Latest Recommendations of the European Germ Cell Cancer Group on Diagnosis and Treatment of Germ Cell Cancer

Localization of the tumour

Size

Multiplicity

Extension of the tumour (pT category according to UICC)

Histopathological type (WHO)

In seminoma: presence of syncytiotrophoblasts

In spermatocytic seminoma: any sarcomatous elements

In pluriform tumours: description and percentage of each individual component

Presence of TIN

Immunohistochemistry: AFP and hCG for detection of yolk sac tumour and choriocarcinoma CD31/FVIII for vascular invasion (pluripotency-related markers such as OCT4, NANOG, LIN28, AP-2 gamma for TIN, seminoma, embryonal cell carcinoma)

Table 1.2 shows the different types of germ cell tumours according to the WHO classification.

Table 1.2

WHO classification of germ-cell tumours of the testis [10]

Histological type	ICD-O-M
Intratubular germ cell neoplasia, unclassified	9064/2
Others
Tumours of one histological type (pure forms)
Seminoma	9061/3
(Subtype) Seminoma with syncytiotrophoblastic cells
Spermatocytic seminoma	9063/3
(Subtype) Spermatocytic seminoma with sarcoma
Embryonal carcinoma	9070/3
Yolk sac tumour	9071/3
Trophoblastic tumours
Choriocarcinoma	9100/3
Trophoblastic neoplasms other than choriocarcinoma
Monophasic choriocarcinoma
Placental site trophoblastic tumour	9104/1
Teratoma	9080/3
Dermoid cyst	9084/0
Monodermal teratoma
Teratoma with somatic type malignancies	9084/3
Tumours of more than one histological type (mixed forms)
Mixed embryonal carcinoma and teratoma	9081/3
Mixed teratoma and seminoma	9085/3
Choriocarcinoma and teratoma/embryonal carcinoma	9101/3
Others

WHO World Health Organization

The clinical stage is defined by the UICC TNM classification (Table 1.3). Patients with metastatic disease are classified according to the classification of the International Germ Cell Cancer Collaborative Group (IGCCCG), which also pays regard to the elevation of tumour markers (Table 1.4).

Table 1.3

TNM classification – UICC 2009 [11]

pT		Primary tumour
pTX		Primary tumour cannot be assessed
pT0		No evidence of primary tumour (e.g. histological scar in testis)
pTis		Intratubular germ cell neoplasia (carcinoma in situ)
pT1		Tumour limited to testis and epididymis without vascular/lymphatic invasion: tumour may invade tunica albuginea but not tunica vaginalis
pT2		Tumour limited to testis and epididymis with vascular/lymphatic invasion, or tumour extending through tunica albuginea with involvement of tunica vaginalis
pT3		Tumour invades spermatic cord with or without vascular/lymphatic invasion
pT4		Tumour invades scrotum with or without vascular/lymphatic invasion
N		Regional lymph nodes clinical
NX		Regional lymph nodes cannot be assessed
N0		No regional lymph node metastasis
N1		Metastasis with a lymph node mass 2 cm or less in greatest dimension or multiple lymph nodes, none more than 2 cm in greatest dimension
N2		Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, any one mass more than 2 cm but not more than 5 cm in greatest dimension
N3		Metastasis with a lymph node mass more than 5 cm in greatest dimension
pN		Pathological
pNX		Regional lymph nodes cannot be assessed
pN0		No regional lymph node metastasis
pN1		Metastasis with a lymph node mass 2 cm or less in greatest dimension and 5 or fewer positive nodes, none more than 2 cm in greatest dimension
pN2		Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or more than 5 nodes positive, none more than 5 cm; or evidence or extranodal extension of tumour
pN3		Metastasis with a lymph node mass more than 5 cm in greatest dimension
M		Distant metastasis
MX		Distant metastasis cannot be assessed
M0		No distant metastasis
M1		Distant metastasis
M1a		Non-regional lymph nodes(s) or lung
M1b		Other sites
S		Serum tumour markers
Sx		Serum marker studies not available or not performed
S0		Serum marker study levels within normal limits
		LDH (U/l) hCG (mlU/ml) AFP (ng/ml)
S1		<1.5 × N and <5,000 and <1,000
S2		1.5–10 × N or 5,000–50,000 or 1,000–10,000
S3		>10 × N or >50,000 or >10,000
N indicates the upper limit of normal for the LDH assay
Except for pTis and pT4, where radical orchiectomy is not always necessary for classification purposes, the extent of the primary tumour is classified after radical orchiectomy; see pT in other circumstances. TX is used if no radical orchiectomy has been performed
According to the 2002 TNM classification, stage I testicular cancer includes the following substages:
Stage IA	pT1	NO	MO	S0
Stage IB	pT2, pT3, or pT4	NO	MO	S0
Stage IS	Any pT/TX	NO	MO	S1–3

AFP alpha-fetoprotein, hCG human gonadotropin, LDH lactate dehydrogenase, UICC International Union Against Cancer

Table 1.4

IGCCCG prognostic grouping classification [12]

Prognosis	5-year survival	Non-seminoma	Seminoma
Good	90 %	Testis or primary extragonadal retroperitoneal tumour	Any primary localization
		No non-pulmonary visceral metastases	No non-pulmonary visceral metastases
		Low markers	Any marker level
		AFP <1,000 ng/ml
		ß-hCG <1,000 ng/ml (<5,000 IU/l)
		LDH <1.5 × normal level
Intermediate	75 %	Testis or primary extragonadal retroperitoneal tumour	Any primary localization
		No presence of non-pulmonary visceral metastases	Presence of non-pulmonary visceral metastases (liver, CNS, bone, intestinum)
		No presence of non-pulmonary visceral metastases	Any marker level
		Intermediate markers
		AFP 1,000–10,000 ng/ml and/or
		ß-hCG 1,000–10,000 ng/ml (5,000–50,000 IU/l) and/or
		LDH 1.5–10 × normal level
Poor	50 %	Primary mediastinal germ cell tumour with or without testis or	–
		Primary retroperitoneal tumour and
		Presence of non-pulmonary visceral metastases (liver, CNS, bone, intestinum) and/or
		High markers
		AFP >10,000 ng/ml and/or
		ß-hCG >10,000 ng/ml (50,000 IU/l) and/or
		LDH >10 × normal level

AFP a-fetoprotein, ß-hCG human chorionic gonadotropin, CNS central nervous system, IGCCCG International Germ Cell Cancer Collaborative Group, LDH lactic dehydrogenase

Spiral computerized tomography (CT) scans of the thorax, abdomen and pelvis remain the staging procedures of choice. Magnetic resonance tomography (MRT) can be an alternative, but should be done only at institutions with special expertise in evaluating testis cancer patients [13]. Positron electron tomography (PET) has no role as a staging procedure [14, 15]. Imaging of brain or bones only is mandatory in patients with visceral metastases or in case of symptoms.

AFP, hCG and LDH should be performed before and after orchiectomy. To define a clinical stage I, marker normalization is mandatory. Therefore in case of still elevated markers post-orchiectomy several marker controls might be necessary before finally to define the clinical stage. If markers do not normalize, it is declared as stage IS disease. In patients with metastatic disease, pre-chemotherapy markers instead of pre-orchiectomy markers should be used to allocate the IGCCCG category [12, 16].

Because further treatment might influence the hormonal status and fertility of the patient a baseline assessment including testosterone, luteinising hormone (LH), follicle-stimulating hormone (FSH) and, if possible, a semen analysis should be performed.

Patients should also be informed about cryoconservation.

1.5 Treatment of Patients with Seminoma CSI

Rete testis infiltration and tumour size >4 cm have been recognized as risk factors for occult retroperitoneal lymph node metastases in a retrospective analysis [17]. A metaanalysis of patients managed by surveillance showed a 5-year relapse rate of 12 % in patients without any risk factor, a relapse rate of 16 % in case of one risk factor and of 32 % in patients with both risk factors. Based on these data, a risk-adapted strategy was recommended with surveillance for patients without any risk factors and adjuvant treatment in those with one or two risk factors. Options for adjuvant therapy are a single course of carboplatin (AUC 7) or paraaortal/paracaval radiation with 20 Gy. Recent data about the induction of secondary malignancies after adjuvant radiotherapy reduced the choice of this strategy [18–20]. Since the latest prospective series from the Canadian Group could not validate the rete testis infiltration and tumour size >4 cm as risk factors, many physicians already favour surveillance independent of any risk factor [21]. On the other hand, a prospective Spanish trial could at least confirm the negative predictive value of these factors [22]. Therefore, no definitive recommendation can be given.

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