A primary pure yolk sac tumor of the lung exhibiting CDX-2 immunoreactivity and increased serum levels of alkaline phosphatase intestinal isoenzyme

Malignant extragonadal germ cell tumors primary to the lung are quite uncommon lesions, but pure yolk sac tumor is even more exceptional. This is believed to be the first reported case of yolk sac tumor of the lung in which an intense and diffuse immunoreactivity for CDX2, a marker of intestinal differentiation reportedly expressed also in gonadal yolk sac tumor, was associated with increased serum levels of the alkaline phosphatase intestinal isoform. Nine months after radical surgery and adjuvant chemotherapy, the patient is alive and well without evidence of recurrent or metastatic disease and with serum levels of the alkaline phosphatase intestinal isoform within normal limits. The pathologist should be aware of yolk sac tumor arising in the lung and that alkaline phosphatase intestinal isoform could become an additional serum marker for such a tumor.     

Alpha-fetoprotein in germ cell tumors. An immunohistochemical study

Total 40 cases of testicular and ovarian germ cell tumors and one case of extragonadal germ cell tumor were studied for the presence of alphafetoprotein (AFP) by indirect immunoperoxidase technique. All seminomas (7 cases) and teratomas (13 cases) were negative for AFP; while 85% of the pure embryonal carcinomas, (E.C.) all pure yolk sac tumors (Y.S.T.) (7 cases) and all embryonal carcinoma and yolk sac components in mixed tumors were AFP positive. Immunostaining of tumor marker appeared to help only in differentiating seminomatous and nonseminomatous tumors and hence does not provide any additional information for classification of these tumors.     

Recent developments in the pathology of germ cell tumors

This article describes some of the recent developments in the pathology of germ cell tumors of the testis. Many germ cell tumors show different types of differentiation. Two different explanations for this phenomenon include the differentiation of other germ cell elements from totipotential embryonal carcinoma cells or the direct differentiation of neoplasms from a malignant intratubular germ cell. Although the concept that there is a subset of seminomas having a poorer prognosis still exists, the histologic identification of such "anaplastic seminoma" remains an unachieved goal, and we, therefore, do not recommend the use of the term anaplastic seminoma at present. A recent analysis of spermatocytic seminomas has failed to demonstrate that they are capable of meiotic division. They are composed of cells differentiating in the direction of spermatocytes, but they have not achieved that stage. The prognosis, in general, remains excellent, although recently sarcomas have been reported in association with spermatocytic seminomas with metastasis of the sarcomatous elements. The presence of human chorionic gonadotropin-producing syncytiotrophoblastic giant cells in otherwise pure seminomas does not appear to adversely affect the prognosis. Yolk sac tumors have a varied histology that many pathologists do not recognize. The presence of intercellular basement membrane (parietal differentiation) is useful in the recognition of yolk sac tumor. Sometimes solid foci of yolk sac tumor may be mistaken for seminoma, and alpha-fetoprotein and cytokeratin stains may be useful in this situation, although the presence of basement membrane, hyaline globules, and focal microcysts by light microscopy may obviate the need to use them. Hepatic and enteric (or endometrioid) differentiation may occur in yolk sac tumors and cause diagnostic confusion. The development most "non-germ" cell malignancies in patients with germ cell tumors appears to occur by transformation of aneuploid teratomatous elements at the primary or metastatic site. The identification of such malignancies depends on the recognition of invasion by the elements rather than on high-grade cytologic atypia. Unusual patterns of choriocarcinoma and yolk sac tumor may be encountered following chemotherapy, and there is circumstantial evidence that some sarcomas and carcinomas occurring in patients with testis cancer may develop directly from yolk sac tumor.     

Evidence for the transformation of seminoma to yolk sac tumor, with histogenetic considerations.

Recent ultrastructural, cytogenetic, and ploidy analyses indicate that seminoma acts as a precursor from which other forms of testicular germ cell tumor may originate. Ten cases of primary or metastatic testicular germ cell tumors were investigated that showed possible transformation of seminoma to yolk sac tumor. Such transformation was identified in six cases in which foci of abrupt change from seminoma to various patterns of yolk sac tumor occurred, often at the periphery of otherwise pure lobules of seminoma. Immunostains for cytokeratins, placental-like alkaline phosphatase, and alpha-fetoprotein demonstrated the expected changes in reactivity at the foci of such transformation. Four additional cases were regarded as either seminomas with artifactual microcystic change or the close association of seminoma and yolk sac tumor but lacking evidence for transformation. These data support the theory that seminoma is not an "endpoint" neoplasm but may serve a precursor role in the progression to nonseminomatous germ cell tumors.     

Epidermal growth factor receptor is a marker for syncytiotrophoblastic cells in testicular germ cell tumors

The epidermal growth factor receptor (EGFR) has been implicated in the pathogenesis, therapy and prognosis of various tumor types. The aim of this study was to investigate EGFR expression in a large series of testicular germ cell tumors (TGCTs). A total of 88 TGCTs (37 of pure type and 51 of mixed type) comprising a total of 44 seminoma, 49 embryonal carcinoma, 32 yolk sac tumor, 28 teratoma and 7 choriocarcinoma components were immunostained for EGFR. EGFR reactivity was observed in the stromal cells of embryonal carcinoma (29%) and in epithelial compartments of teratoma (71%). In addition, EGFR staining was consistently detected in syncytiotrophoblastic cells of choriocarcinoma, seminoma, embryonal carcinoma and yolk sac tumor components. EGFR staining, similar to beta-human chorionic gonadotropin (HCG) immunohistochemistry, was efficiently able to identify syncytiotrophoblastic cells in TGCTs. This study shows that EGFR is expressed in a subset of testicular germ cell tumors and suggests that EGFR may be a useful marker for syncytiotrophoblastic cells.     

i(12p) in a malignant ovarian tumor

We have found one or more copies of i(12p) in an ovarian germ cell tumor, histologically a yolk sac tumor. This chromosome marker is characteristically associated with germ cell tumors in males. This report indicates that further investigation is necessary to establish the role of the i(12p) marker in the pathogenesis of germ cell tumors also in females.     

Intrarenal pure yolk sac tumor: an extremely rare entity

Yolk sac tumor (endodermal sinus tumor) is a malignant germ cell tumor that usually arises in the gonads. Extragonadal germ cell tumors are rare and have been described in case reports. We report a pure intrarenal yolk sac tumor in a 1-year-old boy who presented with a huge abdominal mass and was operated for suspected Wilms tumor. The tumor exhibited histopathologic and immunohistochemical features identical to those of an endodermal sinus tumor of gonadal origin. The purpose of this report is to add a rare tumor to the differential diagnosis of pediatric renal neoplasms.     

Interphase cytogenetics on paraffin sections of paediatric extragonadal yolk sac tumours

Germ cell tumours in children are more often extragonadal than in adults and the most frequent type is the yolk sac tumour. Limited cytogenetic data exist on extragonadal yolk sac tumours in children. We applied in situ hybridization (ISH) to interphase cell nuclei of four paediatric extragonadal pure yolk sac tumours and one yolk sac tumour component of a mixed germ cell tumour using paraffin-embedded tissue sections. The panel of chromosome-specific DNA probes was selected on the basis of their relevance in adult germ cell tumours and consisted of five DNA probes specific for the (peri)centromeric regions of chromosomes 1, 8, 12, and/or 17, X and/or one DNA probe specific for the subtelomeric region of chromosome 1 (p36.3). Only one tumour failed to show numerical and structural chromosome aberrations with the DNA probes used. The other four had an increased incidence of numerical chromosome aberrations with an over-representation of at least one chromosome. The DNA indices determined in the paraffin-embedded tumour material correlated well with the in situ hybridization findings. In only a few cases were chromosomes over-represented, when compared with the corresponding DNA indices. Recently, we have shown that the short arm of chromosome 1 is a non-random site of deletion in paediatric gonadal pure yolk sac tumours. The occurrence of similar deletions in one extragonadal pure yolk sac tumour and in one yolk sac tumour component, in conjunction with two further ISH reports, suggests that the loss of gene(s) in this region is an important event in the pathogenesis of paediatric malignant germ cell tumours of nearly all sites.     

Gonadal teratomas: a review and speculation

Teratomas of the ovary and testis are confusing because, despite histologic similarities, they exhibit different biologic behaviors, depending mostly on the site of occurrence and the age of the patient. Thus, most ovarian teratomas are benign, and most testicular teratomas are malignant, with the exception of those occurring in children. These general statements, however, do not hold true for ovarian teratomas that are "immature" or exhibit "malignant transformation" and for dermoid and epidermoid cysts of the testis, categories of ovarian and testicular teratomas that are malignant and benign, respectively. This review concentrates on some of the "newer" observations concerning these interesting and confusing neoplasms, including diagnostically deceptive patterns. It is the author's opinion that much of the confusion regarding gonadal teratomas can be clarified by the concept that the usual ovarian teratoma derives from a benign germ cell in a parthenogenetic-like fashion, whereas the typical postpubertal testicular example derives from a malignant germ cell, mostly after evolution of that originally malignant cell to an invasive germ cell tumor (ie, embryonal carcinoma, yolk sac tumor, etc). The postpubertal testicular teratomas can therefore be thought of as an end-stage pattern of differentiation of a malignant germ cell tumor. The pediatric testicular teratomas, as well as dermoid and epidermoid cysts of the testis, however, must derive from benign germ cells, in a fashion similar to most ovarian teratomas. The teratomatous components of mixed germ cell tumors of the ovary, on the other hand, likely have a pathogenesis similar to that of postpubertal testicular teratomas.     

Nichtseminomatöse Keimzelltumoren

The group of non-seminomatous germ cell tumors can be morphologically and therapeutically distinguished from the group of seminomas. The group of non-seminomatous germ cell tumors includes embryonal carcinoma, yolk sac tumor, choriocarcinoma and teratoma. All entities can occur rarely in pure form or much more commonly in mixed germ cell tumors consisting of more than one histological type. The non-seminomatous germ cell tumors are also characterized by the appearance of an isochromosome 12p, i(12p) and arise from a common precursor lesion called intratubular germ cell neoplasia of the unclassified type (ITGCNU). Various immunohistochemical markers are used to distinguish the different tumor components in addition to morphological characteristics.     

D2-40 immunohistochemistry in the differential diagnosis of seminoma and embryonal carcinoma: a comparative immunohistochemical study with KIT (CD117) and CD30.

The distinction between seminoma and embryonal carcinoma based on morphology alone can sometimes be problematic, requiring the use of immunohistochemistry to facilitate diagnosis. D2-40 is a monoclonal antibody that reacts with an oncofetal antigen expressed by fetal germ cells and testicular germ cell tumors. The diagnostic value of D2-40 immunohistochemistry in distinguishing seminoma from embryonal carcinoma has not been determined. D2-40 immunoreactivity was evaluated in a series of testicular germ cell tumors and compared with that of KIT (CD117) and CD30, to assess the relative utility of this marker in discriminating between seminoma and embryonal carcinoma. Forty testicular germ cell neoplasms were examined, which included 19 seminomas, three embryonal carcinomas, three teratomas, one yolk sac tumor, and 14 mixed germ cell tumors. The 14 cases of mixed germ cell tumors contained components of seminoma (n=7), embryonal carcinoma (n=11), teratoma (n=10), yolk sac tumor (n=2), and choriocarcinoma (n=1). All cases of pure seminoma and the seminomatous components of mixed germ cell tumors exhibited positive immunoreactivity for D2-40. Focal positivity for D2-40 was also observed in 29% of the embryonal carcinoma samples. D2-40 immunoreactivity in seminomas was characterized by diffuse membrane staining, whereas for embryonal carcinomas, staining was focal and distributed along the apical surfaces of the neoplastic cells. Immunohistochemical staining for KIT was observed in 92% of the seminoma samples and in none of the embryonal carcinomas. Conversely, CD30 expression was identified in 93% of the embryonal carcinoma samples and in none of the seminomas. Other germ cell components showed no immunoreactivity for D2-40, KIT, or CD30. KIT and CD30 are effective immunohistochemical markers in separating seminoma from embryonal carcinoma. Although a highly sensitive marker for seminomas, D2-40 positivity was also observed in a subset of embryonal carcinomas, thus limiting the utility of this antibody for discriminating between these two malignancies.     

Human testicular germ cell tumors in vitro and in athymic nude mice

Four cell lines derived from pure and mixed types of human testicular germ cell tumors in vitro and in nude mice were examined by light and electron microscopies. The NEC8 and NEC15 cell lines in vitro were composed of embryonal carcinoma cells with potentiality of trophoblastic differentiation. All of the tumors formed in nude mice by both cell lines were pure embryonal carcinomas. On the other hand, the NEC14 and ITO-II cell lines showed morphological differentiation from embryonal carcinoma cells to trophoblastic cells and to yolk sac tumor cells in vitro. In nude mice, these cell lines formed mixed tumors which consisted of embryonal carcinoma, yolk sac tumor, immature teratoma or trophoblastic cells. Our data suggest that some embryonal carcinomas have multipotentiality of morphological differentiation but that others have little such potentiality.     

HUMAN TESTICULAR GERM CELL TUMORS IN VITRO and IN ATHYMIC NUDE MICE

Four cell lines derived from pure and mixed types of human testicular germ cell tumors in vitro and in nude mice were examined by light and electron microscopies. The NEC8 and NEC15 cell lines in vitro were composed of embryonal carcinoma cells with potentiality of trophoblastic differentiation. All of the tumors formed in nude mice by both cell lines were pure embryonal carcinomas. On the other hand, the NEC14 and ITO-II cell lines showed morphological differentiation from embryonal carcinoma cells to trophoblastic cells and to yolk sac tumor cells in vitro. In nude mice, these cell lines formed mixed tumors which consisted of embryonal carcinoma, yolk sac tumor, immature teratoma or trophoblastic cells. Our data suggest that some embryonal carcinomas have multipotentiality of morphological differentiation but that others have little such potentiality.     

The most common, clinically significant misdiagnoses in testicular tumor pathology, and how to avoid them

Testicular tumors are both increasing in frequency and disproportionately occur in young men; furthermore, different forms of neoplasm require different treatments. These considerations make the accurate diagnosis of testicular tumors especially important. Many of the critical distinctions involve the differentiation of seminoma from one or more potential mimics because seminoma is not only the most common testicular neoplasm but it is also the only malignant testicular tumor that is commonly treated with radiation, which is ineffective in other malignancies of the testis. For the most part, accurate diagnosis can be achieved by careful light microscopic evaluation, although appropriate immunostains can provide diagnostic assistance if doubt persists. This article discusses a number of clinically important differential diagnoses in the testis that are common sources of misinterpretations. These include: seminoma versus embryonal carcinoma, seminoma versus yolk sac tumor, seminoma versus Sertoli cell tumor, seminoma with syncytiotrophoblast cells versus choriocarcinoma, granulomatous seminoma versus granulomatous orchitis, intertubular seminoma versus orchitis, lymphoma versus seminoma or embryonal carcinoma, dermoid cyst versus teratoma, scar versus regressed germ cell tumor, and "anaplastic" spermatocytic seminoma versus usual seminoma or embryonal carcinoma.     

Alpha-Fetoprotein Subtractions in Germ Cell Tumors Identified by Con A or LCH Crossed-Line Affinity Immunoelectrophoresis

ABSTRACT: Using concanavalin A (Con A) crossed-line affinity immunoelectrophoresis and lentil lectin (LCH) crossed-line affinity immunoelectrophoresis, alpha-fetoprotein (AFP) subfractions were studied in sera including three sera from nude mice heterotran-splanted with human yolk sac tumor of the ovary and three sera from patients with yolk sac tumor, mature solid teratoma, or immature solid teratoma of the ovary. In sera of nude mice bearing yolk sac tumor or from a patient with yolk sac tumor, subfractions from yolk sac and those from fetal liver were identified. Since AFP subfractions from yolk sac and fetal liver can be differentiated according to the carbohydrate moieties, our findings indicate that AFP produced by yolk sac tumor and fetal yolk sac are to some extent differently glycosylated. We also found that AFP in both mature and immature solid teratoma was composed of two subfractions ontogenetically originating from yolk sac or fetal liver. All these findings indicate that more than two different factors are responsible for the AFP synthesis in germ cell tumor of the ovary.     

Primary yolk sac tumor of the urachus

Pure yolk sac tumor is the most common malignant gonadal tumor of infants and toddlers. However, the majority of extragonadal germ cell tumors in the midline are either seminomas (germinomas) or teratomas, and pure yolk sac tumors account for only a small fraction of these lesions. To date, only 1 primary urachal pure yolk sac tumor has been reported in the literature. We describe another case, occurring in a 7-month-old male infant who presented with a rapidly enlarging intra-abdominal tumor with marked engorgement of the superficial venous plexus around the umbilicus. With periodic follow-up for 3 years following surgical extirpation of the tumor and adjuvant chemotherapy, this patient is still alive without evidence of disease. Notably, the glandular elements predominating in the frozen sections resulted in the initial misdiagnosis of the tumor as a urachal adenocarcinoma, although the entirely resected specimen revealed typical histologic patterns and Schiller-Duval bodies. Immunohistochemistry showed that the tumor cells were diffusely reactive to alpha-fetoprotein, alpha(1)-antitrypsin, and cytokeratin. Tumor cells were negative for p53 protein, but revealed overexpression for MDM2 protein. Flow cytometry demonstrated a diploid DNA content with S-phase being as high as 55.36%. This case emphasizes that pure yolk sac tumor can occur primarily in the remnant of the urachus in young children.     

OCT4、CD117、CD30在生殖细胞肿瘤中的表达及鉴别诊断意义

目的 研究OCT4、CD117、CD30在不同生殖细胞肿瘤类型中的表达,及其在鉴别诊断中的应川价值。方法 应用免疫组织化学技术EnVision法检测OCT4在63例生殖细胞肿瘤的表达情况,包括21例睾丸精原细胞瘤,7例卵巢无性细胞瘤,8例中枢神经系统生殖细胞瘤,8例胚胎性癌,6例卯黄囊瘤,10例成熟性畸胎瘤,3例术成熟性畸胎瘤。25例非生殖细胞肿瘤的表达情况作为对照,包括8例颗粒细胞瘤,4例透明细胞癌,5例间质细胞瘤,4例弥漫性大B细胞淋巴瘤,4例恶性黑色素瘤中的表达情况,同时柃测CD117和CD30在所有生殖细胞肿瘤中的表达情况。结果OCT4住100％的精原细胞瘤（21／21）、8／8的生殖细胞瘤、6／7的无性细胞瘤,以及7／8的胚胎性癌中阳性表达,定化于细胞核;仅在1例卵黄囊瘤和1例透明细胞癌中有弱阳性表达,其余生殖细胞肿瘤及非生殖细胞肿瘤中均为阴性。CD117在90．5％（19／21）的精原细胞瘤、7／8的生殖细胞瘤以及5／7的无性细胞瘤中阳性表达,主要定位于胞膜;1例卵黄囊瘤的部分区域胞膜弱表达,在畸胎瘤中鳞状上皮基底层的黑色素细胞阳性表达,所有胚胎性癌中均是阴性。CD30在6／8的胚胎性癌中表达阳性,定位于细胞膜;只有1例生殖细胞瘤有弱的阳性表达,主要定位于胞质,其余精原细胞瘤、生殖细胞瘤、无性细胞瘤中均是阴性表达;另外在1例卵黄囊瘤中有局灶的胞质内阳性表达,在畸胎瘤中均是阴性。结论OCT4是标记精原细胞瘤、生殖细胞瘤、无性细胞瘤和胚胎性癌的一种特异而敏感的指标;联合应用OCT4、CD117和CD30对于诊断和搭别诊断精原细胞瘤、生殖细胞瘤、无性细胞瘤和胚胎性癌具有较高的应用价值。