Histology in mixed germ cell tumors. Is there a favorite pairing?

PURPOSE: Mixed germ cell tumors account for approximately 30% to 50% of testicular tumors. To our knowledge a systematic review with statistical analysis of the associations of histological subtypes in mixed germ cell tumors has not been done previously. It was our impression that such associations exist. Delineating concordant histological types may provide insight into the ontogeny of testicular tumors and also have important clinical implications. MATERIALS AND METHODS: We retrospectively reviewed the testis cancer data base at our institution. The primary tumor of orchiectomy specimens was examined in 2589 patients. Of these patients mixed histology was noted in 1765 (68.2%). ORs were calculated for all possible combinations of teratoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma and seminoma. In addition, we evaluated the association of various histological types with teratoma at post-chemotherapy retroperitoneal lymph node dissection. RESULTS: Of 10 possible combinations of histological types in the primary tumor, positive correlations were noted in 4. The strongest correlation was found between teratoma and yolk sac tumor (OR 2.58, p <0.001). Teratoma or yolk sac tumor in the testis was associated with teratoma in the pathology specimen at post-chemotherapy retroperitoneal lymph node dissection. CONCLUSIONS: The strongest associations of histological subtypes in mixed germ cell tumors were seen between yolk sac tumor and teratoma. Similar associations are seen in late relapse and in some cases of prepubertal tumors. Further study of these associations may prove valuable in understanding the biology and clinical behavior of germ cell tumors.     

Profiles of epitope-defined markers in sera from patients with testicular germ cell tumors

Summary Epitope-defined tumor markers of AFP (FA), HCG (PM), PLAP (H7) and CEA (D/AH) were determined by monoclonal antibodies in sera of patients with germ cell tumors of the testis. Characteristic profiles of PLAP (H7) were seen in localized and metastatic seminoma and in sera of patients with mixed tumors with seminoma components. PLAP (H7) levels started to rise 10 months before clinical detection of recurrence in one case. Persisting elevated levels of PLAP (H7) in several cases were indicative of metastafic seminoma. PLAP (H7) occurred rarely in sera of patients with metastasing non-seminomatous tumors. AFP (FA) detected in seminoma sera led to identification of non-seminomatous disease in one case. High AFP (FA) alone occurred in yolk sac tumors, HCG (PM) with AFP (FA) or PLAP (H7) in patients where the tumors had components of teratoma and/orembryonal carcinoma, moderately elevated levels of AFP (FA) and sometimes also HCG (PM) occurred.     

The pathology of late recurrence of testicular germ cell tumors

A total of 91 men had histologically documented late recurrences of testicular germ cell tumors characterized by a complete response to treatment with a subsequent disease-free interval of at least 2 years and no evidence of a second primary lesion. Ninety percent of the patients for whom information was available received chemotherapy shortly after their initial diagnosis of testicular germ cell tumors; most of the other patients were known to have stage I disease initially. Overall, 60% of patients had teratoma in their late recurrences, including 20 patients (22%) in whom teratoma was the only element. Thus, teratoma was the most common type of neoplasm in late recurrences. Excluding teratoma coexisting with other types of neoplasms, yolk sac tumor was the most frequent type of tumor in patients with late recurrence. It occurred in 47% of patients, either alone or with teratoma, another nonteratomatous germ cell tumor type, or a "nongerm cell malignant tumor." Unusual types of yolk sac tumor, including glandular, parietal, clear cell, and pleomorphic patterns, were seen frequently in late recurrences and often raised differential diagnostic problems with "nongerm cell" carcinomas. A smaller number of late recurrences consisted of other types of neoplasms. Twenty percent of patients with late recurrence had a nonteratomatous germ cell tumor other than yolk sac tumor, either alone, with yolk sac tumor, or with a "nongerm cell malignant tumor." Most of these nonteratomatous germ cell tumors other than yolk sac tumor were embryonal carcinoma, although rarely seminoma and choriocarcinoma were encountered. "Nongerm cell malignant tumors," including both sarcomas and carcinomas of various types, occurred in 23% of late-recurrence patients, either alone or with a nonteratomatous germ cell tumor. Late recurrences were seen in many different sites in these patients, including the retroperitoneum, abdomen, pelvis, liver, mediastinum, lung, bone (femur, vertebra, and rib), lymph nodes outside the retroperitoneum and mediastinum (supraclavicular, neck, and axillary regions), scrotum and inguinal regions, adrenal gland, chest wall, and buttocks. Follow-up data were available for 79 of the 91 patients studied. Duration of follow-up ranged from 2 months to 13 years after the patient's first late recurrences; the mean length of follow-up was 4.8 years. Patients whose late recurrences consisted of teratoma only had the most favorable outcomes, with 79% having no evidence of disease at last follow-up. Patients whose late recurrences consisted of pure "nongerm cell malignant tumor" or pure germ cell tumor (yolk sac tumor or other types) had a much worse prognosis: Only 36% to 37% were alive with no evidence of disease. Patients with two different types of nonteratomatous malignancies in their late recurrences had a dismal clinical course: Only 17% with both yolk sac tumor and other nonteratomatous germ cell tumor had no evidence of disease, whereas no patient with both nonteratomatous germ cell tumor and "nongerm cell malignant tumor" was disease free. Late recurrences consisting of teratoma alone often have a favorable outcome, but the prognosis in all other patients is poor. Furthermore, late recurrence is not likely to respond to chemotherapy and is best treated by surgical excision when possible.     

An immunohistochemical study on neuron specific enolase in testicular germ cell tumors]

Testicular germ cell tumors obtained from 44 patients were immunohistochemically studied using anti-neuron specific enolase (NSE) antibody. The level of NSE in the serum was also measured in 9 patients before and after extirpation of the tumor. As for tumor cells of seminoma, 19 of 20 pure seminomas and all 9 of mixed type were positive for NSE. On the contrary, a spermatocytic seminoma was NSE-negative. As for embryonal carcinomas, some tumor cells were NSE-positive in 13 of 15 of mixed type. In yolk sac tumor, a few tumor cells were also NSE-positive in 8 of 21 of both pure and mixed types. Some NSE-positive cells were found in teratomatous components of 10 of 14 mature and immature teratomas of both pure and mixed types. These were in neural cells, chondrocytes, and glandular epithelial cells. Spermatogonia in 5 normal testes were NSE-positive. NSE level in the serum was elevated before extirpation and decreased after extirpation in 4 of 5 cases of seminoma of pure type and in 1 of 2 of mixed type which included seminomatous elements. All of these cases were either in the advanced stage or had a rather large primary tumors. Immunohistochemical study of testicular germ cell tumors using anti-NSE antibody may facilitate histological diagnosis, and serum NSE level may be useful for monitoring the clinical course as well as for clinical diagnosis of seminoma.     

组织芯片技术检测人睾丸基因TDRG1在睾丸肿瘤组织中的表达

目的:探讨人睾丸基因TDRG1在睾丸肿瘤组织中的蛋白表达及其病理学意义。方法:运用组织芯片技术、免疫组化法检测人睾丸特异基因TDRG1在睾丸肿瘤组织和正常睾丸组织中的表达。结果:15例正常人睾丸对照组中11例(73.3%)TDRG1蛋白表达为阳性;26例精原细胞瘤中7例(26.9%)TDRG1蛋白表达为阳性,7例畸胎瘤中4例(57.1%)TDRG1蛋白表达为阳性。而12例胚胎癌中10例(83.3%)TDRG1蛋白表达为阳性,10例卵黄囊瘤中8例(80.0%)TDRG1蛋白表达为阳性。精原细胞瘤实验组与正常人睾丸对照组相比较,两组间具有极显著性差异(P<0.01)。畸胎瘤实验组与正常人睾丸对照组相比较,两组间具有显著性差异(P<0.05)。而胚胎癌组和卵黄囊瘤组与正常人睾丸对照组相比较,没有显著性差异(P>0.05)。结论:TDRG1蛋白在精原细胞瘤和畸胎瘤的表达水平较正常对照睾丸组织显著降低,TDRG1可能为候选的抑癌基因。     

Serum lactate dehydrogenase and its isoenzymes in men with maldescended testes

Serum lactate dehydrogenase and lactate dehydrogenase isoenzymes were determined as a screen for testicular germ cell neoplasia in 130 men with maldescended testes. A testicular tumor was found on clinical examination in 1 patient, which was revealed to be embryonal carcinoma, teratoma, yolk sac tumor and carcinoma in situ on orchiectomy. Subclinical testicular germ cell neoplasia was found on testicular biopsy in 3 men (1 with microinvasive seminoma and 2 with carcinoma in situ). These 4 patients had normal serum lactate dehydrogenase and serum lactate dehydrogenase isoenzymes. Elevated serum lactate dehydrogenase was noted in 3 men without testicular germ cell neoplasia: 1 had predominantly increased serum lactate dehydrogenase isoenzymes 1 to 3 and 2 had slightly increased serum lactate dehydrogenase isoenzymes 3 and 4. Serum lactate dehydrogenase and lactate dehydrogenase isoenzymes were not sensitive to detect testicular germ cell tumors in a subclinical stage.     

A case report: simultaneous bilateral testicular tumors with different cell types--complete response after combination chemotherapy of cisplatin and irrinotecan hydrochloride--

A 38-year-old man was admitted to our hospital complaining of bilateral scrotal swelling. On examination, the patient was found to have bilateral testicular tumors with jugular chain lymph node and para-aortic lymph node metastasis. He underwent bilateral inguinal orchiectomy. Histopathological examination of the excised tumors revealed seminoma, embryonal carcinoma, yolk sac tumor and immature teratoma in the right testis and seminoma in the left testis. The patient was treated postoperatively with two courses of BEP (bleomycin, etoposide, cisplatin) therapy and two courses of EP (etoposide, cisplatinum) therapy. The patient had lung metastasis during the follow-up period and we treated him with salvage combination chemotherapy of cisplatin and irinotecan hydrochloride (CPT-11). After the third course of cisplatin and CPT-11 chemotherapy the lung metastasis disappeared and we performed retroperitoneal lymph node dissection. The patient has remained free of disease 11 months after discharge.     

Primary mediastinal germ cell tumors

The most frequent site of extragonadal germ cell tumors is the mediastinum. The majority (80%) of mediastinal germ cell tumors are benign mature teratomas, which can be easily removed. Malignant germ cell tumors account for approximately 20% of all cases and are clinically classified into seminoma and non-seminomatous germ cell tumors. Seminomas are radiosensitive and have relatively a good prognosis. Patients with non-seminomatous germ cell tumors had a very poor prognosis, however, the introduction of cis-platinum based chemotherapy has improved the prognosis of patients with these tumors. Three hundred twenty nine cases of malignant mediastinal germ cell tumors have been described in the literature and reports up to 1988 in Japan. The types and cases are following: [table: see text] Multi-drug chemotherapy with cis-platinum has improved the prognosis of patients with embryonal carcinoma and yolk sac tumors, although patients with choriocarcinoma have yet a poor response to the combination chemotherapy. Five year survivors have consisted of 19 patients with seminomas and five patients with non-seminomatous germ cell tumors. Most long survival patients have undergone surgical resection of tumors. The results suggested that the improvement for prognosis requires earlier prognosis and complete surgical removal of tumors associated with chemotherapy combining further effective regimens.     

Seminoma with tubular, microcystic, and related patterns: a study of 28 cases of unusual morphologic variants that often cause confusion with yolk sac tumor

We report 28 testicular seminomas with cystic spaces of variable nature, sometimes accompanied by solid and hollow tubular patterns (12 cases). The spaces often suggested reticular or microcystic patterns of yolk sac tumor, and the solid and hollow tubular patterns often added to the diagnostic confusion. The tumors occurred in men 21 to 55 years old and on gross examination had the typical appearance of seminoma. On microscopic examination, the spaces ranged from small, closely packed and relatively regular to dilated, more dispersed and somewhat irregular. The hollow tubules appeared to result from central discohesion within nests of tumor. The spaces, particularly when large, often contained occasional tumor cells or inflammatory cells within pale edema fluid. The cytologic appearance of the cells lining the spaces, and in the surrounding tumor, retained the typical features of seminoma cells. Thirteen tumors (46%) either lacked (8 cases) or had very scant (5 cases) lymphocytes in the cystic and tubular areas, and hyaline globules were absent. Thirteen of 13 tumors were immunopositive for OCT-3/4 in the nontypical and typical areas; 9 of 10 were placental alkaline phosphatase positive, and 7 of 10 were c-Kit (CD117) positive. The same 13 cases were negative with cytokeratin (AE1/AE3) and alpha-fetoprotein stains. Distinction from yolk sac tumor is aided by the observation that the spaces of yolk sac tumor are often more irregular in their individual shapes and frequently form anastomosing channels. Additionally, the spaces of yolk sac tumor randomly merge with various other yolk sac tumor patterns. The cells lining spaces in yolk sac tumor are often flattened with compressed nuclei and lack the typical prominent nucleoli of seminoma cells. Paucity of lymphocytes and intracystic edema, however, are not differentially helpful, although basophilic fluid favors yolk sac tumor. A panel of immunostains (AE1/AE3, OCT-3/4, and alpha-fetoprotein) is helpful in the differential with yolk sac tumor in especially problematic cases. The edema and paucity of lymphocytes may suggest spermatocytic seminoma, but the varied cell types of that neoplasm are absent.     

Biology of testicular tumors.

Testicular tumors arise from the germ cell line and therefore exhibit characteristics of both neoplastic and normal growth and differentiation. Experimental model systems of animal and human tumors have been reviewed with emphasis on the biologic characteristics of these tumors. The embryonal carcinoma cell is the totipotential stem cell that resembles normal germ cells in many ways and is capable of differentiating along the somatic pathways to form endoderm, mesoderm and ectoderm cell types (teratoma) or along extraembryonic pathways to form trophoblast (choriocarcinoma) or yolk sac (endodermal sinus tumor). Markers of the extraembryonic cell types have been defined, and the cell surface characteristics of embryonal carcinoma cells are being intensively studied. Clarification of the biology of testicular tumors will provide the basis for future rational therapy.     

睾丸肿瘤的诊断

目的 :提高睾丸肿瘤的诊断水平。　方法 :回顾 1 992年 9月～ 2 0 0 1年 1 2月睾丸肿瘤 57例病人的症状、体征 ,影像学、肿瘤标记物和病理资料。　结果 :1 8例病人 (31 .3 % )延迟就医。术前查甲胎蛋白 (AFP) 1 1例 ,5例阳性。检测绒毛膜促性腺激素亚单位 (β HCG) 6例 ,1例阳性。二维B超及彩色多普勒血流显像超声 (CDFI)的灵敏度分别为 93 .5 % (45/ 4 7)、96 .4 % (2 8/ 2 7)。 55例行根治性睾丸切除术 ,2例行单纯睾丸切除术。后腹膜淋巴结清扫术 1 9例 ,淋巴结阳性 1 1例 ,阴性 8例。石蜡切片 57例 ,精原细胞瘤 2 2例 ,胚胎癌 9例 ,畸胎瘤 7例 ,卵黄囊瘤3例 ,混合性生殖细胞瘤 9例 ,恶性淋巴瘤 4例 ,其他 3例。其中 2 6例行术中冰冻切片 ,2 3例 (88.5 % )与石蜡切片报告符合。　结论 :病人需强化健康意识 ,尽早就医 ;术中常规冰冻切片 ,明确良、恶性肿瘤 ,是提高诊断水平 ,避免延误诊治的根本途径     

Localization of alpha-fetoprotein and human chorionic gonadotropin to specific histologic types of nonseminomatous testicular cancer

We used an indirect immunoperoxidase technique to localize alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) to specific histologic types of testicular germ cell cancers. Among 20 nonseminomatous tumors studied, yolk sac tumor reacted for AFP in 13 of 15 cases, teratoma in 3 of 11 cases, and embryonal carcinoma in 3 of 14 cases. Syncytiotrophoblasts alone reacted for HCG in 14 of 15 cases, and syncytiotrophoblasts associated with choriocarcinoma reacted for HCG in 2 of 2 cases. There was a close correlation between the tissue demonstration of AFP and HCG and elevated serum levels of AFP and HCG, respectively. We conclude that in nonseminomatous testicular cancer yolk sac tumor is the primary site of synthesis of AFP, and syncytiotrophoblasts are the only site of synthesis of HCG.     

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.     

Chemotherapy of disseminated germ cell testicular tumors with cis-diamminedichloroplatinum and other drugs

The effect of single CDDP therapy and PVB therapy was examined in 7 cases of stage III germ cell testicular tumors with measurable metastases. The mean age of the patients was 30.6 years old, and their histological types of primary sites were seminoma in 3 cases, embryonal carcinoma in 2, immature teratoma in 1 case and embryonal carcinoma + teratoma in 1 case. In 1 case of seminoma, 375 mg of CDDP was administered. In 1 case of embryonal carcinoma + teratoma, 100 mg of CDDP and then 2 courses of PVB therapy were performed, and 3 courses of PVB therapy were given in all other cases. Three cases showed complete response, 2 cases partial response and 2 cases no change. Pulmonary metastatic nodules were extirpated after the PVB therapy in 1 of the cases showing no change, and the histological examination of these nodules was found to be mature teratoma. As a result, the effectiveness of the chemotherapy alone was 71.4%, and that of chemotherapy + surgical operation was 85.7%. Significance of intensive chemotherapy and necessity of extirpation of residual metastatic nodules after intensive chemotherapy in the management of advanced germ cell testicular tumors are stressed.     

Immunological tissue markers in the diagnosis of testicular cancer

Summary Immunohistochemistry greatly contributes to the accuracy of the diagnosis in testicular germ cell tumors (TGCT). Human chorionic gonadotropin (HCG) and alphafetoprotein (AFP) are the most used markers in testicular cancer, where the immunostaining is positive in non-seminomatous TGCT. Pure seminoma does not produce these proteins but some are combined with syncytiotrophoblastic cells which elaborate HCG, producing elevated HCG serum levels and positive immunostaining. Other markers deserve mention. Among these there are placental alkaline phosphatase (PLAP), ferritin (Fe), pregnancy specific beta₁-glycoprotein (SP₁), human placental lactogen (HPL), carcinoembrionic antigen (CEA) and alpha₁-antitrypsin (A₁AT). In addition, the recognition of intermediate filament proteins, such as keratin and vimentin, allow differentiation between seminoma and embryonal carcinoma.     

Spontaneous maturation in the metastatic region of a bilateral testicular germ cell tumor

A case of bilateral testicular germ cell tumor of different cell types was found to have a mature teratoma in the metastatic region. Histology of the right testis revealed seminoma and embryonal carcinoma while the left testis revealed seminoma and mature teratoma. A mature teratoma, containing cartilage components, was also found in the right para-aortic lymph node. The findings of the case are described and the literature on cases with maturation in the metastatic region are reviewed.     

Pituitary‐tumour‐transforming‐gene 1 expression in testicular cancer

Genomic instability is a feature of germ cell tumours. The pituitary‐tumour‐transforming‐gene 1 (PTTG1) is the major effector of chromosome segregation during mitosis, protecting the cell from aneuploidy. The protein expression of this gene has been evaluated in testicular tumours by immunohistochemistry. Formalin‐fixed and paraffin‐embedded specimens of testicular tissues from 83 patients undergoing therapeutic orchidectomy for seminomas (n = 53), embryonal carcinoma (n = 10), yolk sac tumour (n = 10) and teratoma (n = 10) were examined. Seminoma was associated with in situ carcinoma (CIS) in 23 samples. PTTG1 immunostaining was performed using rabbit anti‐PTTG1 as a primary antibody. In CIS, only isolated cells showed nuclear staining for PTTG1. In the peripheral area of seminoma, PTTG1 was mostly detected as localised in the nucleus; in the central area of seminoma, PTTG1 staining was more intense in cytoplasm. PTTG1‐positive cells were also present in the areas of seminoma infiltration. On the other hand, in embryonal carcinoma, cells had a diffuse positive immunostaining, mainly cytoplasmatic, while we did not observe an expression of PTTG1 in yolk sac tumour and mature teratoma. We firstly identified the PTTG1 expression pattern in normal testis, CIS and testicular cancer. Further investigation is needed to clarify the functional activity of PTTG1 in testicular oncogenesis.     

A clinical study of testicular tumors

Fifty-eight of the 44,698 patients seen at our Department, between 1972 and 1984 had a testicular tumor. The incidence rate was 0.13%. The mean age of these 58 cases was 28.6 years and two peak distributions, one in the 0 to 5 year and another in 26 to 30 year age group were observed. Among them, 54 patients (93.1%) had chief complaints of painless testicular swelling at initial examination. The vast majority of them had unilateral tumors; 28 in the right and 29 in the left. Only one patient had bilateral seminomas. Histologically, 30 of them (51.7%) were seminoma, 8 were embryonal carcinoma (13.8%), 2 were teratoma (3.5%) and the remaining 18 had tumors of double or multiple histological type. Most of the seminomas were treated by a combination of high orchiectomy and radiotherapy, and chemotherapy was done mainly for non-seminomatous cases. The 5-year survival rate calculated by the Kaplan-Meier method was 100% for patients with low stage (I, II) seminomas and 62% for those with non-seminomatous tumors.