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Ectopic pregnancies are the main sources of pregnancy-related morbidity and mortality in the first trimester. They are usually located in the ampullary part of the fallopian tube and the incidence increases in the setting of assisted reproductive techniques, older age at the time of the first pregnancy, and prior adnexal procedures. The clinical aspects and diagnostic challenges of an ectopic pregnancy for the pathologist are to be outlined. A review of the relevant literature was performed. Proof of gestational tissue is of utmost importance in the pathological-anatomical evaluation of an ectopic pregnancy. A complete evaluation of the specimen of a presumed tubal abruption or after milking out should be performed. Abnormal placentations (blighted ovum, embryonal molar pregnancy) as well as gestational trophoblastic disease (GTD, e.g., partial/complete molar pregnancy, choriocarcinoma) can occur in the setting of an ectopic pregnancy. Caution must be taken to differentiate a trophoblast hyperplasia secondary to the tubal microenvironment from GTD. p57 immunohistochemistry can help exclude a molar pregnancy. Only 50% of ectopic pregnancies are associated with tubal pathologies (e. g. inflammation, tubal adhesions). Chorionic villi and trophoblast epithelia can demonstrate regressive changes after prior methotrexate treatment. Rarely, immunohistochemistry with GATA-3, p63, β‑HCG, PAX-8, and WT-1 can be used in the differential diagnosis of trophoblastic epithelium. Ectopic pregnancies are associated with significant morbidity and mortality. A thorough evaluation of the specimen can help guide management and follow-up.

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.

Testicular germ cell tumors are generally rare but represent the most common solid neoplasms in young men. They are subdivided into seminomas and non-seminomatous germ cell tumors. Usually the diagnosis of a seminoma is straightforward due to the characteristic morphology, although problems in differential diagnosis can occur because of unusual histological growth patterns. This article describes the challenging differential diagnosis with respect to seminomas versus non-seminomatous germ cell tumors, sex cord stromal tumors, lymphomas and non-neoplastic conditions, such as scars and inflammatory changes. In addition, prognostic factors for seminomas are presented and discussed.

We report on a 26-year old female patient with thoracic pain and dyspnea, in whom a large tumorous mass in the anterior mediastinum with a pleural effusion was diagnosed by computed tomography and magnetic resonance imaging. After rapid progression of tumor growth and detection of malignant cells within the pleural effusion operative intervention including resection of the tumor was performed. Histologic examination of the tumor revealed the typical morphology of a large mediastinal choriocarcinoma. The excessively high hCG-levels returned to normal values post-operatively. A thorough history making revealed an ectopic pregnancy which had made unilateral salpingectomy necessary. Although primary histologic examination of the tubarian tissue had shown no malignancy, a secondary look revealed a choriocarcinoma with identical histological features compared to the mediastinal tumor. Thus, final diagnosis of a mediastinal metastasis of a tubarian choriocarcinoma in ectopic pregnancy was made. We discuss this extremely rare disease and provide a short overview of the literature.

A 29-year-old woman developed pruritic urticarial plaques and vesicles 3 months after delivery of a healthy daughter. Two months later pemphigoid gestationis (PG) was diagnosed based on histopathological and immunopathological findings. At the same time elevated serum levels for beta-HCG and a large mass in the liver were noted. A liver biopsy confirmed the diagnosis of metastatic choriocarcinoma, which was responsible for the PG metastasis. Upon initiation of chemotherapy, complete healing of the PG was observed within 4 weeks and autoantibodies to BP180NC16A could no longer be identified. In parallel, both a decrease of beta-HCG levels and tumor size was observed.

Invasiveness is a characteristic feature of malignant tumors considerably determining the prognosis of affected patients. For assessment, apart from in vitro procedures with limited validity, tests on animal models have been established which certainly should be replaced by alternative methods whenever possible. The chorioallantoic membrane (CAM) of fertilized avian eggs represents an epithelial-lined membrane composed of all three blastodermic germ layers. In an "in ovo" assay cancer cells can be applied to this membrane after sinking (CAM assay). Tumor growth and invasiveness should be monitored in succession.Hybrid chorionic carcinoma trophoblast cells were expanded in cell culture and spread over the CAM of hen's eggs after sinking followed by further incubation at 37 degrees C. The growth and development of the tumors were assessed macroscopically and finally (immuno-)histologically. Additionally, cytokeratin 19 was determined by enzyme-linked immunosorbent assay following homogenization of the tumor cells. RESULTS. Macroscopically, development of solid tumors was evident. Histological and immunohistochemical analysis revealed initial intraepithelial followed by cone-shaped infiltration of the CAM by the tumor cells. Tumor growth could be correlated with quantitative cytokeratin 19 measurements.Histomorphological appearance of the tumors was comparable with those results achieved in an immunodeficient mouse model. In addition, the CAM assay can be used for qualitative assessment of invasiveness of malignant tumors and yields quantitative results regarding growth kinetics. In contrast to conventional animal models, there is no need for official approval. Finally, this method is economical and facilitates processing many cases within a short time.

The non-villous forms of gestational trophoblastic disease (GTD) include a wide range of morphologic different lesions and cover a wide range of differential diagnosis. Choriocarcinomas (CCA) represent the most malignant form displaying a dimorphic pattern with proliferation of syncytio- and zytotrophoblast. An early start of chemotherapy is of great prognostic impact. Placental site nodule (PSN) and exaggerated placental site (EPS) are non-neoplastic lesions of the intermediate trophoblast without tumorous appearance, whereas placental site trophoblastic tumor (PSTT) and epitheloid trophoblastic tumor (ETT) represent tumorous neoplasms with a potential for local invasion and metastases. PSNs are incidental findings of highly polymorphic cells. In EPS chorionic villi are almost present, endometrial glands and spiral arteries are completely engulfed by intermediate trophoblastic cells without necroses. In PSTT the monomorphic, occasional multinucleated giant cells separating individual muscle fibers and charactersitically blood vessel walls are extensively replaced by trophoblastic cells and fibrinoid material. The ETT consists large necrotic areas with hyalinisation. Typically small blood vessels with preserved walls are located within the center of glycogen-rich monomorphous proliferation of trophoblastic cells.

The case of 36-year-old tercipare is described who developed choriocharcinoma in a previous pregnancy. During the first term labour the patient developed cardiac arrest, so reanimation and sectio cesarea was performed. A male new-born was delivered in good condition, but even after intensive therapy and reanimation occurred death of parturient woman with picture of disseminate intravascular coagulopathia (DIK). On autopsy and on histology there was no sign of malignant disease, so it was not possible to connect previous choricarcinoma with amniotic fluid embolism. Maybe was place of choriocarcinoma "locus minoris resistentiae" which later resulted with failure in placentation what was hard to prove. On autopsy we found embolia of lung with a microthrombosis of terminal circulation with punctiformis bleeding in mucous, what stands for DIK.

Es wird ein Fall einer 36-jährigen Terzipare mit Fruchtwasserembolie beschrieben, die während der letzten Schwangerschaft ein Chorionkarzinom entwickelte. Während der ersten Entbindungsperiode kam es zum kardialen Arrest, der einen Kaiserschnitt und eine Reanimation erforderte. Trotz intensiver Therapie und Reanimation verstarb die Gebärende an einer disseminierten intravasalen Koagulopathie. Die Obduktion, sowie die histologische Untersuchung zeigten keine Hinweise auf eine maligne Erkrankung. Somit fällt es schwer einen Zusammenhang zwischen dem vorhergehenden Chorionkarzinom und der Fruchtwasserembolie zu ziehen. Vielleicht war der Ort des vorhergehenden Chorionkarzinoms ein „ locus minoris resistentiae” der mit einer fokalen Malplazentation verbunden ist. Die Obduktion und die histologische Untersuchung beweisen eine Embolisierung der Lunge mit Fruchtwasser, sowie das Auftreten von Mikrothromben in den Kapillaren und punktförmigen Blutungen auf den Schleimhäuten. Dieser Befund spricht für eine disseminierte intravasale Koagulopathie.

Choriocarcinoma are malignant neoplastic tumors from the trophoblastic tissue with a tendency to early metastases. Beside pulmonary metastases there are often cerebral metastases, leading to intracerebral hemorrhage often responsible for the first clinical symptoms. In young women, symptoms like vaginal or pulmonary bleeding or neurologic disturbances shortly after a hydatiform mole or a normal pregnancy, accompanied by high levels of HCG in serum and CSF, choriocarcinoma should be considered. Choriocarcinoma are very sensitive to chemotherapy, which consists--depending on the stage of the disease--of a mono- or polychemotherapy. Cure rates are high, even in extended stages with cerebral metastases--as in the case described. Brain metastases with or without oncotic aneurysms can be rapidly controlled by immediate whole brain irradiation. Surgical interventions may be necessary in the case of life threatening bleedings. Levels of HCG in serum and cerebrospinal fluid are good markers to control the effect of therapy. But--as shown in this patient--levels of HCG in CSF may decrease protracted without affecting prognosis. Oncotic aneurysms are rarely reported and mostly detected post mortem. The presented case leads to a more optimistic attitude and demonstrates efficacy of immediately started radio- and chemotherapy.

We describe the third case world-wide of a chorangiocarcinoma, a tumour with an abnormal trophoblast proliferation in combination with a hypervascular chorangiosis of the villous stroma. The lesion was an incidential finding by a healthy 31-year-old woman, gravida 1, para 1 when the pregnancy was terminated at 34 weeks gestation because of fetal distress and intrauterine growth restriction. Hormonal levels were within the normal range. Mother and infant had an uneventful postpartum course. Immunohistochemical studies of the abnormal trophoblasts demonstrated strong immunoreactivity for HCG and in 80% for Ki 67. The semiquantitative expression of angiogenic growth factors (VEGF, bFGF, Ang-1 und Ang-2, PDGF) in the tumour trophoblasts was similar to that seen in the normal villi. The pathogenesis of this tumour with a villous vascular response is curious and unclear. Possibilities include the occurrence of a variant of a chorion carcinoma, the occurrence of a new tumour entity or of two separate lesions, a chorangioma and incidential chorion carcinoma, present together as a "collision" tumour. Another possibility is a composition tumour or a reactive lesion of trophoblasts and the villous vascular tree.

The paper reports on four patients with choriocarcinoma. In two of them, the choriocarcinoma was found after abortion, in one of them following termination of pregnancy, and in the last patient a hydatidiform mole was present. In all patients increased beta-HCG was found. One patient had lung metastasis at the time of diagnosis. In another patient, choriocarcinoma was suspected owing to ultrasonographic vaginal examination. According to the Bagshawe Score, 3 patients were low-risk and were subjected to methotrexate. One patient was medium-risk and received PEB chemotherapy. All four patients are regarded as cured.

One week after returning from a two-week holiday in Sri Lanka a 35-year-old man started to have recurrent bouts of fever, up to 39.2 degrees C, as well as pain over the left upper abdomen, the back of the right thorax and bilateral pain on pressure with swelling of both breasts. He went to the Tropical Institute in Munich to have malaria excluded. There signs of cholestasis were noted and sonography revealed multiple round foci in the liver. As he had lost 10 kg in 3 weeks he was admitted to a medical unit for further tests. Physical examination now showed bilateral gynaecomastia and marked pressure resistance in the upper abdomen. Proprioceptor reflexes were greatly increased but equal bilaterally.Inflammatory parameters were raised (C-reactive protein 22.6 mg/dl, ferritin level 2674 micrograms/l, erythrocyte sedimentation rate 50/82 mm), there also were a leucocytosis (20,600 WBC/mm3) and a raised lactate dehydrogenase level of 613 U/l. In addition, thyroid stimulating hormone was reduced to0.03 microU/ml, while free thyroxine was raised to 2.7 ng/dl. The pregnancy test was positive. On quantitative analysis the human beta-chorionic gonadotropin (hCG) level was markedly raised to 193,200 mIU/ml. Abdominal and thoracic computed tomography revealed multiple round metastasis-like masses in the liver and in the lung, and a thickened cardia. Serology for malaria, amoebiasis and echinococciasis was negative, sonography of the testes and thyroid was unremarkable. Endoscopy revealed a polypoid tumour at the gastro-oesophageal junction which histologically was an undifferentiated hCG-positive choriocarcinoma.The neoplasm at first responded with partial remission (hCG minimally 39 mIU/ml) to chemotherapy (PEI schema: cisplatin, etoposide, ifosfamide) but then progressed, also under treatment of recurrences with paclitaxel, ifosfamide and cisplatin. The patient has since received high-dosage chemotherapy with autologous stem-cell transplantation.

A 29 year-old woman presented with continuous metrorrhagia and a positive pregnancy test 3 1/2 months after vaginal birth. Transvaginal sonography showed a 3.5 x 4 x 4 cm mostly echogenic uterine mass with diffuse myometrial invasion in the right fundal region. Colour Doppler sonography revealed extensive low impedance flow in the periphery of the mass suggestive of a trophoblastic tumor. Histological examination of curettage specimens revealed a chorionic carcinoma. The tumor size as measured by magnetic resonance imaging correlated well with that by sonography. Trophoblastic disease after a normal pregnancy is rare. Early diagnosis can be facilitated by transvaginal colour Doppler sonography.

We report on a case of a 24 years old woman with a high risk metastatic choriocarcinoma. The last pregnancy and delivery was 15 months ago. As a first symptom a complete paralysis of the upper right extremity was found. In the following a rapid progression of the disease with severe multiple cerebral and retroperitoneal bleedings was seen. Among chemotherapy and intensive care treatment the HCG-titre decreased quickly and the bleedings stopped but no change in the neurological condition was observed.

Many factors can alterate the correct implantation of the blastocyste, e.g. alterations of the tubal micro-environment or inflammatory processes. For correct implantation a mature endometrium is necessary. Other alterations, which can cause an abortion are immunological mechanisms. Gestational trophoblastic disease includes the partial and complete hydatidiform mole, as well as the chorioncarcinoma. Proliferations of the intermediate trophoblast are the placental site nodule or plaque, the exaggerated placental site and the placental site trophoblastic tumor. The distinction of the different causes of malimplantation and abortion are necessary to prevent a further disruption of a following pregnancy.

We present the first case in literature of a chorionic carcinoma following in vitro fertilisation. Until now, only two case reports of hydatidiforme mole following IVF are published.

The pregnancy and tumor marker human chorionic gonadotropin (hCG) belongs to the family of the glycoprotein hormones. Information on epitope forming sequences of hCG and its subunits hCG alpha and hcg beta has significant impact on the examination of intra- and extracellular metabolism and the standardization of diagnostic assay systems. Variants of hCG appear in biological fluids with variable modifications on different parts of the molecule. These changes may influence the binding patterns of monoclonal antibodies (MCA), thereby causing erroneous results in hCG immunoassays. The aim of the present work was to investigate the influence of peptide bond cleavages and the loss of certain segments of the molecule, which were induced by proteases on the expression of the seven hCG alpha-(alpha 1-alpha 7), nine hCG beta- (beta 1-beta 9) and four hCG beta-core-fragment-epitopes (beta 10-beta 13), previously identified by us [1-10]. To this end, we digested hCG alpha and hCG beta with chymotrypsin. Hormone fragments were separated by high performance liquid chromatography (HPLC) and subsequently immunochemically examined by direct binding radioimmunoassay (DB-RIA), competitive RIA and immunoenzymometric assays (IEMA). Fractions containing hCG-like immunoreactivity were sequenced by Edman and carboxypeptidase-Y degradation. It appeared that: (I) Amino acids (AA) alpha 41-47 and the peptide bonds between AA alpha 40/41, alpha 47/48 and alpha 29/30 do not influence the expression of the 7 alpha-epitopes, (II) The absence of the hCG beta N-terminus plays a crucial role for the formation of epitopes beta 10 and beta 13. (III) Neither the presence nor the absence of the C-terminal peptide of hCG beta (hCG beta CTP, AA beta 114-145) has any importance for the expression of epitopes beta 1-beta 7 and beta 10-beta 13 (IV).(ABSTRACT TRUNCATED AT 250 WORDS)

The role of inflammatory cytokines on regulation of hCG biosynthesis was studied.JAR choriocarcinoma cells were cultured and treated with interleukin-1 (IL-1), IL-3. IL-4, stem cell factor (SCF), tumor necrosis factor (TNF), and granulocyte or granulocyte-macrophage-colony stimulating factor. hCG concentration was determined by immunoradiometric methods and cell number was enumerated by means of an electronic particle counter.Il-1 and TNF increased biosynthesis of holo-hCG as well as the free alpha- and free beta-subunit and the beta-core protein. Proliferation was not affected by any cytokine tested.Inflammatory cytokines are able to increase the biosynthesis of hCG.

The paper reports on clinical experiences of treatment of 58 patients with Gestational Trophoblastic Tumors (GTT), collected between 1978 and 1991. According to the Bagshawe-Score, 29 patients were at low-risk, 10 patients were assigned to the high-risk category. Among 29 metastatic cases, 5 patients had brain metastasis. In 33 patients, treatment started from the time of diagnosis. In 25 cases, treatment was initiated at other hospitals and patients were referred only after various unsatisfactory treatment measures. Low-risk patients were mainly subjected to methotrexate and folinic acid. Patients at medium-risk received a sequential chemotherapy. In high-risk patients we preferred the CHA-MOCA- or the EMA/CO-regimen. Treatment was successful in 91.4% of patients including all cases of low- and medium-risk. Five patients with brain metastases received systemic chemotherapy combined with intrathecal application of methotrexate and radiotherapy. Three of them could be cured. Patients taken from other hospitals more often underwent primary hysterectomies prior to systemic chemotherapy (40% versus 3%) and more often developed drug resistant tumors due to inadequate primary treatment. Five patients (8.6%) died from their disease, but only one of them received primary treatment in our department. Thus, the outcome (1/33 compared to 4/25) was significantly better for patients treated primarily at specialized centers.

Hydatidiform moles and chorionic carcinomas associated with ectopic pregnancy are extremely rare. We report on three cases of non-metastatic GTD after tubar pregnancy of low and medium risk in the WHO prognostic score and FIGO-stage II in each case. Two of them required several courses of (poly-) chemotherapy to reach complete remission (CR). The follow-up was on average 36.6 months, without any metastases and recurrences. One woman was delivered of a healthy infant. All cases were surgically treated with extirpation of the affected adnexa. Additionally, in one case hysterectomy was necessary to reach CR. As reported in the literature, chorionic carcinomas associated with ectopic pregnancy are often very aggressive and show a metastasis rate of 75% at time of diagnosis. For this reason it is essential, to examine tubar pregnancy by histopathology carefully to define small and in situ changes. The cases presented stress the need for appropriate HCG and clinical monitoring.

We report on a patient with the diagnosis of an adult teratoma metastasizing as choriocarcinoma. The 49-year-old man died of dysfunction of the liver caused by massive metastatic involvement. This case demonstrates the malignant potential of adult teratoma and emphasizes the need for chemotherapy of the same kind as for other malignant germ cell tumours if undifferentiated metastases of the teratoma are present. The chemotherapeutic modalities and the options for surgical treatment of metastatic adult teratomas of the testis are discussed.

Case report of a 20-year-old women with a chorionic carcinoma of the uterine cervix. Subsequently, the aspects of the disease of chorionic carcinoma and cervical pregnancy are discussed, including epidemiology, aetiology, diagnosis and management. Finally, the conclusions of this discussion are compared with the case report.