Clinical outcome of patients with microinvasive adenocarcinoma of the uterine cervix.

BACKGROUND: The objective of this analysis was to present the clinical outcome of patients with microinvasive adenocarcinoma (AC) of the uterine cervix treated at the Department of Obstetrics and Gynecology between 1999 and 2010. MATERIALS AND METHODS: The authors analysed 125 patients with microinvasive AC. The analysis involved the following parameters: women's age at surgery, type of surgery, number of positive lymph nodes, and patient's survival. Additionally, a questionnaire regarding history and symptoms before diagnosis and postoperative follow-up was developed and analysed specifically for this study. RESULTS: The mean women's age at surgery was 40.58 +/- 9.58 years. In 70 women (56%), the performed treatment was conization, 34 women (27.2%) underwent simple hysterectomy, and 24 (19.2%) women had radical hysterectomy. In 14 (11.2%) women, the margins of the cone were not disease-free, in nine of them the authors later performed radical hysterectomy. From 14 women who became pregnant after treatment, 13 (16.9%) of them gave birth. One of the 125 patients diagnosed with microinvasive AC died and the cause of death was rectal carcinoma. CONCLUSION: The authors may conclude that conservative management of patients with microinvasive AC is safe when exact evaluation of tumor extension and surgical margins of the cone are considered, and results in very low risk of recurrence, lymph node disease, and death caused by cancer.

Müllerian papilloma in a patient with Proteus syndrome: case report and review of the literature.

BACKGROUND: Müllerian papilloma is a rare benign tumor of the female genital tract. It mostly affects girls less than five years old. After the treatment long-term follow-up is needed as there is a chance of recurrence, but even then the prognosis is excellent. CASE: A 19-year-old girl with Proteus syndrome presented with vaginal bleeding. The histological examination revealed Müllerian papilloma of the uterine cervix and large bilateral ovarian cystadenomas. The patient was treated with a radical operation, because there were signs of more aggressive behavior in the tumor. The patient is alive and free of disease five years after the operation. CONCLUSION: The medical care of patients affected by rare disorders depends heavily on experiences gained from cases published in the medical literature. Since there is not much experience with tumors in Proteus syndrome we believe that this case can aid in shedding light on this subject.

Comparison of nerve content in removed parametrial tissue after classic radical hysterectomy and nerve-sparing radical hysterectomy--histologic evaluation.

PURPOSE OF INVESTIGATION: The aim of this study was to find whether nerve-sparing radical hysterectomy resulted in a lower amount of nerves in the removed parametrial tissue. METHODS: Histological specimens from nerve-sparing radical hysterectomy (28 cases) were compared with those obtained after classic radical hysterectomy (26 cases). Width of the parametria and vaginal cuff were measured. Using a point counting technique, nerve areal density was determined in cross sections of resected parametria at 0.5 cm (A), 1 cm (B), 1.5 cm (C) from the cervix. RESULTS: The width of the resected parametria was smaller in the study group (right side p < 0.013; left side; p < 0.011). The nerve areal density in the lateral part of the right parametrium was lower in the study group (p < 0.01) (Student's t-test). CCONCLUSION: Modified radical hysterectomy is less radical and is nerve-sparing.

Advanced embryonal rhabdomyosarcoma of the uterine cervix: a case report.

BACKGROUND: Primary embryonal rhabdomyosarcoma (RMS) arising from the uterine cervix is a rare and extremely malignant entity. Young women aged 12-26 years are mostly affected. Before the introduction of effective adjuvant chemotherapy, the prognosis of these lesions was poor. CASE: A 16-year-old girl presented with vaginal bleeding. The histological examination revealed embryonal RMS of the uterine cervix. The patient was treated with a combination of surgery, chemotherapy and radiotherapy. The patient was alive and free of disease five years after the operation. CONCLUSION: A combined modality approach to treating RMS using surgery, multidrug chemotherapy, and radiotherapy has significantly improved survival. The medical community should keep in mind that embryonal RMS of the uterine cervix, despite its malignancy and rarity, can be cured if timely and adequate treatment is given.

Prognostic significance of topoisomerase II alpha and collagen IV immunoexpression in cervical cancer.

OBJECTIVE: The immunohistochemical (IHC) expression of topoisomerase II alpha and collagen IV was studied in cervical cancer. The results of IHC expression for both markers were compared to the clinical and histological factors predicting the course of disease. METHODS: In 114 patients with cervical cancer, treated at the Department of Gynecology and Obstetrics, University Medical Centre Ljubljana between 1995 and 1999, the tumor tissue was analyzed using standard IHC staining (IHS) procedures for topoisomerase II alpha and collagen IV. The obtained results were compared to those obtained by clinical, pathomorphological and morphometric prognostic factors, and the impact of the analyzed factors on the outcome of disease was assessed. RESULTS: A high percentage of IHC expression of topoisomerase II alpha was present in 55.3%, and to collagen IV in 28.1% of cervical cancer patients. In the multivariate analysis the IHS intensity to collagen IV was significantly associated with lymphovascular invasion (OR = 5.906; 95% CI 2.18-15.96). Kaplan-Meier analysis showed a statistically significantly better survival in initial cervical cancer stages (p = 0.001), in tumors with a higher degree of differentiation (p = 0.049), more shallow depth of invasion (p = 0.004), smaller horizontal tumor spread (p = 0.001), in cases with no lymph node metastases (p = 0.001) and no lymphovascular space invasion (p = 0.001), in younger age groups (p = 0.001) and in women with regular menstrual cycles (p = 0.001). CONCLUSION: IHC expression of topoisomerase II alpha and collagen IV was significantly correlated with defense reaction. A negative and weak IHC to collagen IV was a statistically significant independent predictive variable for lymphovascular invasion, related to metastatic spread in the lymph nodes. The two analyzed IHC markers indicate the existence of factors at the molecular level that might complement the assessment of cervical cancer prognosis, resulting in the appropriate choice of type and extent of treatment.

Choroidal melanoma metastasized to the ovary: case report and review of the literature.

BACKGROUND: Malignant melanoma metastases to the female genital tract in only 2.5% of cases. Melanoma is characterized by clinical variability and unpredictable biological behavior with long remissions and relapses that develop rapidly. CASE AND REVIEW: A 57-year-old woman was admitted for hypogastric pain and weight loss. She had presented enucleation of the right eye six years before for malignant choroid melanoma. Gynaecological examination revealed enlarged ovaries. Bilateral salpingo-oophorectomy, hysterectomy, and omentectomy were performed. Final pathology diagnosed a choroidal metastatic melanoma (CMM). The patient died seven months later. Only seven cases of CMM have been reported in the literature. Patients affected by CMM ranged in age from 38 to 83 years (median 51.2 years), the time to relapse ranged from 3-25 years (median 51.2 years), the size of the cysts ranged from 4-17 cm (median 9.7 cm) and the survival period ranged from 2-14 months (median 8.1 months). CONCLUSION: Malignant melanoma is misdiagnosed because of lack of discriminatory symptoms, increased tumor markers, characteristic imaging findings and the capacity to mimic other tumors. Today CMM still represents a challenge for gynecologic oncologists.

Giant pelvic retroperitoneal liposarcoma: case report.

BACKGROUND: Pelvic retroperitoneal liposarcomas are rare tumors of mesenchymal origin. We present a case of a giant pelvic well-differentiated liposarcoma of the retroperitoneum in a woman, presenting with a large abdominal mass. CASE: A 62-year-old woman presented with a rapid abdominal enlargement. Pelvic examination revealed a huge mass occupying the whole pelvis and part of the right abdomen. At surgery, the pelvic organs were displaced to the right side by a retroperitoneal mass that marginally involved the part of the posterior abdominal wall, left parietal peritoneum of the diaphragm, left colic flexure and the left adnexa. The huge mass, uterus, and both adnexa were removed; hemicolectomy and latero-lateral anastomosis were carried out. No adjuvant irradiation was given. The patient is alive and free of disease five years after the operation. CONCLUSION: The gynecologist should consider retroperitoneal liposarcoma in the differential diagnosis of large pelvic or abdominal masses.

Amelanotic malignant melanoma of the uterine cervix with ten-year follow-up.

BACKGROUND: Malignant melanoma (MM) accounts for 3% of cancers that affect women and results in less than 1% of cancer deaths. It is characterized by clinical variability and unpredictable biological behavior. Fewer than ten cases of amelanotic MM (AMM) have been reported in literature. CASE: A 61-year-old woman was admitted for vaginal spotting. A huge, soft cervix with an exophytic lesion was biopsied. A clear cell carcinoma, FIGO Stage IB1, was diagnosed and radically treated. The final pathology showed an AMM of the cervix positive for PAS and HMB 45. The patient is clinically free of disease ten years postoperatively. CONCLUSION: Malignant melanoma of the cervix is often misdiagnosed because of non discriminatory features and the capacity to mimic other tumors. Malignant melanoma of the cervix needs to be diagnosed as quickly as possible because a timely therapy and a long and careful follow-up might result in better survival.

Clinical audit of patients with cervical cancer in Slovenia. Data analysis from 2003-2006.

PURPOSE OF INVESTIGATION: From 2003 to 2006 the data on Slovenian cervical cancer patients who regularly attended a gynecologist were gathered. Data were analyzed in order to improve the efficiency of the cervical cancer screening program. METHODS: Data on all patients newly diagnosed with cervical cancer were collected at three central clinics in Slovenia. The results are a presentation and comparison of detailed information on some characteristics of cervical cancer patients of the group that regularly visited a gynecologist and of the other group who did not. Data were processed by descriptive epidemiological methods. Mantel-Haenzel chi2 and Fisher's p tests were used to evaluate statistical significance. RESULTS: On average, 55% of patients with cervical cancer underwent a gynecological examination five years before the diagnosis. The patients who regularly attended their gynecologist were, in all age groups, statistically significantly younger, the stage of cervical cancer at diagnosis was statistically significantly lower (p = 0.01) and were, in statistically significantly higher percentage, treated surgically (p < 0.01). From 2003 to 2006, each patient had on average five examinations at her gynecologist within the period of five years to six months before the diagnosis of cervical cancer. The average number of collected smear samples was 3.2. CONCLUSION: From the results of our analysis, it may be concluded that improvements are needed in Slovenia in the field of screening for and early detection of cervical cancer.

Efficiency of three surgical procedures in eliminating high-risk human papillomavirus infection in women with precancerous cervical lesions.

PURPOSE OF INVESTIGATION: To establish the efficiency of laser vaporization (LV), large loop excision of the transformation zone (LLETZ) and cold knife conization, done for precancerous cervical lesions, in eliminating high-risk human papillomavirus (HPV) infection. Additionally, we determined whether the same HPV genotype persisted after surgery. METHODS: A total of 214 women were tested for HPV infection by the Hybrid Capture II (HCII) test prior to surgery. HPV-positive women were followed by HCII test ten months after surgery. In persistently HPV-positive women, HPV genotypes were determined by PCR - PGMY09/PGMY11. RESULTS: The HCII test showed elimination of HPV infection after LV, LLETZ and cold knife conization in 67.6%, 86.3%, and 100% (p < 0.05) of women, respectively. In seven (38.9%) women a different HPV genotype was found to be present after surgery, the corrected efficiency thus being 79.4%, 92.7% and 100% (p = NS), respectively. CONCLUSIONS: The three analyzed surgical procedures are effective in eliminating high-risk HPV infection. HPV testing is useful at follow-up, since it can identify a small proportion of women requiring close surveillance and potential treatment.

Clinical audit of patients with cervical cancer in Slovenia--data analysis for the year 2003.

PURPOSE OF INVESTIGATION: The data gathered in 2003 on the patients with cervical cancer who regularly attended their gynecologist were analyzed with the purpose of clinical audit. METHODS: The data on newly detected patients with cervical cancer in 2003 who regularly attended their gynecologist were gathered simultaneously at three Advisory Boards for Gynecology in Slovenia. RESULTS: Of 149 patients in whom, according to our data, invasive cervical cancer had been diagnosed, 92 (61.7%) patients were examined by a gynecologist in the previous five years. In the majority of these patients, cervical cancer was diagnosed in early, localized disease stage. In the periods of 13-24 and of seven to 12 months before the diagnosis of cervical cancer, almost half the patients had Pap II, and three to six months before diagnosis, 67.6% of patients had Pap II. CONCLUSION: These results encourage us to proceed with clinical audits to analyze individual cervical cancer cases, including another independent reevaluation of cervical smears in the five-year period before diagnosis. A suitable calendar of refresher training courses on colposcopy, which should be obligatory for all performing this examination method, also needs to be set up.

Role of human papillomavirus testing in reducing the number of surgical treatments for precancerous cervical lesions.

PURPOSE OF INVESTIGATION: To determine whether the addition of the Hybrid Capture II (HC II) test (Digene Corp., Gaithersburg, MD, USA) to cytological, colposcopical and histological results could reduce the number of surgical treatment procedures for precancerous cervical lesions. METHODS: Surgical treatment of precancerous cervical lesions was performed in 181 women. Priorly, the women were tested for high-risk human papillomavirus (HPV). Sensitivity, specificity, positive and negative predictive value were calculated to assess the performance characteristics of HC II in the detection of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) and grade 3 or worse (CIN 3+). RESULTS: Eighty (44.2%) women had a histological result < CIN 2; 117 (64.6%) women had < CIN 3. Fifty-three (29.3%) women with < CIN 2 tested HPV negative; 69 (38.1%) women with < CIN 3 tested HPV negative (p < 0.05). The sensitivity of HC II for detecting CIN 2+ and CIN 3+ was 76.2% and 87.5%, respectively. CONCLUSION: A high proportion of women were overtreated probably due to cytological and histological overestimations. HPV testing would reduce the number of unnecessary surgical treatments and should be used as an additional screening tool.

Human papillomavirus infection in relation to mild dyskaryosis in conventional cervical cytology.

PURPOSE OF INVESTIGATION: To establish the prevalence and distribution of high-risk human papillomavirus (HPV) genotypes in Slovene women with repeat mild dyskaryosis, and to evaluate three molecular methods for the detection of HPV that could be used as a complementary method to cervical cytology. METHODS: In this prospective study 148 women with three subsequent cervical cytologic tests within two years showing mild dyskaryosis were enrolled. HPV infection was determined using three molecular tests: Hybrid Capture II and two variants of polymerase chain reaction (PCR-PGMY11/PGMY09 and PCR-CPI/CPIIG). RESULTS: HPV was detected in 17 of the 45 women aged < or =30 years and in 21 of the 103 women aged >30 years (37.8% vs 20.4%, p = 0.04). The most common genotype was HPV 16 detected in eight (21.1%) women, the next were HPV 53 and HPV 51, each detected in five (13.2 %) women. The three molecular methods matched in 92.9%. CONCLUSION: Low prevalence of HPV infections indicates that cervical screening programmes in Slovenia are overburdened with mild dyskaryosis. Repeat cytology is not reliable; HPV testing might be useful as a complementary method.

Risk factors and prognostic factors in patients with double primary cancer: epithelial ovarian cancer and breast cancer.

BACKGROUND AND OBJECTIVE: The most important known risk factor for ovarian cancer is the BRCA1-2 mutation, which is clinically often manifested through a positive family history of cancer of the breast and/or ovary. Whether other risk factors and prognostic factors in women with a positive family history of cancer of the breast and/or ovary and/or with BRCA1-2 mutation are important remains to be elucidated. Recent studies have shown that in the double primary breast and ovarian cancer (DPBOC), BRCA1-2 mutation is present in at least 86% of cases. Therefore, the group of patients with DPBOC, especially with epithelial ovarian cancer and breast cancer, is the most suitable for such an analysis. The aim of this study was to verify the hypothesis that, in this group, some other risk factors, in addition to a specific family history of cancer, as well as unfavourable pathomorphological prognostic factors, are more expressed than in a control group of patients with sporadic epithelial ovarian cancer only. METHODS: We compared the study group of 31 patients with DPBOC (epithelial ovarian cancer) to a control group of 62 patients with a single, sporadic epithelial ovarian cancer and negative specific family history. The data were obtained from the Cancer Registry of Slovenia and from clinical records. For every patient, we filled-in a protocol and analysed the data, comparing other risk factors in addition to specific family history and prognostic, clinical, and pathomorphological factors. Statistical analysis was performed using descriptive statistics, chi-square test and t-test. Multivariate analysis was also planned, but the necessary conditions were not met. RESULTS: In the study group, we found a higher percentage of positive non-specific family histories than in the control group, but the difference was not statistically significant. No difference in procreative risk factors was observed between the groups. There was a higher percentage of borderline significance of women from the study group that developed ovarian cancer between 45 and 59 years of age. In the study group, ovarian cancer was significantly more often found at Stage I, although the groups did not differ in detection procedures. Also, we did not find any differences in the distribution of tumour grades or histologic tumour types. CONCLUSION: The results did not confirm our hypothesis, yet they indicated some differences between the groups regarding the risk factors for ovarian cancer. Regarding the prognostic factors, we even found a significantly higher percentage of Stage I epithelial ovarian cancer in the study group, with no difference in the mode of detection. Considering the results that are not typical of BRCA-related cancer (what double primary cancer of the ovary and breast is supposed to be) and previous reports, we find it more likely that the patients with BRCA1-2 mutations represent only a subgroup within the group of patients with double primary breast and ovarian cancer.

[Current surgical management in ovarian cancer recurrences]. / Attuale management chirurgico delle recidive di carcinoma ovarico.

Ovarian cancer is a tumor with a high trend of recurrence and this occurrence consistently increases the difficulty of the patient cure and reduces the efficacy of current treatments. The role of surgery in persistent or recurrent ovarian cancer is controversial and the type of surgery can be different according to the different stages and invasion of tumor; it can be a debulking surgery followed by chemotherapy (to eradicate the most part of ovarian cancer, leaving a minimal tumoral residue), an interval surgery (for advanced ovarian cancer stage in previously operated patients, followed by 2 or 3 inductive chemotherapy cycles and subsequently a cytoreductive redo surgery) and a cytoreductive secondary surgery, after optimal primary surgical treatment and minimal tumoral recurrence. In some cases it is possible either to perform a debulking surgery during a primary (after the conclusion of primary treatment) or a salvage or palliative surgery (to improve, after an acceptable time period, clinical symptoms in patients with progressive cancer or resistant to treatments). The aims of surgical therapy, to be performed in a patient with ovarian cancer relapse, are to reduce, as much as possible, the tumour size, to increase the quality of life and to increase the survival time; in this review different surgical techniques to be carried out in each case, selected for disease staging, for tumour cells kinetic and for surgical goals, are discussed.

[Stress urinary incontinence: an overview on actual surgical trends]. / Incontinenza urinaria da sforzo. Una panoramica su gli attuali trend chirurgici.

Stress urinary female incontinence (IUS) is an unpleasant symptom describing a loss of urine during physical exertion; genuine stress incontinence (GSI) is a socially unacceptable, involuntary loss of urine in absence of detrusor activity from the urethra associated with sudden cough or strain. The incidence of IUS is less than 10% in reproductive-age women but may approach 10-20% in postmenopausal women. The IUS pathophysiology is connected with two specific mechanisms: the urethral-bladder sliding out of anatomical area involves the normal system of endobladder/intraabdominal pressures, with a loss of urine; the second mechanism involves the damaged urethral sphincteric function, with a reduction of the urethral closure pressure and a urinary loss after minimal physical stimulation. The IUS medical therapy is troublesome and often inefficient, and the only approved effective measures are the surgical procedures, actually reserved for cases of unsuccessful medical therapy; surgical treatments can be classified according to the access as: vaginal, abdominal, associated and complex. They intend to reposition the urethral-bladder sliding in its normal intra-abdominal position, to allow equal transmission of increased intraabdominal pressure to the bladder and the proximal urethra. In the scientific literature there are more than one hundred surgical procedures for IUS correction, but the IUS surgical approach is anyway the actual gold standard therapy.

Neoadjuvant chemotherapy for advanced epithelial ovarian carcinoma: a retrospective case-control study.

Neoadjuvant chemotherapy has been proposed as an alternative approach to primary cytoreductive surgery as initial management of bulky ovarian cancer with the aim of improving surgical efficiency and quality of life. The data of a retrospective case-control study including 75 patients with advanced epithelial ovarian carcinoma Stages IIIC and IV are presented. In 20 patients, neoadjuvant chemotherapy (3-5 cycles of cytostatics) was applied before cytoreductive surgery which was followed by chemotherapy, six cycles in total. In 55 patients cytoreductive surgery was applied as the primary treatment followed by six cycles of chemotherapy. A comparison of both groups of patients showed no significant difference regarding patient age, tumor stage, grade and treatment modality (chemotherapy and surgery, without irradiation) applied cytostatics and total number of chemotherapeutic cycles. The data from our study confirmed a statistically significant difference in radicality of cytoreduction that was more extensive when applied in combination with neoadjuvant chemotherapy than when applied as primary cytoreductive surgery (p = 0.009). No statistically significant difference was found in the survival of the two groups (p = 0.79), the response to primary treatment (p = 0.52), relapse (p = 0.88) or disease-free survival (p = 0.61). From the findings of the study and literature review, we may conclude that neoadjuvant chemotherapy followed by interval debulking surgery in patients with advanced epithelial ovarian carcinoma does not have an unfavorable effect on the prognosis.

The SOCS box of suppressor of cytokine signaling-1 is important for inhibition of cytokine action in vivo.

Suppressor of Cytokine Signaling-1 (SOCS-1) is an essential physiological inhibitor of IFN-gamma signaling. Mice lacking this gene die in the early postnatal period from a disease characterized by hyperresponsiveness to endogenous IFN-gamma. The SOCS box is a C-terminal domain shared with over 30 other proteins that links SOCS proteins to an E3 ubiquitin ligase activity and the proteasome, but whether it contributes to inhibition of cytokine signaling is currently disputed. We have deleted only the SOCS box of the SOCS-1 gene in mice and show that such mice have an increased responsiveness to IFN-gamma and slowly develop a fatal inflammatory disease. These results demonstrate that deletion of the SOCS box leads to a partial loss of function of SOCS-1.

Endometriosis-associated ovarian carcinoma (EAOC): an entity distinct from other ovarian carcinomas as suggested by a nested case-control study.

OBJECTIVES: Endometriosis-associated ovarian carcinoma (EAOC) has recently received increasing attention due to its suggested biological behavior, distinctive from those of usual epithelial ovarian cancer. To elucidate some of the controversies on this intriguing entity, a series of patients with EAOC were compared to ovarian carcinoma cases without concomitant endometriosis. METHODS: To control the confounding effect of age, a nested case-control study was designed, where all 58 EAOC patients (mean age 54.5 +/- 11.5 years) were nested with four perfectly age-matched non-EAOC patients (n = 232; mean age 54.7 +/- 11.7 years) selected among 425 women representing all FIGO stages of ovarian carcinomas without endometriosis. Pertinent clinical data and results of analysis of the tumors were subjected to statistical analyses using life-table, univariate (Kaplan-Meier), and multivariate (Cox) survival techniques to disclose dissimilarities in the key biological characteristics of these two groups as well as the independent prognostic predictors of disease outcome. RESULTS: When compared in a case-control design with four perfectly age-matched non-EAOC patients nested to each EAOC case, the patients with EAOC proved to: (1) have a lower stage disease (both FIGO and TNM) (P = 0.000), (2) show a completely different distribution of histological subtypes (significant overpresentation of endometrioid and clear cell carcinomas) (P = 0.0001), (3) have predominantly lower grade lesions (P = 0.029), (4) be devoid of any primary residual tumor (P = 0.0001), and, most importantly (5) have demonstrated a significantly better overall survival (47/58 versus 126/232; OR 2.89, 95% CI 1.56-5.34, P = 0.0001). This better survival was evident (a) in all age groups and (b) for all histological subtypes, but (c) not explained by a better stage-specific survival in any FIGO stage. The two series also differed in their significant prognostic predictors in Kaplan-Meier and Cox analyses. In the EAOC group, the most significant (P = 0.0001) predictors of OS in univariate analysis were age, histological type, observation time for endometriosis, and distribution of endometriosis. In the non-EAOC group, such significant predictors were age, residual tumor, and type of therapy. In the multivariate (Cox) model, age and FIGO stage were the only two significant independent prognostic factors shared by these two series. In addition, histological type and type of therapy proved to be significant independent predictors in the non-EAOC series. CONCLUSIONS: These data suggest that EAOC deviates from the non-EAOC in many of its key biological characteristics. The implications of these data in the diagnosis, treatment policy, and prognostication still require confirmation by further studies, however.

Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3.

Mice lacking suppressor of cytokine signaling 3 (SOCS3) exhibited embryonic lethality with death occurring between days 11 and 13 of gestation. At this stage, SOCS3(-/-) embryos were slightly smaller than wild type but appeared otherwise normal, and histological analysis failed to detect any anatomical abnormalities responsible for the lethal phenotype. Rather, in all SOCS3(-/-) embryos examined, defects were evident in placental development that would account for their developmental arrest and death. The placental spongiotrophoblast layer was significantly reduced and accompanied by increased numbers of giant trophoblast cells. Delayed branching of the chorioallantois was evident, and, although embryonic blood vessels were present in the labyrinthine layer of SOCS3(-/-) placentas, the network of embryonic vessels and maternal sinuses was poorly developed. Yolk sac erythropoiesis was normal, and, although the SOCS3(-/-) fetal liver was small at day 12.5 of gestation (E12.5), normal frequencies of erythroblasts and hematopoietic progenitor cells, including blast forming unit-erythroid (BFU-E) and, colony forming unit-erythroid (CFU-E) were present at both E11.5 and E12.5. Colony formation for both BFU-E and CFU-E from SOCS3(-/-) mice displayed wild-type quantitative responsiveness to erythropoietin (EPO), in the presence or absence of IL-3 or stem cell factor (SCF). These data suggest that SOCS3 is required for placental development but dispensable for normal hematopoiesis in the mouse embryo.