Stem cell factor as a novel diagnostic marker for early malignant germ cells

Abstract

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. Therefore, strategies for early diagnosis of CIS are essential. 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. Here we report the novel finding that immunohistochemical detection of stem cell factor (SCF), the c-KIT ligand, is informative in this context. This was demonstrated in over 400 cases of normal (fetal, neonatal, infantile, and adult) and pathological gonads, as well as TGCT-derived cell lines, specifically in cases of CIS and GB. Both membrane-bound and soluble SCF were expressed, suggestive of an autocrine loop. 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.

Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology

“…KITLG is not expressed in gonads with delayed maturation germ cells. 8,14 For the diagnosis of intratubular germ cell neoplasia, the presence of at least one cross-section of a seminiferous tubule containing a homogeneous population of atypical germ cells with angulated nuclei is required. These cells must show either homogeneous double expression of POU5F1 (nuclear) and TSPY1 (cytoplasmic and membranous) or homogenous expression of POU5F1 (nuclear) in the absence of TSPY1.…”

“…KITLG may be expressed in testes containing pre-intratubular germ cell neoplasia. 14,25 Immunohistochemistry Tissue samples from 36 gonads (22 gonads from patients with expected no AR activity; 9 gonads from patients with expected residual AR activity; 5 gonads from patients with uncertain AR activity) were available for immunohistochemical staining. After antigen retrieval (120 1C, 0.9 Bar), 4-mm-thick …”

“…Thus, the histochemical and morphological pattern resembled that of fetal gonads. 14,26 The findings were classified as delayed maturation in three patients who were older than 6 months.…”

“…The investigation included immunohistochemical detection of POU class 5 homeobox 1 (POU5F1, also known as OCT3/4) and KIT ligand (KITLG, also known as SCF). 13,14 These two markers were only recently applied in the assessment of early changes in germ cells at risk for malignant transformation. To our knowledge, this is the first study exclusively dealing with patients with complete androgen insensitivity syndrome using both markers.…”

Germ cell neoplasia in situ: The precursor cell for invasive germ cell tumors of the testis

“…In this situation, dimorphic expression of pluripotency marker OCT3/4, SCF, TSPY and the location of these cells centrally within the tubule is used to distinguish maturation delay from GCNIS (Stoop et al, 2008).…”