Serum Markers in Testicular Tumors

First tumor marker to be discovered was beta HCG in the year 1930 in the urine of a man with choriocarcinoma.

Point	AFP	HCG	LDH	PLAP
Nature	Glycoprotein	Glycoprotein	Protein	Protein
Mol wt	70kD	38kD	134kD	-
Biological role	Dominant serum protein of the foetus	Secreted by the placental syncitiotrophoblastic cells	Component of the intracellular enzyme system	Fetal isoform of the enzyme alkaline phosphatase
Function	Carrier protein in the foetal blood	Maintains the corpus luteum	Glycolysis	Removal of phosphate from phosphate esters
Adult levels	< 10 ng/mL	< 5 IU/L	NA	NA
Half Life	4.5 days	16 -24 hrs	1 day	-
Seen in	All NSGCT except pure choriocarcinoma	Choriocarcinoma, NSCGT, Seminoma	All depends on disease burden	In seminomas
Not seen in	Choriocarcinoma and Seminoma	NA	NA	NSGCT
% raised in NSGCT	10 -20% stage I 20-40% stage II 40-60% stage III	10 -20% Stage I 20-30% Stage II 40% Stage III	60%	NA
% raised in Seminoma	NA	15-20%	80%	50-70%
Cell of origin	Yolk sac origin	Syncitiotrophoblastic cells	All cells	??
Other cancers	HCC Pancreas Stomach Lung	Trophoblastic differentiation of stomach and lung cancers	Many tumors	Lung Ovaries GI tract
Benign Causes	Liver disease Pregnancy Tyrosinemia	Pregnancy	Many causes	Smokers
Clinical importance	If AFP is raised treat as NSGCT	Can cause gynaecomastia	Prognostic variable only	None
S1	< 1000	<5000	< 1.5 x UNL	-
S2	1000 – 10,000	5000 -50,000	1.5 -10 x UNL	-
S3	>10,000	>50,000	>10 x UNL	-
Use	All	All	All	Histological confirmation
Special	Structure mimics albumin	2 causes > 5000 i.e pregnancy and NSGCT	LDH isoform type 1 is the most specific and mostly raised	PPV <50% even in non smokers so not useful.

Use of Serum Tumour markers

• Diagnosis and Screening:

• AFP is a good marker for NSGCT being raised in about 40% patients overall.

• Presence of an elevated AFP is a marker for a yolk sac element.

• In seminoma with AFP Rx will be like NSGCT.

• HCG is elevated in 60% of patients of NSGCT and 80% patients with choriocarcinoma.

• It may be elevated in 15 -20% patients with Seminoma of testis

• Both AFP and HCG help in diagnosis and typing of the mixed GCTs.

• Another marker that is now considered useful isochoromosome 12p - i(12p) present in 80% of patients with GCTs

• Prognosis and Staging:

  • As per the IGCCCG system in 1997 serum markers have important prognostic value.

  • However this prognostic value is there for NSGCTs only ; seminomas have no difference depending on the serum levels.

  • The categories of IS, IIIC and IIIB indicate the importance of serum markers on the staging system of the AJCC 2002.

• Response to therapy:

  • After a surgical excision the serum levels of serum markers should fall according to their half lives.

  • During CCT, a rate of decline of AFP > 7 days and HCG > 3.5 days is considered a poor prognostic factor.

  • Similarly, when markers fail to decline by > 200 fold after 3 weeks of the 1^st cycle is associated with a poor prognosis.

  • 10 fold decrease in the serum levels over a period of 3 weeks is also associated with a good response to therapy.

  • Markers fail to predict the prognosis in some patients: (False negatives)

    • 20 -30% stage I NSGCT patients with normal markers will relapse

    • 10 -20% patients with negative markers will have residual disease at the RPLN after RPLND

  • False positive marker elevations:

    • Hypogonadic states after CCT and Sx can lead to elevations of LH and cross reactions with HCG assays

    • Liver dysfunction after CCT can also lead to elevations of AFP levels

    • Some patients may have persistent low elevations without recurrence.

  • Utility of markers in selecting treatment:

    • In stage IS patients CCT is a better choice of initial treatment than Surgery

    • Initial cytoreductive surgery of any identifiable leison is preferred in patients with marker rising after 2 yrs instead of salvage CCT

    • Salvage CCT is used when marker elevations are seen in the immediate post CCT period after 1^st line CCT.

• Monitoring recurrence:

  • HCG and AFP rises will be seen in 80-90% patients with combined specificity of 86% and sensitivity of 100%.

  • Isolated LDH increase can be seen in 10% patients with NSGCT at the time of recurrence.