Association of intratubular seminoma and intratubular embryonal carcinoma with invasive testicular germ cell tumors

The classification of intratubular germ cell neoplasia of the testis includes an unclassified type (IGCNU), in addition to various other intratubular lesions that show specific forms of differentiation, such as intratubular seminoma and intratubular embryonal carcinoma. Although IGCNU is recognized as a precursor lesion for testicular germ cell tumors, the relationship between differentiated types of intratubular germ cell neoplasia and invasive germ cell tumors of the testis is not well established. The aim of the present study was to examine the association between invasive testicular germ cell tumors and intratubular neoplastic lesions, with particular emphasis on differentiated types of intratubular germ cell neoplasia. The seminiferous tubules adjacent to 42 testicular germ cell tumors were evaluated for the presence of various forms of intratubular germ cell neoplasia. IGCNU was observed in 37 (88%) of 42 cases, whereas intratubular seminoma and intratubular embryonal carcinoma were seen in 19% and 7% of the cases, respectively. Intratubular seminoma was associated primarily with seminomas or mixed germ cell tumors with a seminomatous component, but was also present in a case of a nonseminomatous germ cell tumor. Intratubular embryonal carcinoma was associated exclusively with nonseminomatous germ cell tumors. All cases of intratubular embryonal carcinoma were identified morphologically and exhibited histologic features corresponding to traditional definitions of this lesion. No examples of intratubular embryonal carcinoma as defined by CD30 expression alone in the absence of an intratubular proliferation were observed. The presence of intratubular seminoma in a nonseminomatous germ cell tumor suggests that it is a true preinvasive lesion rather than a manifestation of intratubular spread of an established invasive seminoma. The low incidence of intratubular embryonal carcinoma supports the theory that most nonseminomatous germ cell tumors evolve initially as seminomas, rather than directly from a differentiated intratubular neoplastic lesion.     

Glypican 3: a novel marker in testicular germ cell tumors

Glypican 3 (GPC3), a membrane-bound heparin sulfate proteoglycan, may play a role in promoting embryonic cell growth and differentiation. GPC3 is mutated in Simpson-Golabi-Behmel syndrome, characterized by tissue overgrowth and an increased risk of embryonal malignancies. Recently, GPC3 was reported to be one of the over-expressed genes in testicular yolk sac tumors by gene expression microarray analysis. However, the presence of the GPC3 protein in germ cell tumors has never been investigated. The purpose of the study was to investigate the GPC3 expression in various histologic components of testicular germ cell tumors using immunohistochemistry and to assess its possible utility as a diagnostic marker. Tumors from 71 patients were examined, including components of 42 seminomas, 37 embryonal carcinomas, 24 yolk sac tumors, 20 teratomas with mature elements, 16 teratomas with immature elements, and 7 choriocarcinomas. Cytoplasmic and membranous immunoreactivity was semiquantitatively evaluated. All yolk sac tumor (24/24) and choriocarcinoma (7/7) components were immunoreactive for GPC3, whereas only 38% of teratomas with immature elements and 8% of embryonal carcinomas expressed GPC3. There was no immunoreactivity in benign testicular tissue, intratubular germ cell neoplasia, seminomas (0/42), or teratomas with mature elements (0/20). We conclude that the oncofetal protein GPC3 is a novel immunohistochemical marker in testicular germ cell tumors with differential expression in defined histologic subtypes. Our findings suggest a possible role of GPC3 in tumor cell differentiation. Furthermore, GPC immunostaining may be useful in the pathologic diagnosis of nonseminomatous germ cell tumors, particularly yolk sac tumor, and choriocarcinoma.     

Genetic abnormalities in men with germ cell tumors

We retrospectively reviewed the genetic abnormalities detected clinically in 455 men with advanced germ cell tumors referred for chemotherapy. Of the patients 49 had extragonadal and 406 had testicular germ cell tumors. Of 19 patients with mediastinal germ cell tumors 4 (21 per cent, 3 with teratocarcinoma and 1 with endodermal sinus tumor) had Klinefelter's syndrome. Three of these patients had a 47XXY and 1 had a 48XXYY karyotype. No Klinefelter's syndrome was observed among 30 consecutive patients with retroperitoneal germ cell tumors or among the 406 with testicular tumors. Karyotypes of 35 consecutive patients with testis cancer without evident congenital abnormalities showed normal chromosomal patterns. We found 2 patients with Down's syndrome and testicular tumor, for an incidence of 0.5 per cent (probably significant). We also describe 2 cases of nonseminomatous testicular cancer and Marfan's syndrome (0.5 per cent incidence versus a 5 of 100,000 incidence of Marfan's syndrome in the general population). Apparently, genetic abnormalities are increased in men with germ cell tumors and we discuss the significance of this association.     

Primary nonseminomatous germ cell tumor of the prostate

We describe a case of a primary nonseminomatous germ cell prostatic tumor and discuss the problem of extragonadal germ cell tumors. Prognosis, staging and management of these tumors are similar to that of metastatic primary testicular germ cell tumors.     

Nonseminomatous germ cell tumor after chemotherapy with residual mass invading the spine

Bony metastasis is a rare feature of metastatic nonseminomatous germ cell tumor. A 25 year-old man presented with back pain radiating down both legs, and a subsequent work-up demonstrated a right-sided testicular mass with bilateral retroperitoneal lymphadenopathy and tumor involvement of the L2 vertebra. Radical inguinal orchiectomy confirmed nonseminomatous germ cell tumor, and the patient underwent chemotherapy with a residual mass and vertebral involvement by MRI. Combined vertebral resection with spinal reconstruction and retroperitoneal lymph node dissection demonstrated residual fibrosis. While bony metastasis of nonseminomatous germ cell tumors is rare, resection with spinal reconstruction can be accomplished with acceptable morbidity.     

Recurrent rhabdomyosarcoma after adjuvant chemotherapy for stage I non‐seminomatous germ cell tumor with malignant transformation

We report a rare case of stage I non‐seminomatous testicular germ cell tumor with malignant transformation. The patient received two cycles of chemotherapy (cisplatin, bleomycin and etoposide) tailored to testicular germ cell tumors as an adjuvant therapy after orchiectomy. However, 22 months later, the patient developed a metastasis in the occipital region that consisted of solely rhabdomyosarcoma through malignant transformation of a teratoma component. This case highlights an issue related to adjuvant chemotherapy for testicular germ cell tumors with components of malignant transformation.     

Klinefelter's syndrome and precocious puberty: a harbinger for tumor

Boys with Klinefelter's syndrome are at an increased risk of precocious puberty. Most cases are either idiopathic or due to a mediastinal tumor. Patients with Klinefelter's syndrome are at a high risk of primary, extragonadal germ cell tumors, which are usually nonseminomatous, but can be a mixed type with seminomatous elements. The differential diagnosis of precocious puberty includes mediastinal tumors, especially in boys with Klinefelter's syndrome.     

Testicular germ cell tumor in patient with Klinefelter syndrome

Although mediastinal germ cell tumors are known to occur with a greater frequency in patients with Klinefelter syndrome, reports of testicular germ cell tumors occurring in such patients are rare. We report a case of a nonseminomatous germ cell tumor in a patient with Klinefelter syndrome and suggest that such an association may occur more frequently than has been reported previously.     

Serum lactate dehydrogenase isoenzyme 1 as a marker of testicular germ cell tumor

Serum lactate dehydrogenase isoenzyme 1 activity was determined repeatedly in 21 men with testicular germ cell tumors in connection with orchiectomy and in 25 without neoplasia who underwent exploration of the testis. The highest level in the men without malignancy was 109 units per 1. and a higher pre-orchiectomy level was found in 15 of the tumor patients: 7 of 11 with seminoma and 8 of 10 with nonseminomatous tumors. In the patients with stage 3 disease serum lactate dehydrogenase isoenzyme 1 was increased more often and the activity was higher than in the stage 1 and 2 cancer patients. Within 1 month after orchiectomy the initially increased level decreased to less than 109 units per 1. in 8 of 10 patients with a stage 1 tumor and it remained higher in 5 with stage 2 or 3 disease. Serum lactate dehydrogenase isoenzyme 1 seems to be a useful marker of testicular germ cell tumor.     

Surgical salvage therapy for malignant intrathoracic metastases from nonseminomatous germ cell cancer of testicular origin: analysis of a single-institution experience

BACKGROUND: Cisplatin-based chemotherapy followed by surgical extirpation of residual benign disease represents the usual sequence of curative therapy for metastatic nonseminomatous germ cell cancer of testicular origin. Occasionally, residual disease is malignant in the form of either a persistent nonseminomatous germ cell cancer tumor or degeneration into non-germ cell cancer. We reviewed our institution's experience with patients undergoing salvage operations to remove malignant intrathoracic metastases. METHODS: From 1981 through 2001, 438 patients with nonseminomatous germ cell cancer had operations to remove residual intrathoracic disease after cisplatin-based chemotherapy at Indiana University Hospital. A subset of 134 patients who underwent 186 surgical procedures to remove malignant metastases is the basis of this review. Fifty-nine patients had removal of pulmonary metastases, 49 had removal of mediastinal metastases, and 26 had removal of both pulmonary and mediastinal metastases. Surgical pathology demonstrated 84 patients with persistent nonseminomatous germ cell cancer tumors, 38 with degeneration into non-germ cell cancer, and 12 with both malignant pathologic categories. RESULTS: There were 4 (3.7%) operative deaths. The overall median survival was 5.6 years, with 55 (42.3%) patients alive and well after a mean follow-up of 5.1 years. Seventeen variables were analyzed by using Cox regression. Of these, older age, pulmonary metastases (vs mediastinal metastases), and 4 or more (vs 1) total intrathoracic metastases were significantly (P < or = .01) predictive of inferior long-term survival. CONCLUSIONS: Salvage thoracic surgery to remove malignant metastases from nonseminomatous germ cell cancer tumors of testicular origin can result in long-term survival in select patients. We identified variables that influence survival in this subset.     

The incidence and management of metachronous testicular germ cell tumors in patients with extragonadal germ cell tumors

ObjectivesThe optimal management of extragonadal germ cell tumor (EGGCT) and metachronous testicular germ cell tumor (MTGCT) has not been determined.Patients and methodsFifty-one consecutive patients with EGGCT were identified. Testicular palpation or ultrasonography to rule out a primary testicular tumor was performed. Pretreatment testicular biopsies were not performed. The incidence and outcome of MTGCT, and the prognosis of EGGCT were evaluated.ResultsTwenty-five and 26 patients, respectively, had mediastinal and retroperitoneal EGGCT. Fourteen and 37 patients, respectively, had seminoma and nonseminoma. Five patients developed MTGCT in patients with retroperitoneal EGGCT. The median interval from the primary treatment for EGGCT to MTGCT diagnosis was 64 months (range 15–120). The cumulative risk of developing MTGCT was 8.3% at 6 y. Five patients underwent an orchiectomy and have survived in the 16-months median follow-up period (range 4–30). Among the patients with seminomatous and nonseminomatous EGGCT, the 5-year survival rate was 84.6% and 78.3%, respectively. Among the patients with retroperitoneal and mediastinal nonseminomatous EGGCT, the 5-year survival rate was 94.7% and 58.8%, respectively.ConclusionsThe prognosis of EGGCT without testicular biopsies was sufficient. EGGCT patients, especially retroperitoneal EGGCT, need long-term follow-up for MTGCT.     

Spontaneous regression of testicular seminoma: case report

A 33-year-old man had a 1-year history of a painless testicular mass and a 2-month history of an enlarging left supraclavicular mass. Biopsy of the supraclavicular mass showed classical seminoma. Massive abdominal lymphadenopathy was demonstrated by computerized tomography. Radical orchiectomy was performed and examination of the specimen showed only fibrous scar tissue consistent with regression of a primary tumor in the testis. While complete regression of a primary testicular tumor with progressive growth of metastases is well recognized in cases of nonseminomatous germ cell tumors, this phenomenon is reported rarely with seminoma.     

Vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum for advanced germ cell testis tumors: Brazilian experience

Disseminated germ cell testicular cancer proved to be highly sensitive to platinum-containing chemotherapy regimens. We present data concerning the treatment of advanced seminoma and nonseminomatous tumors in a developing country. We treated 30 patients with advanced germ cell testis tumors with 3 or 4 cycles of vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum. Surgical resection of residual masses was done 30 days after completion of chemotherapy in 18 patients. The histology of the primary tumor was seminoma in 13 patients and nonseminomatous tumors in 17. Toxicity was mild and no treatment-related deaths occurred. All 13 patients (100 per cent) with seminoma and 12 of 17 patients (71 per cent) with nonseminomatous tumors had a complete response to chemotherapy, and 1 of 17 patients was free of disease after a debulking operation and additional chemotherapy. A total of 3 patients with seminoma and 2 with nonseminomatous tumors had recurrences 5 to 8 months after an initial complete response and received additional chemotherapy (VP-16 regimen) with or without radiotherapy. Complete clinical response was achieved in 4 of 5 patients. Median followup was 24 months (range 8 to 38 months) in the 13 patients with seminoma and 28 months (range 9 to 58 months) in those with nonseminomatous tumors, and 13 (100 per cent) and 12 (71 per cent), respectively, are alive without evidence of disease. These data suggest that the protocol of vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum is highly effective and minimally toxic in the treatment of disseminated germ cell testicular cancer, inducing an 83 per cent long-lasting clinical remission. Seminomas seem to be equally or even more sensitive than nonseminomatous tumors to this platinum-containing chemotherapy regimen. Recurrence after initial complete response can be treated successfully with regimens containing VP-16.     

Classification and pathology of testicular germ cell and sex cord-stromal tumors.

Germ cell tumors of the testis are the most frequent testicular neoplasms, with seminoma predominating. The pathologist must be able to discriminate between seminoma and nonseminomatous germ cell tumors as well as sex cord-stromal tumors and metastatic lesions. Appropriate therapy and accurate prognostic information are dependent on the proper classification of testicular neoplasia. Characteristic histologic features, serum markers, and immunohistochemistry are helpful in this regard. Sex cord-stromal tumors comprise a small minority of testicular neoplasms. It remains critically important not to confuse these neoplasms with testicular germ cell or metastatic tumors, and, again, recognition of the characteristic histologic features, immunohistochemical findings, and clinical information is diagnostic. The urologist can provide the pathologist with key clinical information in the attempt to make a correct diagnosis.     

The role of alkaline phosphatase isoenzymes as tumor markers for testicular germ cell tumors.

The role of serum alkaline phosphatase as a tumor marker for testicular germ cell disease was investigated in 26 patients with testicular seminoma and 13 with nonseminomatous germ cell testis tumors. Placental alkaline phosphatase-like enzyme was elevated in 50% of the stage I seminoma patients and in all patients with stages II to III disease. In addition, liver (tissue unspecific) alkaline phosphatase was elevated in 10 and 83% of the patients, respectively. Lactic dehydrogenase and beta-human chorionic gonadotropin (beta-HCG) were detected in 50 to 60% of the patients with stage I seminoma. By combining placental alkaline phosphatase-like enzyme, lactic dehydrogenase and beta-HCG, 75% of the stage I and 100% of the stages II and III seminoma patients could be identified correctly. Placental alkaline phosphatase-like enzyme in serum also occurred with nonseminomatous germ cell tumor but less frequently, while liver alkaline phosphatase was not detected at all. Thus, placental alkaline phosphatase-like enzyme and liver alkaline phosphatase were predominantly determined in the serum of patients with seminoma. In studies of tumor tissues from 31 of these patients, those with normal serum placental alkaline phosphatase-like enzyme levels had significantly lower tissue placental alkaline phosphatase-like enzyme levels than patients with elevated serum levels (p less than 0.01). Seminoma tissues showed significantly higher levels of placental alkaline phosphatase-like enzyme and liver alkaline phosphatase than nonseminomatous germ cell tumors (p less than 0.01), explaining the infrequent elevation of serum placental alkaline phosphatase-like enzyme and liver alkaline phosphatase found in patients with nonseminomatous germ cell tumors.