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Immunohistochemical and two-parameter flow cytometric studies of DNA topoisomerase II alpha in human epithelial ovarian carcinoma and germ cell tumor.

DNA topoisomerase II alpha (topo II alpha) is associated with active cell proliferation and is a target for chemotherapeutic agents administered to patients with ovarian cancer. To evaluate the biologic significance of topo II alpha expression in human ovarian carcinomas, we examined the expression of this protein immunohistochemically in tissue sections from 99 patients with ovarian cancer (85 common epithelial carcinomas, 14 germ cell tumors). We also measured topo II alpha and nuclear DNA content by two-parameter flow cytometry in 29 cases to evaluate possible qualitative changes of topo II alpha in the cell cycle of ovarian cancer cells. We observed a significant correlation of the labeling indices (LIs) of topo II alpha and Ki-67. The topo II alpha-to-Ki-67 ratio in germ cell tumors significantly exceeded that in common epithelial ovarian carcinomas (P = .038). Among the latter, the topo II alpha-to-Ki-67 ratio was significantly higher in serous cystadenocarcinomas than in mucinous cystadenocarcinomas. Two-parameter flow cytometric analysis revealed that topo II alpha expression was mainly observed in cells at the S to G2/M phases of the cell cycle, but, in some cases, topo II alpha positivity was detected in cells at G1. A significantly higher topo II alpha-to-Ki-67 ratio was detected in tumors with topo II alpha-positive cells at the G1 than in tumors in which topo II alpha-positive cells were not at G1. Results indicated that quantitative as well as quantitative changes in topo II alpha occur in human ovarian carcinomas.

Adult↗

Cytology of fine needle aspirates of primary extragonadal germ cell tumors.

OBJECTIVE: To describe the characteristic cytologic features of fine needle aspirates (FNAs) of primary extragonadal germ cell tumors (PEGCTs). STUDY DESIGN: Thirteen patients with PEGCTs, including 2 seminomas, 2 mixed germ cell tumors, 3 immature teratomas, 1 choriocarcinoma and 5 yolk sac tumors (YSTs) were studied. The final diagnosis of PEGCT in all cases was established by histologic examination of the tumor tissues. Fine needle aspiration was done on either the primary tumor or metastatic foci. The aspirates were stained with one of the Romanovsky stains and Papanicolaou stain. RESULTS: Each type of PEGCT has its own morphologic characteristics. In seminoma, the tumor cells are large and noncohesive, with one to several distinct nucleoli; some lymphocytes are also present. YSTs show many pleomorphic cells with vacuoles in the cytoplasm and nuclei; tumor cells frequently aggregate in a microglandular or papillary pattern. Choriocarcinoma consists of syncytiotrophoblasts and cytotrophoblasts. The former are very large cells with eosinophilic cytoplasm, one to several nuclei and distinct nucleoli; the latter are medium-sized cells with vacuolated, basophilic cytoplasm and eccentric nuclei. Immature teratomas are composed of a mixture of cell types, including elongated epithelioid cells, mesenchymal cells and many large, naked, amorphous nuclei with a homogeneous chromatin pattern. Diagnosis of mixed germ cell tumor is difficult but can be made if two or more subtypes of tumor cells are observed in the FNA. CONCLUSION: Cytologic examination of FNAs of primary or metastatic lesions of PEGCTs, stained either with Romanovsky or Papanicolaou stain, is of diagnostic value for such diseases. The use of immunochemistry can help to confirm the cytologic impression.

Adolescent↗

[A case report of a 6-year-old boy with intracranial yolk sac tumor treated by VAB-6 regimen].

Several clinical trials have demonstrated that cisplatin-based chemotherapy for primary intracranial germ-cell tumors is effective as a neoadjuvant chemotherapy. In this report, we describe a 6-year-old boy, Down syndrome and Hirschsprung's disease with intracranial pure yolk sac tumor treated by combined chemotherapy with cisplatin, vinblastine, bleomycin and cyclophosphamide (modified VAB-6 regimen). He had been admitted to our hospital because of intractable vomiting, and left facial nerve palsy since 1 month before. An MRI revealed an enlarged mass, 4cm in diameter, in the left cerebello-pontine angle with uniformal enhancement by Gd-DTPA, and bilateral ventricular dilatation. He was found to have increased serum alpha-fetoprotein level (AFP 11, 786ng/ml), but not human chorionic gonadotropin beta-subunit. After a partial resection of the tumor, diagnosed as pure yolk sac tumor, and ventriculo-peritoneal shunt, three courses of combined chemotherapy with cisplatin, bleomycin, vinblastine and cyclophosphamide (modified VAB-6 therapy) were carried out. The serum AFP level returned to normal, and the tumor mass entirely disappeared (a complete response) on MRI after the second course of chemotherapy. However, cisplatin-induced vomiting and mild neutropenia and renal tubular injury developed after the third course of chemotherapy. Irrespective of administration of recombinant human G-CSF and broad spectrum antibiotics, he suffered from pneumonia and died of septic shock and multiple organ failure. Autopsy showed microscopic residual tumors. The combination chemotherapy with cisplatin, bleomycin, vinblastine and cyclophosphamide is effective for initial treatment of childhood intracranial yolk sac tumor. It is necessary, however, to reevaluate the cisplatin dosage and treatment schedule in order to reduce such side effects as bone marrow suppression and renal damage.

Antineoplastic Combined Chemotherapy Protocols↗

Recurrent yolk sac tumor following resection of a neonatal immature gastric teratoma.

Gastric teratomas are very rare and usually benign. Only a few cases of gastric teratomas with malignant components have been reported. This report describes recurrence of a yolk sac tumor following resection of a neonatal immature gastric teratoma. Gastric teratoma recurring as a malignant lesion has not been previously reported. Recurrence of immature gastric teratomas should be considered, and a periodic follow-up check with alpha-fetoprotein level should be mandatory.

Endodermal Sinus Tumor↗

[Pulmonary rhabdomyosarcoma generated during treatment of testicular tumor].

A 23-year-old male was admitted to our hospital for the management of pulmonary metastases. He had undergone right high orchiectomy, chemotherapy with four courses of PEB regimen (cisplatin, etoposide, bleomycin) and retroperitoneal lymph node dissection the previous year. The pathological findings showed mixed germ cell tumor (seminoma, yolk sac tumor, embryonal carcinoma) in the testis and mature teratoma in the draining lymph node. Two courses of salvage chemotherapy using a VIP regimen (etoposide, ifosfamide, cisplatin) were performed after diagnosis of pulmonary metastases, but had no affect on tumor size. Video-assisted excision of pulmonary metastases was then performed, giving a pathological diagnosis of rhabdomyosarcoma in all three resected tumors. The operation was followed by three courses of CYVADIC (cyclophosphamide, vincristine, adriamycin, dacarbazin) chemotherapy and oral cyclophosphamide, as a small residual tumor was suspected. These chemotherapeutic interventions have appeared effective, with no apparent recurrence of lesions at present, one year after the excision of pulmonary metastases.

Adult↗

[Induction chemotherapy and radical resection for primary nonseminomatous mediastinal germ cell tumor (NSGCT); report of a case].

A 15-year-old male was admitted to our hospital for treatment of an anterior mediastinal tumor. The tumor was visualized by chest radiography 3 months prior to admission. Computed tomography (CT) revealed a heterogeneous solid tumor located in the anterior mediastinum. Although CT-guided needle biopsy had been performed twice, histologic diagnosis could not be confirmed. We believed this tumor to be nonseminomatous mediastinal germ cell tumor (NSGCT) and started intensive chemotherapy with cisplatin (CDDP) without histologic diagnosis because his serum AFP level was rapidly increasing. After 2 courses of chemotherapy, his serum AFP level returned to the normal range and surgical resection of the tumor with part of right lung was performed. Histopathological examination revealed that the tumor consisted of mature teratoma and yolk sac tumor. He underwent 1 course of chemotherapy post-operatively because a small number of viable cells were histopathologically recognized in the yolk sac component. At the time of writing, the patient is alive without any evidence of recurrence.

Adolescent↗

[Metastatic testicular tumor requiring inferior vena cava resection with polytetrafluoroethylene graft replacement: a case report].

A 31 year-old man with a biopsy-proved retroperiotoneal yolk sac tumor was referred to our clinic. Physical examination revealed a thum- tip sized left supra-clavicular mass, a huge right abdominal mass and a tiny hard mass of the right testis. On CT scan, the abdominal tumor, 13 cm in diameter, encircled the inferior vena cava. Serum levels of LDH, AFP and hCG-beta were 2,585 U/l, 19,922 ng/ml and 6.6 ng/ml, respectively. No visceral metastasis was found. Following the right high orchiectomy, 4 cycles of VIP chemotherapy consisting of ifosfamide, etoposide and cisplatin were given, which resulted in partial response of the retroperitoneal mass and complete regression of the supraculavicular node with normalization of all tumor markers. Thus, retroperitoneal lymph node dissection was carried out. Because of the marked adhesion to the tumor, the inferior vena cava was segmentally resected together with the tumor, which was followed by reconstruction of the vena cava using a 16 cm long polytetrafluoroethylene graft, since no collateral venous route was found on the pretreatment venacavography. Histologically, the tumor was nearly necrotic with mature teratoma in small part. Postoperative clinical course was uneventful except feeling of numbness at the right tip toe, and the inferior vena cava has been patent 18 months after the operation with no evidence of recurrence.

Adult↗

Hyperthermia for the treatment of patients with malignant germ cell tumors: a phase I/II study in ten children and adolescents with recurrent or refractory tumors.

BACKGROUND: Extracranial nontesticular germ cell tumors (GCTs) are rare malignancies in children and adolescents. Cisplatin-containing regimens and complete tumor resection are important determinants for a favorable outcome; however, patients with recurrent tumors that cannot be eradicated by surgical procedures and chemotherapy have a poor prognosis. Noninvasive electromagnetic technologies for superficial and regional deep hyperthermia (RHT) are under investigation to enhance local tumor control in various malignancies. The objectives of this Phase I/II study were to examine 1) whether RHT can be used in combination with platinum-based chemotherapy with acceptable toxicity in children and adolescents and 2) whether this combined regimen can induce objective tumor response in patients with malignant nontesticular GCT that persisted or recurred locoregionally after validated, intensive, cisplatin-based chemotherapy +/- surgery as unsuccessful first-line treatment. METHODS: The authors studied the effects of RHT induced by electromagnetic waves in combination with platinum-based chemotherapy in ten children and adolescents with recurrent or refractory GCTs. RESULTS: Seven of ten patients with recurrent or refractory GCTs had objective responses. Of these, two patients had a partial response and five patients had a complete response. CONCLUSIONS: The results of the current study found that combined RHT and platinum-based chemotherapy can be used in children and adolescents. This regimen was found to induce objective tumor response in 70% of study patients with recurrent or refractory GCTs. The results thus far are encouraging and the study has been extended to patients with a poor response to first-line treatment.

Adolescent↗

[A case of yolk sac tumor of the anterior mediastinum].

A 26-year-old male was clinically diagnosed as having a anterior mediastinal yolk sac tumor because of the elevation of the serum AFP (26,765 ng/ml) and a large mass lesion (13 x 12 x 8 cm) in the anterior mediastinum and right thoracic cavity. After three courses of chemotherapy with CDDP and VP-16, the mediastinal mass reduced in size significantly but the serum AFP level did not reach within normal range. We suspected that the tumor took a resistance to drugs, accordingly the operation was performed. The tumor was completely removed and there were small viable foci of the tumor in part of the tumor. The histological examination revealed the findings of yolk sac tumor. After the operation, the serum AFP level decreased within normal range. He is alive without evidence of recurrence during 18 months after operation. It was noticed that the serum AFP is a useful indicator for determining the chance of operation after chemotherapy.

Adult↗

Genetic analysis of childhood germ cell tumors with comparative genomic hybridization.

BACKGROUND: Germ Cell Tumors (GCTs) in children and adolescents constitute a clinically and histologically heterogeneous group of tumors. Compared to GCTs in adults, the numbers of GCTs in children analyzed with cytogenetic and molecular genetic techniques is limited. However, the data available to date reveal a pattern of cytogenetic aberrations different from that in adults. Comparative genomic hybridization (CGH) is a valuable technique for the genetic profiling of tumors that allows screening for chromosomal imbalances consistent with amplification of oncogenes and loss of putative tumor suppressor genes. As CGH does not require tissue culture, it also allows analysing archival tissue samples. PATIENTS: This study focuses exclusively on GCTs in children younger than ten years of age and summarizes the genetic data of 51 tumors. Eighteen teratomas and 33 malignant GCTs were included. Primary sites were the testis (n=10), coccyx (n=13), mediastinum (n=20), ovary (n=5), CNS (n=2), and the face (n=1). METHODS: The experimental procedure includes differential enzymatic fluorescence labeling of tumor and control DNA followed by comparative hybridization to normal male chromosomes, karyotyping and computerized analysis of the fluorescence profiles. RESULTS: With the exception of one testicular and two ovarian tumors, malignant GCTs in children do not show chromosomal gain of 12p, which is characteristic of GCTs in adult patients. Irrespective of the primary site, childhood GCTs show chromosomal imbalances of chromosome 1 (loss of distal 1p, gain of 1q), deletion of 4q and 6q as well as gain of 20q at a high frequency. CONCLUSIONS: These studies will help guiding further investigations elucidating the role of putative tumor suppressor genes at e.g. 1p36 and 6q. In addition, further studies incorporated in prospective therapeutic protocols are necessary to evaluate the prognostic relevance of specific genetic aberrations.

Adolescent↗

Yolk sac carcinoma derived from the rat epiblast as a renal isograft.

We report the novel observation that a biphasic, parieto-visceral (PYS/VYS) yolk sac carcinoma can develop from the isolated epiblast of the pre-primitive streak rat embryo in a prolonged cultivation in vivo as a renal isograft. Late 7-day rat egg cylinders were dissected free of the ectoplacental cone and the Reichert's membrane. The middle segment of the cylinder, in which the embryonic and the extraembryonic cell layers partly overlap, were also removed. From the rest of the cylinder the 4 cell layers were isolated and transplanted separately under the kidney capsule of isogenic adult males. After 4 weeks the hypoblast was resorbed, the extraembryonic ectoderm gave rise to hemorrhagic cysts and trophoblastic giant cells, the extraembryonic (visceral yolk sac) endoderm formed benign cystic PYS/VYS tumors, and the epiblast developed into a benign teratoma. After prolonged (7-30 weeks) development of these teratomas as isografts, a malignant yolk sac carcinoma (YSC) developed in 45% of them. It destroyed the teratoma and the recipient's kidney, metastasized to peritoneum and other sites, and caused abundant ascites containing clustered tumor cells. The primary tumor was retransplantable subcutaneously as well as intraperitoneally, and displayed the characteristics of the mixed or biphasic PVYS carcinoma, with a progressive loss of the VYS component with time. Several data are apparently in favor of its origin by transdifferentiation rather than from undifferentiated cells.

Animals↗

Cytogenetic analysis of a mature teratoma and a yolk sac tumor component of a late relapse of a disseminated testicular nonseminoma.

We report on the cytogenetics of a primary testicular nonseminoma, a residual mature teratoma after remission-induction chemotherapy, and a late relapse after 9 years of follow-up, in one patient. The late relapse was composed of a mature teratoma and a yolk sac tumor component. Cytogenetic comparison of the different tumors shows that progression of primary testicular nonseminoma to residual mature teratoma and to a late-relapse lesion is accompanied by net loss of chromosomes. In addition, our findings may suggest that transformation to viable cancer in a late-relapse lesion is accompanied by further chromosomal losses.

Adult↗

Primary yolk sac tumor concomitant with carcinosarcoma originating from the endometrium: case report.

BACKGROUND: A primary yolk sac tumor (YST) with carcinosarcoma originating from the endometrium is extremely rare, to our knowledge, this is the third documented instance. Several hypotheses exist is to its histogenesis. CASE: A 65-year-old Japanese woman was diagnosed with a uterine malignancy and underwent surgical treatment and chemotherapy. The postoperative diagnosis was primary carcinosarcoma concomitant with a YST of the uterus. Immunohistochemical staining revealed that the tumor area suspected to be a YST was positive for alpha-fetoprotein. CONCLUSION: We report a case of carcinosarcoma concomitant with a YST of uterus. This case is the third documented instance of a YST with concomitant with carcinosarcoma originating from the endometrium. The histogenesis in this case is suggests aberrantly differentiated somatic cells.

Aged↗

Pure yolk-sac tumor of the lung.

The first case of a pure primary yolk-sac tumor of the lung is presented. The tumor developed in the right upper lobe of a 31-year-old man; preoperatively, the serum alpha-fetoprotein concentration was elevated. Treatment consisted of pulmonary segmentectomy with postoperative combination chemotherapy. The patient is alive and well 13 months after surgery with a normal serum alpha-fetoprotein concentration.

Adult↗

Immunohistochemical detection of p63 in testicular germ cell neoplasia.

p63 is a novel transcription factor-encoding gene with sequence homology to p53. p63 proteins have epithelial stem-cell regulatory functions and play a critical role in tissue development. Study of p63 expression in testicular germ cell tumors has been limited. Thirty-four archival cases of testicular germ cell neoplasia were examined and stained with monoclonal anti-p63 antibody 4A4 using standard methods. Included were 19 seminomas, 1 pure teratoma, 3 pure embryonal carcinomas, 1 pure yolk sac tumor, and 10 mixed germ cell tumors. p63 staining was consistently positive in teratomas in areas of squamous differentiation and in basal reserve-like cells in foci of respiratory/endodermal differentiation. Strong p63 staining was observed within cytotrophoblasts of choriocarcinoma (1/1), whereas focal positivity was detected in embryonal carcinomas (4/10) and yolk sac tumors (2/5). Seminomas and intratubular germ cell neoplasia were p63-negative. These findings may suggest the presence of pluripotent p63-positive stem cell-like nests in yolk sac tumors and embryonal carcinomas or may represent areas of an occult teratoma phenotype undetectable histopathologically on hemotoxylin-eosin sections. p63 positivity in cytotrophoblasts of choriocarcinoma is consistent with gynecologic studies, possibly reflecting the role of p63 in the oncogenesis of neoplastic trophoblasts. The consistent p63 negativity in seminomas may reflect a precommitted embryonic precursor-like phenotype.

Carcinoma, Embryonal↗

[A case of peritoneal metastasis from retroperitoneal yolk sac tumor diagnosed by 67Ga-scan and 18F-FDG-PET].

Yolk sac tumor is one of the histological types of germ cell tumors. Primary retroperitoneal germ cell tumors are extremely rare neoplasms. We report a case of peritoneal metastasis after resection of a primary retroperitoneal germ cell tumor. The peritoneal metastases were detected by 67Ga-scan when CT did not suggest metastatic lesions while the level of alphafetoprotein was still elevated. The 67Ga-scan showed multiple hot spots in the abdomen and pelvis 72 hours after intravenous injection of the tracer and no changes were observed in serial scan taken 6 hours after the first scan. These findings were strongly suggested the dissemination of the malignant tumors. A PET study with 18F-fluorodeoxyglucose was performed and showed extensive uptake in the intraabdominal and intrapelvic cavity. It was also useful for understanding the extension and distribution of the peritoneal metastatic lesions. The sites of the accumulation of 18F-fluorodeoxyglucose corresponded to the results found in postmortem.

Adult↗

Robb-Smith type malignant histiocytosis associated with a mediastinal germ cell tumor.

A 22-year-old Japanese man with a mediastinal germ cell tumor with mixed teratoma and hepatoid alpha-fetoprotein positive, and glandular yolk sac components, also demonstrated widely disseminated malignant histiocytosis involving the lungs, liver, pancreas, spleen, bone marrow and lymph nodes. Sensitivity to chemotherapy was acute and the patient died of disseminated intravascular coagulation syndrome within four months of his initial presentation.

Adult↗