Cost-consequence analysis of extended loading dose of anti-VEGF treatment in diabetic macular edema patients.

BACKGROUND: The DRCR.net Protocol T clinical trial assessed the comparative efficacy and safety of anti-VEGF treatments including aflibercept, ranibizumab and bevacizumab in diabetic macular edema (DME). Post -hoc analyses showed that after a 12-week induction period, there was still DME resolution in an increasing number of patients through week 24. PURPOSE: To assess clinical and cost consequences of extending the anti-VEGF loading dose from 3 to 6 monthly injections in patients with persistent DME in Spain. METHODS: From a hospital pharmacy perspective, a cost-consequence analysis model was developed to estimate the incremental cost needed to obtain an additional response at month 6. To estimate drug treatment costs, ex-factory prices (€, 2019) were considered for aflibercept, ranibizumab and bevacizumab. Response/nonresponse rates at 3/6 months were obtained from the Protocol T 24-week post hoc analysis (n = 546). Persistent DME was present in 50.8 and 31.6% of the 190 aflibercept-treated patients at month 3 and month 6, respectively. Of the 176 ranibizumab- and 180 bevacizumab-treated patients, 53.2 and 72.9%, respectively, had persistent DME at month 3, and 41.5 and 65.6%, respectively, had persistent DME at month 6. Sensitivity analysis considered the split of bevacizumab vials. RESULTS: Extending the loading dose in nonresponder patients would cost €214,862.57, €208,488.98 and €134,483.16 to obtain 37, 21 and 13 additional aflibercept, ranibizumab and bevacizumab responder patients, respectively. The total number of extended injections (months 3-6) used in patients with persistent DME at month 6 was 180, 219 and 354 for aflibercept, ranibizumab and bevacizumab, respectively. CONCLUSIONS: To extend the anti-VEGF loading dose from 3 to 6 injections necessitates investing €5882.77 (8 injections), €10,091.03 (14 injections) and €10,198.59 (30 injections) per additional responder patient (3-month nonresponders and 6-month responders) to aflibercept, ranibizumab and bevacizumab, respectively. For the total of patients treated, on average €7927.02 (14 injections) per additional responder patient would be needed.

The Benefits of Administering Folic Acid in Order to Combat the Oxidative Damage Caused by Binge Drinking in Adolescent Rats.

AIMS: An important mechanism in alcohol-induced injury is biomolecular oxidative damage. Folic acid is supplied to chronic alcoholic patients in order to prevent this situation, as this is the main vitamin deficiency that they suffer from. Acute alcohol exposure, such as binge drinking, is one of the most widespread ethanol consumption models practiced by adolescents. However, there is no evidence of folic acid body profiles after this pattern of consumption. METHODS: Four groups of adolescent rats were used: control, alcohol (exposed to intraperitoneal binge drinking), control folic acid-supplemented group and alcohol folic acid-supplemented group. Folic acid levels, protein, lipid and DNA oxidative damage in serum, and liver glutathione (GSH) and reduced/oxidized glutathione ratio (GSH/GSSG) were measured. RESULTS: Binge-drinking rats had higher lipids and DNA oxidation levels. They also had lower hepatic GSH levels and GSH/GSSG ratio. Folic acid supplementation to binge-drinking rats does not change the serum protein oxidation but decreases lipid and DNA oxidation. Finally, GSH increased to control levels with folic acid supplementation. CONCLUSION: Folic acid supplementation is an economic and efficient therapy against the oxidative damage in lipids and mainly in DNA stability caused by binge drinking during adolescence. It has also been demonstrated that folic acid increases GSH levels, improving the antioxidant status and revealing a hepatoprotective effect during binge drinking.

Use of healthcare resources and costs of acute cardioembolic stroke management in the Region of Madrid: The CODICE Study.

INTRODUCTION: Stroke is the main cause of admission to Neurology departments and cardioembolic stroke (CS) is one of the most common subtypes of stroke. METHODS: A multicentre prospective observational study was performed in 5 Neurology departments in public hospitals in the Region of Madrid (Spain). The objective was to estimate the use of healthcare resources and costs of acute CS management. Patients with acute CS at<48h from onset were recruited. Patients' socio-demographic, clinical, and healthcare resource use data were collected during hospitalisation and at discharge up to 30 days after admission, including data for rehabilitation treatment after discharge. RESULTS: During an 8-month recruitment period, 128 patients were recruited: mean age, 75.3±11.25; 46.9% women; mortality rate, 4.7%. All patients met the CS diagnostic criteria established by GEENCV-SEN, based on medical history or diagnostic tests. Fifty per cent of the patients had a history of atrial fibrillation and 18.8% presented other major cardioembolic sources. Non-valvular atrial fibrillation was the most frequent cause of CS (33.6%). Data for healthcare resource use, given a mean total hospital stay of 10.3±9.3 days, are as follows: rehabilitation therapy during hospital stay (46.9%, mean 4.5 days) and after discharge (56.3%, mean 26.8 days), complications (32%), specific interventions (19.5%), and laboratory and diagnostic tests (100%). Head CT (98.4%), duplex ultrasound of supra-aortic trunks (87.5%), and electrocardiogram (85.9%) were the most frequently performed diagnostic procedures. Average total cost per patient during acute-phase management and rehabilitation was €13,139. Hospital stay (45.0%) and rehabilitation at discharge (29.2%) accounted for the largest part of resources used. CONCLUSIONS: Acute CS management in the Region of Madrid resulted consumes large amounts of resources (€13,139), mainly due to hospital stays and rehabilitation.

Retroperitoneal schwannoma. A complex surgical treatment of a tumor with uncertain behavior.

BACKGROUND: Retroperitoneal schwannoma is a rare nerve sheath tumor; the surgical removal of this tumor is sometimes compromised by its location. The aim of this study is to analyze our experience with the diagnosis and treatment of this type of tumor. METHOD: We present our experience between 1999 and 2011 in the diagnosis and treatment of retroperitoneal schwannoma. During that time, we diagnosed and treated five female patients (four adults and one infant) with the condition. The tumors appeared sporadically and were not associated with neurofibromatosis or other syndromes. Diagnosis was performed by computed tomography (CT) imaging in four cases and by magnetic resonance imaging (MRI) in one case. RESULTS: All patients underwent surgical treatment and complete resection of the lesion. An open resection was performed in four cases, and in the most recent case, the excision was conducted laparoscopically. In all of the cases, the histological diagnosis was retroperitoneal schwannoma, and in one case, there was a melanocytic variant that was not associated with Carney syndrome. At the time of this report, there has been no evidence of recurrence. CONCLUSION: Retroperitoneal schwannoma is a tumor that is difficult to diagnose with imaging techniques, and because of its localization, the tumor is difficult to remove surgically.

Oxidative effects of chronic ethanol consumption on the functions of heart and kidney: folic acid supplementation.

AIMS: The principal aim of this study was to investigate the oxidative effects of chronic ethanol consumption on the functions of the heart and the kidney and the possible modification of this effect by folic acid supplementation. Moreover, in order to find whether this oxidative profile affects cardiovascular function, parameters such as heart rate and glomerular filtration rate were also assessed. METHODS: Four experimental groups of rats were used: control, ethanol-exposed, control supplemented with folic acid and ethanol-exposed plus folic acid. Ethanol-exposed rats were subjected to a chronic ethanol treatment (2 months), in which the level of alcohol reaches 30% v/v. Diet and ethanol solution were provided ad libitum, and folic acid supplementation was 8 vs. 2 ppm. Energy intake, creatinine clearance and heart rate were determined. Antioxidant enzyme activity and lipid and protein peroxidation of the kidney and the heart were measured by the spectrophotometric method. RESULTS: Ethanol increases heart size and catalase (CAT) activity and decreases lipid peroxidation in heart without changing heart rate. However, in the kidney, ethanol decreases CAT activity, increases lipid peroxidation and decreases glomerular filtration rate. Folic acid supplementation avoids these situations; it does not, however, improve glomerular function. CONCLUSION: Chronic ethanol consumption has many effects on the antioxidant enzymatic activity of the heart and the kidney, leading to increased renal lipid peroxidation prevented by folic acid supplementation.

Metabolic syndrome during gestation and lactation: An important renal problem in dams. selenium renal clearance.

BACKGROUND: Metabolic syndrome (MS) in lactating dams leads to several cardiometabolic changes related to selenium (Se) status and selenoproteins expression which produce hypertension. However, little is known about the state of these dams' kidney functions and their Se deposits. METHODS: Two experimental groups of dam rats were used: control (Se: 0.1 ppm) and MS (Fructose 65 % and Se: 0.1 ppm). At the end of lactation (21d postpartum) kidney weight and protein content, Se deposits, and the activity of the antioxidant selenoprotein glutathione peroxidase (GPx) were measured in dams. Kidney functional parameters: albuminuria, creatinine clearance, serum aldosterone and uric acid levels and water and electrolyte (Na+ and K+) balance were also evaluated. Systolic blood pressure (SBP) was measured. RESULTS: In MS dams at the end of lactation Se deposits and GPx activity are higher in the kidney; however, lipid renal peroxidation appears, relative Se clearance increases, and the dams have lost Se by urine. MS dams have polyuria and polydipsia, high uric acid serum levels, albuminuria and high creatinine clearance, implying glomerular renal malfunction with protein loss. They also present hypernatremia, hypokalemia and hyperaldosteronemia, leading to high SBP; however, a natriuretic process is taking place. CONCLUSION: Since these alterations appear, at least in part, to be related to oxidative stress in renal cells, Se supplementation could be beneficial to avoiding greater lipid renal oxidation during lactation.

Cost-effectiveness analysis of treatment sequences containing tofacitinib for the treatment of rheumatoid arthritis in Spain.

OBJECTIVE: To assess the cost-effectiveness of tofacitinib-containing treatment sequences versus sequences containing only standard biological therapies in patients with moderate-to-severe rheumatoid arthritis (RA) after the failure of conventional synthetic disease-modifying antirheumatic drugs (csDMARD-IR population) and in patients previously treated with methotrexate (MTX) who show an inadequate response to second-line therapy with any tumour necrosis factor inhibitor (TNFi-IR population). METHODS: A patient-level microsimulation model estimated, from the perspective of the Spanish Public NHS, lifetime costs and quality-adjusted life years (QALY) for treatment sequences starting with tofacitinib (5 mg twice daily) followed by biological therapies versus sequences of biological treatments only. Concomitant treatment with MTX was considered. Model's parameters comprised demographic and clinical inputs (initial Health Assessment Questionnaire [HAQ] score and clinical response to short- and long-term treatment). Efficacy was measured by means of HAQ score changes using mixed treatment comparisons and data from long-term extension (LTE) trials. Serious adverse events (SAEs) data were derived from the literature. Total cost estimation (€, 2018) included drug acquisition, parenteral administration, disease progression and SAE management. RESULTS: In the csDMARD-IR population, sequences starting with tofacitinib proved dominant options (more QALYs and lower costs) versus the corresponding sequences without tofacitinib. In the TNFi-IR population, first-line treatment with tofacitinib+MTX followed by scAbatacept+MTX➔rituximab+MTX➔certolizumab+MTX proved dominant versus scTocilizumab+MTX➔scAbatacept+MTX➔rituximab+MTX➔certolizumab+MTX; and tofacitinib+MTX➔scTocilizumab+MTX➔scAbatacept+MTX➔rituximab+MTX versus scTocilizumab+MTX➔scAbatacept+MTX➔rituximab+MTX➔certolizumab+MTX was less effective but remained a cost-saving option. CONCLUSIONS: Inclusion of tofacitinib seems a dominant strategy in moderate-to-severe RA patients after csDMARDs failure. Tofacitinib, as initial third-line therapy, proved a cost-saving strategy (€- 337,489/QALY foregone) in moderate-to-severe TNFi-IR RA patients. Key points • Therapeutical approach in rheumatoid arthritis (RA) consisted in sequences of several therapies during patient lifetime. • Treatment sequences initiating with tofacitinib followed by biological drugs provided higher health effects in csDMARDs-IR population, compared with sequences containing only biological drugs. • In both csDMARD-IR and TNFi-IR RA populations, initiating treatment with tofacitinib was associated to lower treatment costs for the Spanish National Health System.

Dietary selenium plus folic acid as an antioxidant therapy for ethanol-exposed pups.

BACKGROUND: Nutrients such as folic acid and selenium are decreased in dams exposed to ethanol during gestation and lactation, affecting their metabolism, antioxidant balance, and the future health of their progeny. We will study whether the supplementation of the maternal diet with folate and selenium can prevent ethanol-induced oxidative liver disorders in the offspring. METHODS: Dams were randomised into four groups: control, alcohol, alcohol+folic acid+Se, and control+folic acid+Se. We determined selenium by graphite-furnace atomic absorption and antioxidant enzyme activities, lipid peroxidation, and protein carbonyl by spectrophotometry in the offspring. RESULTS: Alcohol increased serum Se levels and glutathione peroxidase (GPx) activity. However, in the liver of pups from ethanol-exposed dams a decrease in selenium was provoked and GPx activity increased with the double supplementation. Glutathione reductase (GR) and catalase (CAT) activities increased with ethanol, while double supplementation significantly decreased the GR activity. The supplemented diet reduced the protein peroxidation found in ethanol pups. CONCLUSIONS: These results suggest that folic acid+Se could be effective in neutralising the damage of ethanol consumption in pups since it prevents peroxidation protein products.

Mixed epithelial and stromal tumour of the kidney with luteinised ovarian stroma.

We report a case of a 9-cm mixed epithelial and stromal tumour of the kidney in an obese 70-year-old woman with diabetes. The ovarian-type stroma had a spindle cell component that was positive for progesterone receptors and had the hitherto unreported presence of abundant foci of luteinised stromal cells with characteristic immunohistochemical positivity to alpha-inhibin, calretinin, aromatase and gonadotropin-releasing hormone (GnRH) receptors. We conclude that the stromal component is identical to ovarian cortical stroma. We believe that ovarian-type stroma occurs in extragenital tumours as a result of an epithelial-stromal interaction in an environment of hormonal hyperstimulation.

Pure testicular carcinoid associated with intratubular germ cell neoplasia.

This case report describes for the first time a case of pure testicular carcinoid pre-aortic lymph node metastases in a 25 year old patient with carcinoid syndrome. The simultaneous occurrence of intratubular germ cell neoplasia in the surrounding testicular tissue was identified by OCT4 and placental-like alkaline phosphatase positivity. This confirmed that the tumour had a germ cell origin in the testis, rather than being a metastasis from an extragenital carcinoid.

Status of oral anticoagulant treatment in patients with nonvalvular atrial fibrillation in Spain. REACT-AF Study. / Situación del tratamiento anticoagulante oral en pacientes con fibrilación auricular no valvular en España. Estudio REACT-AF.

BACKGROUND AND OBJECTIVES: Oral anticoagulant therapy is complex due to the need for control and the hemorrhagic risk the therapy entails. This study aims to determine the standard clinical practice in the treatment for preventing stroke in patients with nonvalvular atrial fibrillation (NVAF) in Spain. PATIENTS AND METHOD: The Real Evidence of Anti Coagulation Treatment in AF is a European, multicenter, multinational, observational, retrospectively monitored cohort of patients with NVAF. This study included patients recruited in Spain with at least one visit during the period of inclusion (May 2010/April 2012). The study evaluated the following: a) persistence of oral anticoagulant treatment (time to discontinuation); b) persistence rate (% of patients in treatment) at 6, 12 and 24 months and at 5 years; c) therapeutic compliance (medication possession ratio); d) the correlation between the treatment followed and that recommended by the European Society of Cardiology; and the incidence of stroke and hemorrhagic events. RESULTS: The patients treated with oral anticoagulants (n=7,526) had a median time to discontinuation of treatment of 1.99 years and a persistence rate at 5 years of 26% (discontinuation ≥3 months). The compliance (mean MPR) was 0.54±0.36. The incidence of stroke was 0.3/100 person-years, and the incidence of hemorrhagic events was 2.4/100 person-years. Fifty-eight percent of the patients with NVAF (n=12,514) followed the recommendations of the European Society of Cardiology. CONCLUSION: Forty-two percent of the patients with NVAF did not follow the recommendations of the European Society of Cardiology. We detected low persistence and treatment compliance rates for oral anticoagulants.

Granulosa cell tumor of the ovary with diffuse true hepatic differentiation simulating stromal luteinization.

A case of granulosa cell tumor of the ovary associated with hepatocytic differentiation is reported in a 45-year-old patient with a torsioned ovarian tumor. Serum alpha-fetoprotein (AFP) levels were normal 6 days postoperatively. Histopathologically, the granulosa cell tumor was typically trabecular. Its cells had nuclear grooves and were positive only for vimentin. Scattered diffusely throughout the tumor were small groups of regular polygonal cells, the cytoplasm of which secreted bile and was strongly positive for keratin, carcinoembryonic antigen (CEA), alpha-1-antitrypsin (A1AT), and ferritin and moderately positive for fibrinogen and ceruloplasmin. These results unequivocally identified them as hepatic cells. The AFP negativity of the hepatic cells was interpreted as a sign of terminal hepatocytic differentiation. The scattered arrangement of the hepatocytes simulated stromal luteinization. As neither a primary liver tumor nor any associated germ cell tumor was found, the histogenesis of the hepatic cells was thought to be metaplastic.

Ovarian prostatic tissue originating from hilar mesonephric rests.

Nonteratoid prostatic differentiation in the ovary of a parous, phenotypically normal, postmenopausal woman is reported for the first time, to the authors' best knowledge. The patient was a 70-year-old woman who underwent bilateral oophorectomy following pelvic ultrasound examination that showed enlargement of the left ovary and an equivocally abnormal Doppler signal. Histologic examination showed a normal right ovary and a left ovary enlarged by hilar cystic dilatation related to a proliferation of mesonephric remnants exhibiting various types of epithelial metaplasia, including hyperplastic rete and epididymal-like and clear cell epithelia resembling the lining of the seminal excretory system. These were closely associated, occasionally even merging, with a discrete area of prostatic acinar and smooth muscle differentiation in the cyst wall. The identity of the prostatic tissue was confirmed immunohistochemically by positive staining with prostate specific antigen and prostatic acid phosphatase. The lesion was associated with an incidental, microscopic hemangioma. A developmental malformative origin of this abnormality cannot satisfactorily be explained by current embryologic concepts. A hypothesis of a metaplastic induction of prostatic tissue by mesonephric remnants is proposed, since complex metaplastic changes coexisted within the cysts and even showed epithelial transitions with the prostatic acini.

Ovarian endometrioid tumors with yolk sac tumor component, an unusual form of ovarian neoplasm. Analysis of six cases.

The clinical, morphological, and immunohistochemical findings in six cases of ovarian endometrioid tumors (five endometrioid carcinomas and one carcinosarcoma) with a yolk sac tumor (YST) component are described. The age of the patients ranged from 31 to 73 years (average, 53), and only two patients were premenopausal. Two cases were stage Ia tumors, three stage III, and one stage IV. A substantial postoperative elevation of alpha-fetoprotein (AFP) was seen in two patients and a mild increase in another two. All six patients had surgery and postoperative cisplatin-based chemotherapy regimens, four of whom died of tumor 3 to 14 months after surgery without response to treatment. Only a stage Ia patient is alive and well 1 year after surgery. The tumors were large (average, 17 cm). Benign endometrioid lesions were found in the homolateral ovary in two cases and in the contralateral ovary in another two. All cases had endometrioid ovarian carcinomas (EOC) of various types admixed with typical YST components. Immunohistochemically, EOC areas differed from YST in their positivity for OC 125, CA 19.9, and nuclear estrogen and progesterone receptors and in their negativity for AFP, which was conspicuously positive in the YST areas. The clinicopathological profile of ovarian endometrioid tumors with YST also differs from that of YST in that it occurs in the same age range as EOC, it shows coexistence of benign endometrioid lesions, and it has a poor response to chemotherapy. The histological pattern in transitional areas may be difficult to differentiate from "endometrioid-like" (enteroblastic) YST and clear cell tumors. Ovarian endometrioid tumors with YST component should be considered a variant of endometrial carcinoma. Its recognition is necessary in view of its unusually aggressive behavior and poor prognosis.

Mesonephric adenocarcinoma of the uterine corpus: CD10 expression as evidence of mesonephric differentiation.

Mesonephric (wolffian) neoplasms of the female genital tract are infrequent and found in sites where embryonic remnants of wolffian origin are usually detected, such as the uterine cervix, broad ligament, mesosalpinx, and ovary. Their diagnosis is difficult because of the absence of specific immunohistochemical markers for mesonephric derivatives. We present the first report of adenocarcinoma of mesonephric type arising as a purely myometrial mass without endometrial or cervical involvement in the uterine corpus of a 33-year-old woman. The tumor showed a combination of patterns, with retiform areas, ductal foci, and small tubules with eosinophilic secretion, which merged with solid sheets of cells with a sarcomatoid appearance. Immunohistochemically, neoplastic cells were diffusely positive for cytokeratin 7, epithelial membrane antigen, and CD15 and focally positive for BerEP4 and vimentin. A hitherto unreported feature was the positivity for CD10 in neoplastic cells, which was also present in a large number of control tissues obtained from male mesonephric derivatives and female mesonephric remnants and tumors. Furthermore, CD10 was negative in controls from müllerian epithelia of the female genital tract and in their corresponding tumors. Therefore, the expression of CD10 by mesonephric remnants may be useful in establishing the diagnosis of tumors with mesonephric differentiation.

A multicentric European study testing the reproducibility of the WHO classification of endometrial hyperplasia with a proposal of a simplified working classification for biopsy and curettage specimens.

This study was designed to assess intraobserver and interobserver agreement in the diagnosis of 56 endometrial specimens by five European expert gynecologic pathologists using the WHO classification and to establish which histologic features are significantly associated with each classification category. The seven categories were simple hyperplasia, complex hyperplasia, atypical hyperplasia, well-differentiated adenocarcinoma, proliferative endometria, secretory endometria, and other. Slides were reviewed twice for diagnosis, with accompanying evaluation of a checklist of histologic features. These seven categories were eventually reduced to four and three for the purposes of data analysis. The four modified diagnostic categories consisted of hyperplasia (previously simple hyperplasia and complex hyperplasia), atypical hyperplasia, well-differentiated adenocarcinoma, and cyclical endometrium (previously proliferative, secretory, and other). The three diagnostic categories consisted of hyperplasia, endometrioid neoplasia (previously atypical hyperplasia and well-differentiated adenocarcinoma), and cyclical endometrium. Intraobserver and interobserver agreement was assessed using the percentage agreement and kappa statistics. The associations among the various histologic features and diagnoses was analyzed using multiple logistic regression to identify those features that were useful for distinguishing diagnostic categories. When using seven categories, kappa values ranged from 0.53 to 0.74 (percentage agreement, 61-79%) and from 0.33 to 0.59 (percentage agreement, 43-63%) for intraobserver and interobserver agreement, respectively. When using four categories, kappa values ranged from 0.68 to 0.73 (percentage agreement, 77-80%) and from 0.39 to 0.64 (percentage agreement, 54-73%) for intraobserver and interobserver agreement, respectively. When using three categories, kappa values ranged from 0.70 to 0.83 (percentage agreement, 80-89%) and from 0.55 to 0.73 (percentage agreement, 70-82%) for intraobserver and interobserver agreement, respectively. Data were analyzed in each diagnostic category. When using four or three diagnostic categories, the mean intraobserver and interobserver agreements varied less between categories and achieved higher values, with smaller 95% confidence intervals. The mean percentage agreement was lowest for complex hyperplasia and for atypical hyperplasia. For distinguishing cyclical endometrium versus hyperplasia, the useful histologic feature was glandular crowding. For hyperplasia versus atypical hyperplasia and for hyperplasia versus endometrioid neoplasia, the useful features were nuclear enlargement, nuclear pleomorphism, vesicular chromatin, and nucleoli, but of these, only nuclear pleomorphism achieved substantial mean intraobserver and interobserver agreements. For discriminating atypical hyperplasia from well-differentiated adenocarcinoma, the only useful feature was stromal alterations, which achieved only fair mean intraobserver and interobserver agreements. In summary, in endometrial biopsy or curettage specimens, the lack of agreement in the diagnoses of complex hyperplasia and atypical hyperplasia and the lack of reproducibility in the recognition of the histologic feature of stromal alterations to differentiate atypical hyperplasia from well-differentiated adenocarcinoma suggest that the histologic classification should be simplified by including a combined category for simple and complex hyperplasia, called hyperplasia, and a combined category for atypical hyperplasia and well-differentiated adenocarcinoma, called endometrioid neoplasia. Diagnoses of hyperplasia and endometrioid neoplasia are highly reproducible between observers from different institutions. Glandular crowding is the best histologic feature to differentiate cyclical endometrium from hyperplasia, whereas nuclear pleomorphism is the reproducible cytologic feature to differentiate hyperplasia from endometrioid neoplasia.

Immature endodermal teratoma of the ovary: embryologic correlations and immunohistochemistry.

Two grade 2 ovarian immature, predominantly endodermal teratomas are reported. The teratomas were in stage I and occurred in two girls, 9 and 10 years of age, who were treated with triple chemotherapy. These neoplasms differed from the usual immature ovarian teratoma as they contained no neuroectodermal components and had high alpha-fetoprotein and low human chorionic gonadotropin levels as their serum markers despite the absence of other concomitant germ cell tumors. The epithelia of the teratomas demonstrated exclusively the embryologic development of endoderm, ranging from early endoderm to tissues similar to esophagus, liver, and intestinal structures. All epithelial derivatives were positive for alpha-fetoprotein and alpha 1-antitrypsin. Liver and esophagus expressed fibrinogen, while intestine and esophagus were positive not only for carcinoembryonic antigen and chromogranins but also for thyroglobulin, thus reflecting yet another type of endodermal differentiation into thyroid. Focal human chorionic gonadotropin positivity associated with primitive intestinal and esophageal epithelia may reflect the early embryologic relationships between endoderm and trophoblast. These cases demonstrate that simultaneous alpha-fetoprotein and human chorionic gonadotropin secretion may occur in immature teratoma. The mesenchymal component also showed a wide range of differentiation, from primitive mesoblastic cells to differentiated cells, such as hemopoietic foci, smooth muscle, bone, and cartilage. Both the primitive endoderm and the mesenchyme co-expressed vimentin and keratin, reflecting their intimate developmental relationships and possibly supporting the hypothesis of mesenchyme originating from endoderm, as suggested by previous embryologic studies. Since endodermal and mesenchymal areas similar to those described here are found in association with yolk sac tumors and embryonal carcinoma, it is possible that the present cases may represent an endodermal differentiation accomplished by either of these developmentally related germ cell tumors.

Ectopic somatic endoderm in secondary human yolk sac.

Three secondary human yolk sacs (SHYSs) showing heterotopic endodermal tubular structures of the gut-forming type were analyzed from a series of 180 SHYSs. These structures were similar to the early somatic endoderm involved in the formation of gut and lung. They may have arisen either as sequestrations in growth-disorganized embryos or as a phenomenon of differentiation from extraembryonal endoderm, which would indicate that extraembryonal tissues such as the SHYSs retain the capacity to differentiate somatic endoderm in developmentally altered embryos. It is possible that these structures may be the precursors of placental hepatic tissue and teratomas. Their morphologic resemblance to similar structures found in glandular, polyvesicular, and intestinal human yolk sac tumors provides yet another example of the similarity between SHYSs and yolk sac tumors.

Yolk sac tumors with pure and mixed polyvesicular vitelline patterns.

Four cases of polyvesicular vitelline tumor are presented; two were of a previously unreported pure type, and the other two were mixed with endodermal sinus tumor. The morphologic features of the vesicles favor an endodermal origin, as originally proposed by Teilum. Marked specialization of the vesicular lining cells, seen ultrastructurally, suggests a differentiation toward gut structures and mature yolk sac. One case of pure polyvesicular vitelline tumor showed massive erythropoiesis. We propose that the pure tumor reflects an intermediate degree of differentiation within the selectively endodermal yolk sac tumor group, that is, a further stage of organization than the endodermal sinus tumor. In our cases of pure polyvesicular vitelline tumor, the marked degree of differentiaiton was correlated with an improved prognosis, as in the case of the possible homologue of this tumor, the yolk sac tumor of the infant testis. In contrast, the two cases of the tumor admixed with endodermal sinus tumor illustrated the low survival rate expected in the pure endodermal sinus tumor; in these cases the metastases had no polyvesicular component. Because of the significance of such a difference in prognosis we emphasize the importance of an accurate diagnosis, suggesting that a large number of sections be taken in order to demonstrate any endodermal sinus tumor component that may be present, and that the possibility of pure polyvesicular vitelline tumor always be considered in the differential diagnosis of multicystic ovarian tumors.

Hepatocytic differentiation in retiform Sertoli-Leydig cell tumors: distinguishing a heterologous element from Leydig cells.

Sertoli-Leydig cell tumors (SLCT) of the ovary are rare sex cord-stromal neoplasms. A minority of SLCT are characterized by a pattern resembling that of the rete ovarii and frequently have a range of homologous and heterologous tissues. Approximately 20 cases of SLCT have been reported to have elevation of serum alpha-fetoprotein (AFP) levels, or tissue immunoreactivity for AFP, a protein usually associated with germ cell neoplasms, especially yolk sac tumor. We identified hepatocytic differentiation in five cases of retiform SLCT (RSLCT), and confirmed immunohistochemically that these cells are hepatocytes rather than Leydig cells. Hepatocytes are positive for keratins (AE1/3 and Cam 5.2), AFP, and ferritin, negative for vimentin, and show weak to moderate staining for inhibin. Leydig cells are negative for keratins, positive for vimentin, and intensely positive for inhibin. Immunohistochemistry is needed to distinguish hepatocytic differentiation from Leydig cells with certainty. Including the cases in this report, hepatocytic differentiation has been associated with a retiform pattern in SLCT in 14 of 25 cases (56%). The association of these two patterns appears to be characteristic of a relatively primitive sex cord-stromal neoplasm.