Testicular Tumours: Intratubular Germ Cell Neoplasia

Intratubular germ cell neoplasia:
Intratubular germ cell neoplasia is thought to be the precursor of most germ cell tumours. It is the testicular equivalent of carcinoma in situ. Fifty percent of patients with intratubular germ cell neoplasia will develop an invasive tumour in 5 years.
Intratubular germ cell neoplasia (ITGCN) is now well established as a precursor to invasive germ cell tumours, with the exception of spermatocytic seminoma and possibly infantile germ cell tumours that include infantile yolk sac tumour and infantile mature teratoma.
Among all the invasive germ cell tumours in adults, spermatocytic seminoma is the one type that is not associated with ITGCN, unclassified type.
ITGCN is seen adjacent to an invasive tumour in most cases or in the contralateral testis following orchiectomy for invasive germ cell tumour in a few cases.
It can also be seen in the following settings:
i) cryptorchid testes ; ii) dysgenetic testes ; iii) testes of infertile males and testes of healthy males.
The atypical germ cells commonly extend into the rete testis in a pagetoid pattern.
ITGCN has been classified similarly to invasive germ cell tumours as :
I) undifferentiated or unclassified ITGCN and
II) differentiated ITGCN.
The differentiated category is further subdivided as intratubular classic seminoma, intratubular spermatocytic seminoma, intratubular embryonal carcinoma, intratubular yolk sac tumour, and intratubular syncytiotrophoblast cells.
Microscopic features: There is a pagetoid pattern of large cells with clear cytoplasm, hyperchromatic nuclei, prominent nucleoli and frequent mitoses. The cells may resemble seminoma cells and are present along thickened / hyalinized tubular basement membrane. The cells displace Sertoli cells toward the lumen. Spermatogenesis is usually absent. Some calcifications (microliths) may be present.

Abstract:
Pagetoid spread of intratubular germ cell neoplasia into rete testis: a morphologic and histochemical study of 100 orchiectomy specimens with invasive germ cell tumors. Hum Pathol. 1994 Mar;25(3):235-9.
Intratubular germ cell neoplasia (ITGCN) is now considered to be the preinvasive phase of testicular germ cell tumors with the exceptions of spermatocytic seminoma, pure yolk sac tumor, and mature teratoma. Pagetoid spread of ITGGN into rete testis is a common yet unpublished finding in these cases. We reviewed 100 cases of testicular germ cell tumors from the Surgical Pathology service of Parkland Memorial Hospital (Dallas, TX) to evaluate the frequency of this pattern of spread. Additional sections were obtained from selected cases and were stained with anti-placental alkaline phosphatase, anti-low molecular weight keratin (clone AE1), and various lectins to highlight the process. Pagetoid spread of ITGCN into rete testis was identified in 24 of 60 cases (40%) in which histologic sections contained both ITGCN and rete testis. The incidence of pagetoid ITGCN involvement of the rete testis was lower in pure seminoma (seven of 25 cases [28%]) than in testes containing nonseminomatous germ cell tumors (17 of 35 cases [49%]). AE1 stained the epithelial cells of the rete testis but not the cells of the ITGCN, whereas placental alkaline phosphatase stained the neoplastic cells but not the epithelial cells of the rete testis. These stains were useful in delineating two cases in which the pagetoid involvement was so extensive that they were misdiagnosed as invasive seminomas. Pagetoid spread of ITGCN is a relatively common finding in testicular germ cell tumors and rarely can be mistaken for invasive seminoma. Immunohistochemistry can be helpful in distinguishing florid pagetoid spread from invasive seminoma.

Abstract:
Intratubular germ cell neoplasia (ITGCN) with p53 and PCNA expression and adjacent mature teratoma in an infant testis. An immunohistochemical and morphologic study with a review of the literature.Am J Surg Pathol.1994 Sep;18(9):947-52.
Intratubular germ cell neoplasia (ITGCN) and mature teratoma of the testis are uncommon findings in children. We report a case of a 3-year-old boy with both ITGCN and mature teratoma--a unique finding in our experience. Immunohistochemical markers, including placental alkaline phosphatase (PLAP), 43-9F, p53, and proliferating cell nuclear antigen (PCNA), as well as the periodic acid-Schiff (PAS) stain, were applied to the ITGCN. PLAP and 43-9F were not detected, whereas p53 and PCNA nuclear expression was detected in approximately 5% of atypical germ cells. Abundant clumped intracytoplasmic glycogen deposits were identified within atypical germ cells. Our findings indicate that both PCNA and p53, in addition to a PAS stain, may be useful markers in detecting malignant intratubular germ cells.

Abstract:
The prepubertal testis (prenatal and postnatal): its relationship to intratubular germ cell neoplasia: a combined Pediatric Oncology Group and Children's Cancer Study Group.1: Hum Pathol.1997;28(4):404-10.
Seminiferous tubules adjacent to germ cell tumors (GCT) in prepubertal boys frequently contain increased germ cells with abundant, clear cytoplasm. These cells are placental alkaline phosphatase (PLAP) negative and are usually not considered to represent intratubular germ cell neoplasia (ITGCN). A recent case report found p53 and proliferating cell nuclear antigen (PCNA) positivity in such cells and equated these PLAP-negative cells with ITGCN. Because the proto-oncogene c-kit is also a marker of ITGCN, immunohistochemical tests for c-kit and PLAP were performed on 28 testes adjacent to prepubertal GCT in children aged 2 to 45 months. Additional slides from testes not associated with GCT from 18 preterm infants and children ages 19 weeks to 7 years were also tested. An adult testis with seminoma and ITGCN served as a positive control. PCNA, PLAP, and p53 were tested on available slides. No intratubular germ cells adjacent to GCT in prepubertal children were positive for PLAP or c-kit; five of seven were positive for PCNA; p53 was present in the two examined. These results indicate that germ cells adjacent to infantile GCT are proliferative but not neoplastic and offer additional evidence that intratubular germ cells and GCT in prepubertal boys are different from those of adolescents and adults.

Abstract:
Intratubular malignant germ cells in testicular biopsies: clinical course and identification by staining for placental alkaline phosphatase. Mod Pathol. 1988 Nov;1(6):475-9.
This study was undertaken to determine the clinical course of patients with intratubular malignant germ cells (ITMGCs) and to evaluate the reliability of placental alkaline phosphatase (PLAP) for detection of these cells. Eight patients with ITMGCs in testicular biopsy were followed. Four patients received no further immediate treatment. Two of these showed no evidence of disease after 190 and 132 mo; one developed seminoma at 38 mo, and one developed seminoma of the contralateral testis in 61 mo. The remaining four patients underwent immediate orchiectomy. Orchiectomy findings were invasive seminoma in three testes, intratubular seminoma in one, and residual ITMGCs in one testis (one patient had bilateral orchiectomy). Also studied were two testicular biopsies from patients with known retroperitoneal germ cell tumors, respectively, seminoma and teratoma. Both had ITMGCs in their testes. Immunoperoxidase stains for PLAP gave a positive result in all biopsies showing intratubular malignant germ cells. PLAP was not demonstrated in spermatogonia in 471 control biopsies which did not show germ cell neoplasia. Two other patients with incidental seminoma on biopsy for infertility are discussed. These results show that ITMGCs show a high rate of progression to invasive disease, but can show an indolent course. PLAP is a sensitive and specific marker for ITMGC, facilitating diagnosis.