. There were no signs of epididymitis or spermatic cord involvement. There was no evidence of hydrocele. There was no evidence of supraclavicular lymphadenopathy. On per-abdominal palpation, no mass was palpated. The USG of the scrotum showed well-defined hypoechoic lesion in the upper pole of left testis with minimal peripheral vascularity diagnostic of neoplasia. CT scan of the thorax and abdomen was done after surgery, which showed no evidence of lung metastasis, but heterogeneously enhanced paraaortic LN metastasis were present.

Semen analysis was performed before semen cryopreservation. The semen parameters are elicited in [Table 1].
Table 1: Semen parameters

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The value for the tumor markers we as follows:

  • LDH – 364 U/L
  • Beta hCG - <2 mIU/ml
  • AFP – 0.55 ng/ml
  • CEA – 2.35 ng/ml.


The stage of disease was Stage II b in view of testicular lesion with positive paraaortic LNs and retroperitoneal mass with elevated LDH levels.

In view of metastatic disease, patient was advised orchidectomy followed by chemotherapy and was referred for fertility preservation. The patient was advised sperm freezing. Three samples were frozen, but as the semen sample was oligoasthenospermic the patient desired one fresh cycle intrauterine insemination.

Female partner was 27 years old, presented in August 2013 with secondary infertility 1 year. She had undergone I medical termination of pregnancy in 2009. She had regular menstrual cycles, and on examination, hirsutism, acne, and bilateral galactorrhea were present. On pelvic examination, the uterus was normal with no adnexal pathology. Her hormonal profile [Table 2] and hysterosalpingography was normal. At transvaginal USG both ovaries were enlarged (volume of the right ovary 13 cc and the left ovary 11.7 cc) with antral follicle count of 15 and 14 in the right and left ovary, respectively.
Table 2: Hormonal Profile of the female partner

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As the semen sample was oligoathenospermic patient wanted to undergo one fresh cycle of intrauterine insemination before orchidectomy and chemotherapy. One cycle of ovulation induction with recombinant FSH (Rec FSH) 50 IU with intrauterine insemination was done. The cycle was unsuccessful.

Husband underwent orchidectomy with four cycles of chemotherapy, which consisted of combination of etoposide and cisplatin (EP). The wife came after 8 months for intrauterine insemination with frozen sample. She conceived in the 3rd cycle of intrauterine insemination, where ovulation induction was done with Rec FSH 50 IU in the first two cycles and human menopausal gonadotropin 75 IU in the third cycle. She delivered a healthy female baby 2.6 kg in weight at 37 weeks.

The surveillance for this patient after orchidectomy and chemotherapy included history and physical examination, evaluation of serum tumor markers (beta-hCG, LDH, and AFP), chest radiography and CT scan of the abdomen and pelvis. For the first 2 years the evaluation was done at 6 monthly intervals after which it has been done yearly. The patient is disease free for the past 4½ years.


  Discussion Top


Improvement in outcome after treatment are related to a better understanding of the natural history of testicular tumors, improved staging and surgical techniques, the use of tumor markers to guide patient management, and the introduction of effective platinum-based combination chemotherapy.[7],[10],[12] High cure rates in early stage disease have resulted in a shift of focus in reducing treatment-related effects on reproductive function. As the effect of radio/chemotherapy on the gonads cannot be predicted it is best for the patient to opt for fertility preservation techniques before orchidectomy and radio/chemo therapy. Radical inguinal orchiectomy with high ligation of the spermatic cord at the level of the internal ring is the procedure of choice for primary tumor. Subsequent therapy depends on the presence or absence of distant and LN metastasis, histology, or other risk factors. In most early stage carcinomas radio or chemotherapy is offered after orchidectomy. Except for those men who present with life-threatening advanced disease most other patients with advanced disease are advised radical orchiectomy prior to chemotherapy. Only those few men who present with life-threatening advanced disease undergo systemic chemotherapy prior to orchiectomy.

Before embarking on the treatment plan it is important to exactly diagnose whether the tumor is a pure seminomas or NSGCTs as both differ in their clinical and biological behavior. Seminomas are more likely to present with localized disease and at an early Stage I (80%). Fifty percent have Stage II and only the remaining 5% present with distant metastasis at Stage III. Seminomas rarely spread via the bloodstream beyond the retroperitoneal LNs to other areas (e.g., liver, lung, bones, or brain). Usually, Stage III disease with distant metastases is seen more frequently in men with NSGCTs. Moreover seminomas are exquisitely sensitive to radiation therapy, whereas NSGCTs are more radioresistant. Although serum tumor markers are helpful at the time of initial diagnosis of testicular cancer and for prognostication, their main utility is for subsequent follow-up of disease status after primary treatment. Men with persistently elevated postorchiectomy serum tumor markers and normal imaging studies are categorized as having clinical stage 1s disease. The elevated markers generally indicate the presence of occult metastatic disease and should be treated similarly to men with advanced or Stage III disease.[13]

Criteria used to define good and intermediate risk for men with advanced seminoma are described below:

  • Good risk – Patients with advanced seminoma are classified as having good risk if metastases are limited to the lungs and/or LNs, regardless of the primary site
  • Intermediate risk – Patients with metastases at sites other than the lungs or LNs
  • Those with AFP outside the normal range or beta-hCG >1000 international units/L are considered to have NSGCT and are stratified accordingly.


Stratification of NSGCTs is based upon the primary site of the tumor, the extent and location of metastatic disease, and the degree of elevation of serum tumor markers following orchiectomy

  • Good risk – if they meet all of the following conditions: testicular or retroperitoneal primary tumor, metastases limited to the lungs and/or LNs with postorchiectomy tumor markers as follows:
  • Serum AFP <1000 ng/mL
  • Beta-hCG <5000 milli-international units/mL
  • LDH <1.5 times the upper limit of normal.
  • Intermediate risk – if all of the following criteria are present: testicular or retroperitoneal primary tumor with metastases limited to the lungs and/or LNs.


Postorchiectomy tumor markers must be in the range defined below, and none can be higher than the upper limit of the ranges below:

  • Serum AFP 1000–10,000 ng/mL
  • Beta-hCG 5000–50,000 milli-international units/mL
  • LDH 1.5–10 times ULN.
  • Poor risk – if any of the following are present: mediastinal primary site, with or without metastases, metastases to organs other than the lungs (e.g., liver, bone, or brain metastases).


Postorchiectomy tumor markers:

  • Serum AFP >10,000 ng/mL
  • Beta-hCG >50,000 milli-international units/mL
  • LDH >10 times ULN.


Stage-wise treatment is elicited in [Figure 2] (seminoma) and [Figure 3] (NSGCTs) below.
Figure 2: Stage-wise treatment of testicular seminoma

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Figure 3: Stage-wise treatment of nonseminomatous germ cell tumor

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Chemotherapeutic regimens:

  • Standard Bleomycin-EP (BEP) (bleomycin 30 units on days 1, 8, and 15; etoposide 100 mg/m2 on days 1–5; cisplatin 20 mg/m2 on days 1–5) administered on a 21-day cycle
  • EP-Due to the association of bleomycin with occasional, but serious and potentially fatal, pulmonary toxicity, EP for four cycles has been evaluated as an alternative regimen to BEP (Etoposide 120 mg/m2day s 1–3; Cisplatin 100 mg/m2day 1) every 21 days
  • Value incentive plan (VIP) (ifosfamide 1200 mg/m2, etoposide 75 mg/m2 and cisplatin 20 mg/m2) every 21 days for 4 cycles[14],[15],[16],[17]
  • Carboplatin-despite the improved toxicity profile associated with carboplatin, it is not recommended instead of cisplatin because it is associated with decreased survival.[18],[19],[20]


Surveillance for men with seminoma is by examination and or by imaging. The value of monitoring serum tumor markers is unclear. Whereas in men with NSGCTs periodic surveillance of the serum concentrations of beta-hCG and AFP is the most sensitive means of detecting early relapse.

As the peak incidence of TGCTs occurs between the ages of 15 and 35 years, fertility is one of the main concerns. Testicular cancer therapy can result in subfertility or sterility due to gonad removal or permanent damage to germ cells from adjuvant therapy. Therefore, it is important to counsel the patients regarding fertility preservation prior to treatment. Testicular tumors have a good prognosis and survival with the right management.

Prognosis – the most extensive data on prognosis base on histology and risk classification for men with advanced TGCTs come from an analysis of 5202 patients with NSGCTs and 660 men with seminoma.[21] About 90% of men with advanced seminoma had good-risk disease and an excellent prognosis following orchiectomy alone. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 90% and 92%, respectively. About 56% of men with NSGCTs had good-risk metastatic NSGCTs and 5-year PFS and OS rates were 89% and 92%, respectively. About 28% of men with NSGCTs had intermediate-risk disease with 5-year PFS and OS rates were 75% and 80%, respectively and 16% had poor-risk disease with 5-year PFS and OS rates for these patients were 41% and 48%, respectively. There were two studies that reported better results even in poor risk patients with the BEP regimen.[22],[23] [Figure 4] gives the survival rate posttreatment.
Figure 4: Posttreatment survival rate

Click here to view


Most relapses for patients with metastatic TGCTs occur in the first 2 years. The optimal treatment of relapsed GCTs depends on the response to prior therapy, the location and timing of the relapse, and the tumor histology. Men who are chemotherapy-naιve at the time of recurrence should be treated with a cisplatin-based combination regimen (e.g., BEP). Retroperitoneal LN dissectionis an alternative to chemotherapy in properly selected patients to assess the risk. For men who relapse following postorchiectomy chemotherapy, one must administer VIP, particularly in men who were not previously treated with etoposide. Men who relapse during or within 4 weeks after initial chemotherapy have platinum-refractory disease and should undergo high-dose chemotherapy. Relapses after 2 years are uncommon and if it occurs an aggressive surgical approach in addition to systemic therapy should be adopted. Resection of the redundant tumor appears to be crucial to achieving long-term survival.


  Conclusion Top


Seminoma is the most common type of tumor arising from the testis with pure seminoma accounting for 40% of the cases. The incidence of testicular seminoma remains to be relatively low and majority of them presented in early stage of the disease with a 5 years survival rate of 98%–99%. Orchidectomy with LN dissection is the primary treatment. It serves as primary treatment and also establishes the correct diagnosis. Optimal therapy postorchidectomy requires estimating the likelihood of recurrence. Key elements that need to be considered for risk stratification include the histology (seminoma versus NSGCT), the presence or absence of metastases, and the degree of elevation in serum tumor markers.[24],[25],[26] Risk classification helps in planning treatment postorchidectomy. In Stage I disease, radiotherapy or single agent carboplatin appeared to be the preferred adjuvant treatment. Advanced disease patients are best treated with combination chemotherapy, namely, EP/bleomycin, EP chemotherapy with excellent outcome. Options for fertility preservation include semen freezing, TESE and freezing and testicular tissue freezing. Fertility can be achieved optimally with these methods.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]



 

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