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testicular carcinoma in situ

Monday 2 January 2012

Carcinoma in situ (CIS) of the testis

Carcinoma in situ (CIS) is the precursor of malignant testicular germ cell tumors (GCTs) of adolescents and young adults, being the neoplastic counterpart of primordial germ cells/gonocytes.

Carcinoma in situ cells will develop into invasive seminoma/nonseminoma.

Gonadoblastoma (GB) is the precursor of invasive GCTs in dysgenetic gonads, predominantly dysgerminoma (DG).

In this process, part of the Y chromosome (GBY region) is involved, for which TSPY is a candidate gene.


- germ cell/placental alkaline phosphatase (PLAP)
- c-KIT
- OCT3/4
- testis-specific protein on the Y chromosome (TSPY)

In contrast to c-KIT, PLAP is positive in all cases.

The immature germ cells of GBs are positive for OCT3/4, whereas the mature germ cells are negative for this marker, but positive for TSPY.

In every gonadoblastoma, a minor population of germ cells positive for both markers could be identified, similar to most CIS cells and early invasive dysgerminoma.

On progression to an invasive tumor, TSPY can be lost, a process that is also detectable in invasive testicular GCTs compared to CIS.

GB is a heterogeneous mix of germ cells, in which the OCT3/4-positive cells have the potential to undergo progression to an invasive tumor.

These early invasive stages are initially also positive for TSPY (like CIS), supporting a positive selection mechanism.

Therefore, OCT3/4 in combination with TSPY is valuable to identify malignant germ cells in dysgenetic gonads.

This could allow better prediction of the risk of progression to a GCT.

GB represents the earliest accessible developmental stage of malignant GCTs.


Carcinoma in situ (CIS) of the testis is the pre-invasive stage of type II testicular germ cell tumours (TGCTs) of adolescents and adults.

These tumours are the most frequently diagnosed cancer in Caucasian adolescents and young adults.

In dysgenetic gonads, the precursor of type II GCTs can be either CIS or a lesion known as gonadoblastoma (GB).

CIS/GB originates from a primordial germ cell (PGC)/gonocyte, ie an embryonic cell.

CIS can be cured by local low-dose irradiation, with limited side effects on hormonal function.

Various markers are informative to diagnose CIS in adult testis by immunohistochemistry, including c-KIT, PLAP, AP-2gamma, NANOG, and POU5F1 (OCT3/4).

OCT3/4 is the most informative and consistent in presence and expression level, resulting in intense nuclear staining.

In the case of maturational delay of germ cells, frequently present in gonads of individuals at risk for type II (T)GCTs, use of these markers can result in overdiagnosis of malignant germ cells.

This demonstrates the need for a more specific diagnostic marker to distinguish malignant germ cells from germ cells showing maturation delay.

Stem cell factor (SCF)

Immunohistochemical detection of stem cell factor (SCF), the c-KIT ligand, is informative in this context. SCF immunohistochemistry can be a valuable diagnostic tool, in addition to OCT3/4, to screen for precursor lesions of TGCTs, especially in patients with germ cell maturation delay.


- Stem cell factor as a novel diagnostic marker for early malignant germ cells. Stoop H, Honecker F, van de Geijn GJ, Gillis AJ, Cools MC, de Boer M, Bokemeyer C, Wolffenbuttel KP, Drop SL, de Krijger RR, Dennis N, Summersgill B, McIntyre A, Shipley J, Oosterhuis JW, Looijenga LH. J Pathol. 2008 Sep;216(1):43-54. PMID: 18566970

- Identification of germ cells at risk for neoplastic transformation in gonadoblastoma: an immunohistochemical study for OCT3/4 and TSPY. Kersemaekers AM, Honecker F, Stoop H, Cools M, Molier M, Wolffenbuttel K, Bokemeyer C, Li Y, Lau YF, Oosterhuis JW, Looijenga LH. Hum Pathol. 2005 May;36(5):512-21. PMID: 15948118