1.3.1 Presentation and histopathology
Germ cell TC often presents with a painless, unilateral, scrotal tumor.44 Some degree of pain is however experienced by 10-20% of patients.44 Further confirmed suspicion of the TC diagnosis is done by scrotal ultrasound and measurement of tumor markers. The confirmation of TC diagnosis is done through a radical inguinal orchiectomy, which also serves as the primary treatment. In some cases, symptoms from metastatic sites initiate the diagnostic process, for instance abdominal pain due to large retroperitoneal metastases.45 It is import to offer cryopreservation of sperm and to discuss testicular prothesis with the patient before orchiectomy.
The surgical specimen is sent for histopathological examination. Germ cell TC derived from GCNIS accounts for 95% of all testicular malignancies.40,46 The remaining 5% (lymphoma,
spermatocytic tumors, sex-cord stromal tumors, sarcoma, prepubertal non-GCNIS related tumors) are out of scope of this thesis and thus will not be further described.14,40
Germ cell TC is divided into two distinct histopathological subgroups; pure seminomas and nonseminomas as defined by the 2016 World Health Organization (WHO) classification.40 About 55-60% of patients are diagnosed with pure homogenous seminoma histology, which resembles the gonocyte arrested at a pre-differentiated stage.14,45 Nonseminomas, on the other hand, are
heterogenous tumors that may contain a variety of cell types including embryonal carcinoma (resembling undifferentiated stem cells), choriocarcinoma and yolk-sac (both with extraembryonic differentiation), and teratoma.14,45 Teratomas can in rare cases display a somatic differentiation, histologically resembling sarcoma or adenocarcinoma.46 Nonseminomas may also contain components of seminoma.
Additional current pathological evaluation includes tumor staging according to the TNM classification 8th edition, and information regarding tumor vascular invasion, stromal rete testis invasion, invasion of tunica albuginea, tunica vaginalis, epididymis or the spermatic cord invasion, and whether GCNIS is present or absent.15
There are several clinical differences between the two subgroups. Seminoma patients are generally 10 years older at diagnosis than patients with nonseminoma, with a peak incidence at 35 years.14 Overall, 85% of seminomas are diagnosed with clinical stage I vs 60% of
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nonseminomas.46,47 With no adjuvant treatment, recurrence will develop in 10-20% of stage I seminoma, and the risk might be influenced by tumor size and whether invasion in rete testis is present.9 Seminomas metastasize in a predictable, stepwise and relatively indolent manner via the lymphatic system in the retroperitoneum, and visceral metastases are very uncommon.48,49
Recurrences are generally diagnosed within the first 3 years of follow-up.50 In stage I
nonseminoma, the presence of lymphovascular invasion in the tumor predicts the risk of occult metastases and the risk of recurrence.51,52 About one-third of tumors are diagnosed with
lymphovascular invasion, and if present, the risk of recurrence is 50% in stage 1 nonseminoma if no adjuvant treatment is administered.47,53,54 Recurrences most commonly occur in the retroperitoneum within 2 years after orchiectomy,50,53,55as nonseminomas most commonly metastasize through the lymphatics to the retroperitoneum, and may also continue to supradiaphragmatic lymph nodes.56 Hematogenous spread of nonseminomas to lung, bone or brain may occur, but is relatively infrequent.56
In 2-5% of cases, germ cell cancer presents with an extragonadal localization without a testicular tumor.57 Extragonadal germ cell cancers were excluded from this study.
1.3.2 Tumor markers
Serum tumor markers include Alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (beta-hCG). At diagnosis, 50-70% of patients with nonseminoma have elevated serum AFP.58 AFP is secreted by some yolk sac and embryonal carcinomas, while not by pure seminomas or
choriocarcinoma. Thus, an elevated AFP is inconsistent with a seminoma diagnosis. Beta-hCG is produced by all choriocarcinomas, 40-60% of embryonal carcinomas and 10-20% of seminomas.58 The level of beta-hCG produced by seminomas is generally lower than the levels produced by nonseminomas. In nonseminoma, normal tumor markers are more common in stage 1 vs. metastatic disease; In stage I, 45% have normal levels of AFP or beta-hCG pre-orchiectomy, and both markers are negative in 33%. In metastatic disease, only about 15% have one or both tumor markers
normal.58 The peak levels of tumor markers and the half-life kinetics are important for final staging and treatment evaluation.46
Additionally, elevation of lactate dehydrogenase is present in 40-60% of TC patients. It is not specific for germ cell TC, but is used for prognostic classification.15
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For the last decade, new microRNA-based tumor markers have yielded promising results in TC.59 The most promising is microRNA (miR)-371a-3p, expressed by both TC and GCNIS tissues, and superior to the classic TC tumor markers with a sensitivity and specificity of >90% in all histological subtypes except teratoma.60,61 Further studies to validate this marker for clinical use are ongoing.
1.3.3 Clinical staging
The clinical staging of TC is based on histopathological information, serum tumor markers and computed tomography scans of thorax, abdomen and pelvis (preferably done before orchiectomy).
According to the modified Royal Marsden Hospital Staging system as first described by Peckham et al.62 and later modified by the Swedish and Norwegian Testicular Cancer Group (SWENOTECA),15 patients are designated to clinical stage I-IV (Table 1).
Table 1. Clinical staging of testicular cancer according to the Royal Marsden Hospital Staging System.62
Stage Description I No metastases
Mk+ No metastases, but persistent elevation of serum tumor markers II Metastases involving abdominal lymph-nodes.
A: <2 cm B: 2-5 cm C: >5-10cm D: >10 cm
III Metastases involving supradiaphragmatic lymph-nodes.
Abdominal lymph-nodes according to stage II (A-D) IV Metastases involving extra-lymphatic tissue/organ
Abdominal lymph-nodes according to stage II (A-D)
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From 1997, the prognostic group classification according to The International Germ Cell Cancer Collaborative Group has also been used to decide upon treatment strategy in metastatic disease (Table 2).10 According to an update of this classification, 5-year overall survival for nonseminoma patients is 96% in good prognosis group, 89% in intermediate and 67% in poor prognosis group.63 For seminoma, updated 5-year overall survival is 95% for good prognosis group and 88% in intermediate prognosis group.64 The inclusion in our study cohort started 16 years before the prognostic group classification was introduced, and information regarding tumor markers was not included in our clinical database. Thus, it was not possible for us to allocate the study cohort according to this classification.
Table 2. Prognostic classification according to the Germ Cell Consensus Classification10
Prognosis Nonseminoma Seminoma
Good Primary tumor in testis or retroperitoneum, No non-pulmonary visceral metastases, and good markers (beta-hCG <5000 IU/L, AFP <1000 µg/L and LDH <1.5 x ULN)
Any primary site, no-non-pulmonary visceral
metastases, and normal AFP, any beta-hCG and any LDH Intermediate Primary tumor in testis or retroperitoneum,
No non-pulmonary visceral metastases, and any intermediate markers (beta-hCG
≥5000 - ≤ 50000 IU/L or AFP ≥1000 -
≤10000 µg/L or LDH ≥1.5 - ≤10 x ULN)
Non-pulmonary visceral metastases
Poor Primary tumor in mediastinum or non-pulmonary visceral metastases or any poor markers (beta-hCG >50000 IU/L or AFP
>10000 µg/L or LDH >10 x ULN)
No seminomas have poor prognosis
Abbreviations: beta-hCG, beta-human chorionic gonadotropin; IU, international units; AFP, alpha-fetoprotein, LDH, lactate dehydrogenase; ULN, upper limits of normal.
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