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Placental implantation anomalies in first-trimester abortions may determine severe bleeding leading to hysterectomy. There are very few cases of urgent hysterectomy post-abortion reported in the literature, related to placenta accreta spectrum, but in any of them is considered association with benign trophoblastic lesions. We report the case of a woman, who underwent surgical voluntary abortion by vacuum aspiration during first trimester, without any apparent surgical complications. Immediately, after this procedure, the patient had massive vaginal bleeding; an emergency hysterectomy was performed. Histological examination showed an exaggerated placental site (EPS). Morphological findings describe a trophoblastic tumor-like lesion, which differs from placenta accreta and often considered an asymptomatic occasional feature. Proliferative index, evaluated by double immunostain for CK8-18 and Ki-67, was unremarkable (

Background: Intimal sarcomas are rare malignant mesenchymal tumors arising from the heart and large blood vessels. Their intraluminal growth leads to vascular obstructive symptoms and peripheral neoplastic embolization. Direct infiltration of the lungs or metastases to the pulmonary system, occur in 40% of cases and extrathoracic spread is frequent, also in presentation. Intussusception is an unusual event in adults, accounting for Case Presentation: We describe a rare case of a 50-year-old man suffering of bowel obstruction due to intussusception sustained by a small bowel metastasis of a primary cardiac intimal sarcoma. One year and a half before the onset of abdominal symptoms, a grade II intimal sarcoma was removed from his left atrium and consequently he followed a chemotherapy protocol. Four months later a CT scan revealed local recurrence. Eighteen months after heart surgery he referred to the ER with abdominal pain. CT scan showed an ileal intussusception and the patient was scheduled for surgery. A tract of 10 cm ileus was removed containing an intramural polypoid solid mass. Histological analyses revealed a grade II intimal sarcoma consistent with his first diagnosis.Conclusion: Primary heart tumors are late found and often partially resected, therefore metastatic pathways are to be expected. Adult small bowel intussusception is a rare event and caused by a malignancy in one third of cases. Therefore, our recommendation is to always resect the tract involved in order to perform a proper diagnosis.

Skin manifestations of COVID-19 infections are diverse and are new to the dermatology community. We had the opportunity to examine the clinical and histopathological features of several patients who were divided into 3 groups. The first group included 8 COVID-19–positive patients who were hospitalized and quarantined at home. The second group included children and young adults who presented with chilblain erythema, erythema multiforme, and urticaria-like lesions. This group of patients was negative for the COVID-19 gene sequences by polymerase chain reaction but had a high risk of COVID-19 infection. The third group included clinically heterogeneous and challenging lesions. These patients were not subject to either polymerase chain reaction tests or serological analyses because they sought dermatological attention only for a dermatosis. The histopathological analysis of these cases showed a wide spectrum of histopathological patterns. What appears to be constant in all skin biopsies was the presence of prominent dilated blood vessels with a swollen endothelial layer, vessels engulfed with red blood cells, and perivascular infiltrates, consisting mainly of cytotoxic CD8+ lymphocytes and eosinophils. In 2 cases, there was diffuse coagulopathy in the cutaneous vascular plexus. In the early phases of the disease, there were numerous collections of Langerhans cells in the epidermis after being activated by the virus. The presence of urticarial lesions, chilblains, targetoid lesions (erythema multiforme–like lesions), exanthema, maculohemorrhagic rash, or chickenpox-like lesions associated with the histopathological features mentioned previously should cause clinical dermatologists to suspect the possibility of COVID-19 infection, especially in patients with fever and cough.

Summary About one-third of endometrial carcinomas (ECs), mainly of endometrioid histology, harbor the mismatch repair (MMR) defects and microsatellite instability (MSI). Among these, ECs arising in women with Lynch syndrome (LS) account for a large proportion. To date, no somatic genetic analyses have been published comparing LS-ECs with sporadic ECs. In this work, we examined the mutational profiles of a well-characterized series of sporadic and LS-related ECs, performing exonic targeted sequencing of 16 genes mainly involved in MSI ECs. Next-generation sequencing analysis was performed in 35 ECs on the MiSeq platform (Illumina, San Diego, CA), and the mutational profile was analyzed integrating molecular and immunohistochemical data. PTEN, ARID1A, and ARID2 were the most frequently mutated genes regardless of MSI status or family history. MSI ECs showed a higher mutational load than MMR-proficient cases, exhibiting an MMR-deficient mutational signature. Among MSI tumors, LS-related and sporadic ECs exhibited similar mutational profiles, with MSH2 as the most commonly mutated gene. KRAS mutations seemed to be more common in sporadic MSI ECs than in LS-related ECs even if further studies are needed to confirm this finding. MMR-deficient ECs carried a higher mutational load and an excess of C>T transitions compared with MMR-proficient ECs, suggesting that the use of a small gene panel may be adequate to highlight significant differences between these 2 groups. An integrated analysis of genetic and epigenetic features of LS-related and sporadic ECs provides useful insights into disease biology and diagnostic classification of these tumors.

Microsatellite instability (MSI) testing is tricky in gynaecological cancers (GC). Thus, we aimed to describe the instability patterns to improve MSI test interpretation in sporadic and hereditary GCs. Ninety-five cases, including uterine and ovarian cancers, with known genetic and immunohistochemical (IHC) features, were analysed for MSI by a mononucleotide repeats pentaplex (MRP). We identified 13 ambiguous cases that did not fully meet MSI criteria (‘borderline’ cases, B-MSI), which were mainly represented by MSH2/MSH6-deficient and Lynch syndrome cases. Also, we evaluated nine additional loci of candidate MSI markers that did not improve the detection of MSI cases, but might be useful for discordant or borderline samples. In conclusion, although MSI and IHC test are highly concordant, a subset of ambiguous MSI cases deserves a careful interpretation in particular when MSH2/MSH6 are involved.RPL22andSRPRtesting may be useful to integrate MRP panel for the analysis of critical cases.

Primary marginal zone B-cell MALT-type lymphomas of the uterine corpus are exceedingly rare entities, with only 6 cases reported in the literature to date. We present the additional case of a 70-yr-old white woman who underwent a laparoscopic total hysterectomy with bilateral salpingo-oophorectomy for an asymptomatic ovarian cyst. At microscopic examination, endometrial samples showed a dense, nodular lymphocytic infiltrate, suggestive of a lymphoproliferative disorder. Morphology, immunohistochemistry, and molecular analysis supported the diagnosis of MALT-type lymphoma of the endometrium. Benign reactive conditions, such as endometritis and other small B-cell lymphomas were ruled out. Moreover, we investigated the pathogenesis of our case, focusing on Chlamydia trachomatis infection, chromosomal translocations affecting the NF-kB pathway, and discussing the role of autoimmunity in the development of MALT-type lymphomas.

Background: While the association between anxiety and postpartum depression is well known, few studies have investigated the relationship between these two states and parenting stress. Furthermore, a number of studies have found that postpartum depression affects mother-infant emotion regulation, but there has been only one study on anxiety and emotion regulation and no studies at all on parenting stress and emotion regulation. Therefore, the primary aim of our study is to identify, in a community sample of 71 mothers, the relationship between maternal depression, anxiety, and parenting stress. The second aim is to examine the relationship between anxiety, postpartum depression, and parenting stress and mother-infant emotion regulation assessed at 3 months. Methods: Mother-infant interaction was coded with a modified version of the Infant Caregiver and Engagement Phases (ICEP) using a microanalytic approach. The Edinburgh Postnatal Depression Scale (EPDS), State-Trait Anxiety Inventory (STAI), and Parenting Stress Index-Short Form (PSI-SF) were administered to the mothers to assess depression, anxiety, and parenting stress, respectively. Results: Analysis revealed correlations between anxiety and depression, showing that parenting stress is associated with both states. In a laboratory observation, depression was correlated with both negative maternal states and negative dyadic matches as well as infant positive/mother negative mismatches; anxiety was correlated with both negative maternal states and infant negative states as well as mismatches involving one of the partners having a negative state. Multiple regression analysis showed that anxiety is a greater predictor than depression of less adequate styles of mother-infant emotion regulation. Parenting stress was not shown to predict such regulation.

ObjectiveRecent data from the literature indicate gynecological cancers (GCs) as sentinel cancers for a diagnosis of Lynch syndrome (LS). Clinical approaches to identifying LS have low sensitivity, whereas somatic tests on GCs may be a more sensitive and cost-effective strategy.MethodsA series of 78 GCs belonging to 74 patients sent to the Genetic Counselling Service were investigated using microsatellite instability, immunohistochemical expression of mismatch repair (MMR) genes, and MLH1 promoter methylation.ResultsThe presence of microsatellite instability was observed in 67.5% of GCs, and the absence of immunohistochemical expression of at least 1 of the 4 MMR proteins was observed in 71.4% of GCs, showing 96.1% concordance between the methods. Methylation analysis using methylation specific multiplex ligation-dependent probe amplification performed on 35 samples revealed MLH1 promoter hypermethylation in 18 cases (54%). Molecular analysis identified 36 LS carriers of MMR variants (27 pathogenetic and 9 variants of uncertain significance), and, interestingly, 3 LS patients had MLH1 methylated GC.With regard to histological features, LS-related GCs included endocervical cancers and also histological types different from the endometrioid cancers. The presence of peritumoral lymphocytes in GCs was statistically associated with LS tumors.ConclusionsSomatic analysis is a useful strategy to distinguish sporadic from LS GC. Our data allow the identification of a subset of LS patients otherwise unrecognized on the basis of clinical or family history alone. In addition, our results indicate that some clinicopathological features including age of GC diagnosis; presence of peritumoral lymphocytes; isthmic, endocervical sites, and body mass index value could be useful criteria to select patients for genetic counseling.

Background: A compromised base excision repair (BER) promotes carcinogenesis by accumulating oxidative DNA-damaged products as observed in MUTYH-associated polyposis, a hereditary colorectal cancer syndrome marked by adenomas and cancers with an accumulation of 8-oxoguanine. Remarkably, DNA global demethylation has been shown to be mediated by BER, suggesting a relevant interplay with early colorectal tumourigenesis. To check this hypothesis, we investigated a cohort of 49 adenomas and 10 carcinomas, derived from 17 MUTYH-associated polyposis patients; as adenoma controls, we used a set of 36 familial adenomatous polyposis and 24 sporadic polyps. Methods: Samples were analysed for their mutational and epigenetic status, measured as global LINE-1 (long interspersed nuclear element) and gene-specific LINE-1 MET methylation by mass spectrometry and pyrosequencing. Results: MUTYH-associated polyposis adenomas were strikingly more hypomethylated than familial adenomatous and sporadic polyps for both DNA demethylation markers (P=0.032 and P=0.007 for LINE-1; P=0.004 and P

Ovarian carcinosarcomas (OCS), also known as malignant mixed mesodermal/Mullerian tumors, are rare neoplasms (1%-4% of all malignant ovarian tumors) composed of high-grade malignant epithelial and mesenchymal elements. OCS occurs in older women. It is associated with a poor outcome and is usually not involved in inherited cancer syndromes. We present 2 cases of OCS; one arising in a patient with a pathogenetic BRCA1 mutation and the other in a woman affected by Lynch Syndrome (LS) carrying a MSH6 germline mutation. To the best of our knowledge, this is the first time that this second type of case has been reported. In this study, we investigated somatic impairment of the wild-type BRCA1 and MSH6 alleles in the OCS of these 2 patients. We also explored in both OCS, the occurrence of TP53 loss of function, which is a genetic alteration known to occur in BRCA-linked ovarian tumorigenesis but not in LS tumors. Moreover, we also provide further data about the histogenesis of OCS.

Objective To evaluate the risk factors potentially involved in the development of cervical intraepithelial neoplasia (CIN) recurrence after cervical conization in a long-term follow-up period. Study design Consecutive patients with histologically proven CIN who had undergone either cold knife conization or a loop electrosurgical excision procedure were enrolled and scheduled for serial follow-up examinations over a 10-year period. Data were stored in a digital database. Multivariate analysis was performed to identify factors for recurrence. Results Between January 1999 and December 2009, 282 patients fulfilled the inclusion criteria and were included in the final statistical analysis. After a median follow-up of 26.7 months (range 6–100), 64 (22.7%) women developed histologically confirmed recurrence. The 2-year recurrence-free survival was 83.7% and 66.7% for women with negative and positive margins, respectively ( p = 0.008). The 5-year recurrence-free survival was 75.4% and 50.3% for patients with negative and positive margins, respectively ( p = 0.0004). Positive surgical margin was the most important independent predictor of recurrence [HR 2.5 (95%CI 1.5–4.5), p = 0.0007; Wald 11.338]. After multinomial logistic regression the indication for conization based on persistent CIN1 was the only independent predictor for negative margin [OR 0.3 (95%CI 0.1–0.7), p = 0.008]. Conclusions Our study demonstrated that the surgical margin status represents the most important predictor for CIN recurrence after conization. After excisional therapy, close follow-up is mandatory for the early detection of recurrent disease. The identification of risk factors for recurrence may guide clinical decision-making on expectant management versus re-intervention.

A recent body of evidence indicates an active role for stromal (mis)-regulation in the progression of neoplasias. Within this conceptual framework, genes belonging to the growing but still poorly characterized class of tumor antagonizing/malignancy suppressor genes (TAG/MSG) seem to play a crucial role in the regulation of the cross-talk between stromal and epithelial cells by controlling malignant growth in vivo without affecting any cancer-related phenotype in vitro. Here, we have functionally characterized the human RNASET2 gene, which encodes the first human member of the widespread Rh/T2/S family of extracellular RNases and was recently found to be down-regulated at the transcript level in several primary ovarian tumors or cell lines and in melanoma cell lines. Although we could not detect any activity for RNASET2 in several functional in vitro assays, a remarkable control of ovarian tumorigenesis could be detected in vivo. Moreover, the control of ovarian tumorigenesis mediated by this unique tumor suppressor gene occurs through modification of the cellular microenvironment and the induction of immunocompetent cells of the monocyte/macrophage lineage. Taken together, the data presented in this work strongly indicate RNASET2 as a previously unexplored member of the growing family of tumor-antagonizing genes.

Background Treatment of pulmonary recurrence from colorectal cancer involving the main bronchus usually entails palliation using interventional bronchoscopy, because the prognosis is generally very poor. Surgical experience has clarified that in this setting pneumonectomy should only be performed in carefully selected patients showing favorable prognostic profiles (defined by low carcinoembryonic antigen serum levels pre-thoracotomy), solitary and completely resectable pulmonary metastasis, and long disease-free intervals. In the few long-term survivors after pneumonectomy for late-recurrent colorectal cancer, the disease has a relatively indolent metastatic course and genetic and epigenetic profiling may provide further insight regarding tumor evolution. Case presentation We describe a rare case of late hilar-endobronchial and lymph nodal recurrence of rectal cancer, sequential to hepatic metastasectomy, that we successfully treated with pneumonectomy and chemotherapy (leucovorin, 5-fluorouracil and oxaliplatin regimen); the patient achieved 7-year relapse-free survival after lung metastasectomy and 24-year overall survival after primary rectal cancer resection. To our knowledge, this is the longest survival reported after sequential liver resection and pneumonectomy for recurrent colorectal cancer. In our case the primary rectal cancer and its recurrences showed identical immunohistochemical patterns. The primary rectal cancer and the matched metastases (hepatic, pulmonary and lymph nodal) demonstrated no KRAS, NRAS, BRAF and PIK3CA mutations, a microsatellite stable phenotype, and no tumor protein p53 alterations or recurrent copy number alterations on chromosome 8. High genetic concordances between the paired primary tumor and metastases suggest that the key tumor biological traits remained relatively conserved in the three metastatic sites. Minor differences in gene specific hypermethylation were observed between the primary tumor and lung and nodal metastases. These differences suggest that epigenetic mechanisms may be causally involved in the microenvironmental regulation of cancer metastasis. Conclusion The exceptionally long survival of the patient in our case study involving favorable clinical features was related to an excellent response to surgery and adjuvant chemotherapy; however, genetic or epigenetic factors that remain unidentified cannot be excluded as contributory factors. Our findings support the concept of a common clonal origin of the primary cancer and synchronous and late metastases, and suggest that aberrant DNA methylation may regulate tumor dormancy mechanisms.

Objective To assess whether pelvic lymphadenectomy at surgical staging for endometrial carcinoma is an independent risk factor for the occurrence of postoperative complications. Methods Women with uterine cancer who underwent radical abdominal hysterectomy type I or II of Piver–Rutledge with or without pelvic lymph nodes dissection were considered. The occurrence of intraoperative and early postoperative complications (deep vein thrombosis, lymphocysts, febrile morbidity, extraoperative site infections, wound dehiscence, rela-parotomy, and death) was prospectively recorded. Non parametric tests, receiver characteristic curve analysis, and multiple logistic regressions were used for statistical purposes. Results Two hundred six subjects were enrolled, of whom 133 underwent pelvic lymphadenectomy. The rate of postoperative complications was 26.7% (55 of 206). Women with complications had a higher median (range) number of lymph nodes removed than those without complications (17 [3–62] versus 11 [1–74], P

Ovarian metastases from colorectal carcinoma frequently mimic primary ovarian carcinomas. The present study was performed to identify possible criteria helpful in differential diagnosis. Twenty-three ovarian metastases from colorectal carcinomas and 23 primary ovarian carcinomas were evaluated clinicopathologically and immunostained with antigastric M1 antigen, cathepsin E, CA125, vimentin, estrogen and progesterone receptors, cytokeratins 7 and 20, and alpha-inhibin antibodies. We performed a conventional and molecular cytogenetic study on 5 ovarian metastases from colorectal carcinoma using direct preparation, Q banding techniques, and fluorescence in situ hybridization. Integration of clinicopathologic, immunohistochemical, and cytogenetic features is helpful for the differential diagnosis of metastases of colorectal carcinomas from primary ovarian carcinomas. Bilaterality, extrapelvic spreading, high mitotic index, and cytokeratin 20 immunoreactivity, and lack of M1, CA125, and cytokeratin 7 immunoreactivity favor the diagnosis of ovarian metastases from colon carcinomas. The identification of 13q gain as a peculiar, sensitive, and specific marker of colorectal carcinomas seems relevant.

Metastases to the pituitary occur more frequently in patients with widespread cancer and mainly involve the posterior lobe. A few cases of metastatic carcinoma to a pituitary adenoma have been described so far. Here, the authors present an additional case of a clear cell renal cell carcinoma (CCRCC) metastatic to a FSH/LH/α-subunit pituitary adenoma and systematically review the literature. Immunohistochemistry and electron microscopy were performed to characterize both neoplastic components at the morphological level. Moreover, it was hypothesized that expression of VEGF and of the corresponding receptor VEGFR1 could be implicated in the development of the carcinomatous metastasis within the adenoma.

We report a rare case of an ovarian mucinous cystadenoma in which there were peculiar neuroendocrine micronests composed of gastrin-immunoreactive cells. There was no clinical evidence of hypergastrinemia. The mucinous component of the neoplasm was represented by columnar cells mostly expressing a gastric phenotype with MUC5AC and claudin 18 positivity, which was consistent with the presence of interspersed gastrin cells. The tumoral stroma displayed areas of luteinization with cells intensely positive for α-inhibin, MART-1 and calretinin.

Lynch syndrome is a genetic disease, caused by a germ-line mutation in a mismatch repair gene, related to an increased risk of developing colorectal and extracolonic cancer. Despite that, the incidence of primary peritoneal cancer after adnexectomy remains unknown. We here report a case of primary peritoneal cancer in a woman affected by Lynch syndrome who underwent hysterectomy+salpingo-oophorectomy for endometrial cancer 13 yr before. Morphology and immunophenotype allowed to differentiate peritoneal malignancy from the previously diagnosed endometrial carcinoma. Physicians should be aware of the potential risk of primary peritoneal cancer in women affected by Lynch syndrome, despite previous prophylactic surgery.

Objective Increased activity of Sp family of transcription factors is a frequent and critical event in cancer development and progression. Genes governing tumor growth, invasion and angiogenesis are regulated by Sp factors, like Sp1, Sp3 or Sp4, and are frequently over-expressed in tumors. Targeting Sp factors has been explored as a therapeutic approach. Mithramycin (MTM) is a natural antibiotic that binds DNA and inhibit Sp1-dependent transcription. New analogues, named MTM-SDK and MTM-SK, were recently obtained by genetic engineering of the MTM biosynthetic pathway and have demonstrated improved transcriptional and antiproliferative activity in ovarian cancer cell lines in vitro . In the present study we evaluated the activity of the new compounds in human ovarian cancer xenografts. Methods Expression of Sp1 and target proteins in ovarian cancer specimens and tumor xenografts was assessed by immunohistochemistry. Drug-induced silencing of Sp1-regulated genes in cells and tumor xenograft samples was assessed by quantitative RT-PCR. Toxicity and antitumor activity of the compounds were investigated in healthy and tumor-bearing immunocompromised mice, respectively. Results Expression of Sp1 was frequently increased in human epithelial ovarian cancers. MTM-SDK and MTM-SK acted as potent inhibitors of Sp1-dependent transcription both in vitro and in tumor xenografts. Both compounds were well tolerated even after prolonged administration and delayed growth of ovarian tumor xenografts. MTM-SDK was particularly effective against orthotopic tumors leading to a significant increase of survival and delay of tumor progression. Conclusions MTM-SDK and MTM-SK show relevant activity in vivo and represent interesting candidates for treatment of ovarian cancers.

The estrogen receptor (ER)/progesterone receptor (PR)-negative breast carcinomas (BCs) encompass three molecular subtypes: one with human epidermal growth factor receptor 2 (HER) overexpression, one normal like, and the triple negative. The androgen receptor (AR) is expressed in 70–90% of invasive BCs. The aim of our study is to detect the expression of AR in a series of ER/PR-negative BCs to ascertain if there is clinical significance in relation to BC molecular subtypes. A immunohistochemical study for all receptors and cytokeratin expression was performed in 232 cases of ER/PR-negative BCs. According to cytokeratin expression, BCs were classified into two groups: luminal-type BCs (44.2%) and basal-like-type BCs (55.8%). According to the expression of HER2, 59.3% were triple-negative BCs (when ER, PR, and HER2 were negative) and 40.7% were HER2-positive BCs. AR expression was observed in 128 tumors (56.6%). One hundred and ten cases (48.8%) had >10% and 18 (7.8%) had

Aim This study examines the trends and outcomes of breast cancer patients who have undergone surgical procedures at the Department of Surgical Sciences, University of Insubria, Varese, Italy. It also identifies the factors that contributed to the reduction of the breast tumor size over a 13-year period at a tertiary referral center. Methods All breast cancer operations performed at the Department of Surgical Sciences, University of Insubria, Varese, Italy, from January 1992 to June 2005 were examined and data from their surgical pathology reports were also analyzed, using a prospective database. A longitudinal study was performed to compare and analyze the pathological data during three consecutive time periods. The periods were from 1992 to 1996, 1997 to 1999, and 2000 to 2005. Surgical and pathological outcomes included age of the patient at the time of the diagnosis, partial breast resections, mastectomies, axillary lymphadenectomies, tumor size, histological type and stage, and lymph node status. Results The study group was comprised of 3050 patients who underwent breast resection between 1992 and 2005. Quadrantectomy was the preferred surgical approach in 1759 patients (58%). Throughout the longitudinal study, the tumors measuring less than 1cm increased from 13.4% to 15.4%; the number of tumors diagnosed at stage I increased from 44.1% to 56.8%; the most frequent histological type was ductal carcinoma; the number of ductal carcinomas in situ (DCIS) increased from 4% to 6%; and the incidence of lymphadenectomies decreased from 71.6% to 52.5%. Perioperative factors that correlated with the decreased size of the tumor over time were: screening, improvement of diagnostic and therapeutic techniques, and the increased operative use of sentinel lymph node biopsy (SLNB). Conclusions There has been an evolving refinement in surgical technique and perioperative management of breast cancer patients undergoing surgical resection at the Department of Surgical Sciences, University of Insubria, Varese, Italy, during the past decades. The present longitudinal study on 3050 surgical breast cancer patients confirmed the progressive reduction of tumor size at the time of the diagnosis. Perioperative factors that correlated with the decreased tumor size over time were mammography screening, improvement of diagnostic and therapeutic techniques, and the use of SLNB. Furthermore, the study showed that the progressive reduced number of useless axillary lymphadenectomies was mainly due to the increased intraoperative use of axillary SLNB.

Objective. It is uncertain whether pregnancy influences the natural history of cervical intraepithelial neoplasia (CIN). Our aim was to evaluate the evolution of CIN in pregnant women. Design. Prospective study. Setting. Department of Obstetrics and Gynaecology, University of Insubria, Italy. Population. Women with histological CIN during pregnancy. Methods and main outcome measures. Between 2003 and 2007, women with an abnormal Pap-smear during pregnancy underwent colposcopy. Patients with histological CIN were followed during pregnancy with colposcopy every 8 weeks and post-partum evaluation was scheduled 3-6 months after delivery. Women with post-partum histological diagnosis of CIN 2-3 underwent conization. To understand the impact of pregnancy on the evolution of CIN, women with CIN 1 discovered during pregnancy were compared to a group of non-pregnant fertile patients with first diagnosis of CIN 1. Results. A total of 78 women were included: 36 (46.2%) with CIN 2-3 and 42 (53.8%) with CIN 1. In women with CIN 2-3, no invasion was suspected during pregnancy and at post-partum evaluation, no invasive or microinvasive cancer, and 19 (52.7%) persistent CIN 2-3, and 17 (47.3%) regressions were diagnosed. In the group of CIN 1, we recorded six (14.3%) progressions to CIN 2-3, seven (16.6%) persistent CIN 1 and 29 (69%) regressions. The control group of non-pregnant women had a lower regression rate (37/76: 48.7%) in comparison to pregnant women (p=0.03). Conclusions. Expectant management for CIN 2-3 diagnosed during gestation is safe. When discovered during pregnancy, CIN 1 has a significantly higher tendency to spontaneous regression in comparison to non-pregnant condition.

M1, a mucin antigen, and cathepsin E, an aspartic proteinase, are both expressed in normal gastric superficial-foveolar epithelial cells. In this study, we determined by immunohistochemical staining the prevalence of these antigens in 316 gastric cancers representative of the main histologic types and stages of the disease. M1 was expressed in 201 cases (64%) and cathepsin E was expressed in 235 cases (75%) of the 313 cases investigated. Both antigens were expressed more commonly in diffuse and mixed cancers than in glandular tumors. M1 was found in 64 of 83 (77%) diffuse cancers and in 48 of 59 (81%) mixed cancers, but in only 74 of 146 (51%) glandular cancers. For cathepsin E, the prevalence was 93% in diffuse cancer, 81% in mixed cancer, and 71% in the 143 glandular cancers examined. Among 25 mucoid tumors, 15 (60%) expressed M1 but only eight (32%) expressed cathepsin E. Overall, 262 (84%) of the tumors expressed at least one of these antigens and of these, 173 (66%) expressed both antigens. No significant difference in the prevalence of M1 or cathepsin E was found between early and advanced cancer or between metastatic and nonmetastatic cancer. The two markers differed in their intracellular localization. In superficial-foveolar cells, M1 immunostaining was concentrated in secretory granules, Golgi complex, and luminal mucous, whereas cathepsin E was found in the endoplasmic reticulum. Moreover, cathepsin E, but not M1, was found in the enterocytes of duodenal villi and, occasionally, in mucopeptic cells. Parallel histochemical and ultrastructural investigations confirmed the occurrence in gastric cancer of foveolar-type cells, manifested by periodic acid-Schiff- and/or alcian blue-reactive mucous granules having a punctate substructure. We conclude that superficial-foveolar cell differentiation is common in gastric cancer and is a major component of this type of tumor. However, pure foveolar cell differentiation is rare. Rather, most gastric cancers consist of cells exhibiting features of foveolar, intestinal, and mucopeptic cell lines.

Background Cervical carcinosarcomas are rare neoplasms; optimal treatment is unclear. Case 1 A 42-year-old woman underwent abdominal hysterectomy because of bleeding, anaemia and uterine fibromatosis. Histology showed a homologous carcinosarcoma of the cervix. Laparoscopic re-staging (pelvic lymphadenectomy, bilateral salpingo-oophorectomy) was negative for neoplasia. Adjuvant chemotherapy with ifosfamide and cisplatin was performed. At 48 months of follow-up, the patient is NED. Case 2 A 74-year-old woman reporting vaginal bleeding, with carcinosarcoma on the cervical biopsy, underwent radical hysterectomy, bilateral salpingo-oophorectomy, pelvic and paraortic lymphadenectomy. Histology confirmed a homologous carcinosarcoma of the cervix, stage IIb. Whole-pelvis irradiation and brachytherapy were carried out. Nine months later, the patient developed systemic recurrence and died of disease. Aggressive primary therapy can result in cure of early-stage cervical carcinosarcomas. Extracervical disease is associated with a poor prognosis.

Purpose: The methylation status of hMLH1, CDKN2A, and MGMT was investigated in a panel of synchronous cancers of the ovary and endometrium, fulfilling the clinicopathologic criteria for independent primary tumors to define the possible role of epigenetic mechanisms in the development of these cancers. Experimental Design: Bisulfite-converted DNA from 31 tumors (13 endometrial and 18 ovarian carcinomas) and from matched normal tissue of 13 patients was analyzed by a methylation-specific PCR assay at the CpG-rich 5′ regions of all three genes. In all tumors, we also investigated the presence of microsatellite instability and hMLH1 immunohistochemical expression in relation to hMLH1 hypermethylation status. Results: Methylation of hMLH1, CDKN2A, and MGMT was detected in 39%, 41%, and 48% of endometrial and ovarian tumors, respectively. hMLH1 hypermethylation was observed in all tumors of five patients, and it was invariably associated with loss of hMLH1 protein and presence of microsatellite instability. CDKN2A and MGMT methylation was randomly detected among both endometrial (45% and 24% of cases, respectively) and ovarian carcinomas (39% and 39% of cases, respectively). Concordant methylation at two or three genes was observed in 35% of cases. Conclusions: Epigenetic inactivation of hMLH1, CDKN2A, and MGMT may be a common and early event in the development of synchronous primary endometrial and ovarian carcinomas and may qualify as a marker of a field cancerization encompassing the ovary and endometrium. Detection of MGMT hypermethylation may be useful to define a set of gynecologic malignancies with a specific sensitivity to alkylating chemotherapy.

One of the most controversial issues in breast pathology is whether lobular neoplasia (LN) is a risk factor or a precursor lesion of invasive lobular carcinoma (ILC). This is consequent to the fact that no conclusive data on the biology of LN exist. Molecular studies of LN and ILC are scanty, variable, and not consistent. Clonality of 12 cases of LN and ILC present simultaneously in the same block has been studied. Cells from both lesions were obtained by microdissection and were studied for mitochondrial DNA (mtDNA), D-loop sequencing, and neighbor-joining trees. Eight of the same cases were studied with comparative genomic hybridization (CGH) array to have additional data consistent with mtDNA. In all cases, loss of heterozygosity was studied for D16S496,locus 16q22.1 related to e-cadherin. It appears that no fewer than eight cases were genetically very similar (clonal) with mtDNA. Seven of these cases appeared also clonal with CGH array. It is concluded that in the present series, LN and ILC are genetically related lesions in the majority of cases and that LN might be the precursor of ILC.

Fibrous and inflammatory lesions of the breast in patients with early-onset, longstanding insulin-dependent diabetes mellitus (IDDM) can lead to misdiagnosis because the clinical, mammographic, and sonographic findings simulate breast cancer. We report a case of diabetic fibrous mastopathy with suspicious clinical, imaging, and cytologic findings.

Alterations of DNA mismatch repair (MMR) genes are involved in carcinogenesis of sporadic and inherited human cancers characterised by instability of DNA microsatellite sequences (MSI). MSI tumours are usually identified using molecular analysis. In the present investigation, hMLH1 and hMSH2 immunohistochemistry was tested in order to evaluate the utility of this method in predicting MMR deficiency. Colorectal (72), gastric (68), endometrial (44) and ovarian (17) carcinomas were independently evaluated for familial history, histological type of tumour, MSI status and immunohistochemical results. Loss of expression of either hMLH1 or hMSH2 was observed in 51 of 55 (92.8%) MSI tumours, while 145 of 146 microsatellite stable (MSS) tumours expressed both the hMLH1 and hMSH2 gene products. Independently of tumour site, an overall agreement between immunohistochemical and molecular results was observed in 15 hereditary non-polyposis colorectal cancer-related tumours. Among sporadic tumours, only 2 of 60 colorectal and 2 of 66 gastric carcinomas, displaying MSI, expressed both hMLH1 and hMSH2 gene products. All 39 endometrial and 16 ovarian tumours presented a concordant molecular and immunohistochemical profile. These data show that immunohistochemistry is an accurate and rapid method to predict the presence of defective DNA MMR genes and to identify both sporadic and familial MSI tumours.

Fifty-one endometrial cancers were analyzed with regard to whether or how microsatellite instability (MI) was associated with the development of different types of endometrial malignant neoplasms. We investigated 6 loci previously reported as informative for colorectal cancer and a group of 8 loci located on 6q. Replication error (RER+) phenotype was detected in 10 of 51 (19.6%) endometrial cancers (ECs), all but one of which showed endometrioid differentiation. On the contrary, the RER+ phenotype was not detected in serous carcinomas and malignant mixed Müllerian tumors. MI was present in both early and advanced stage ECs. No correlation was found between age, grade, stage, familial pattern, mitotic index, and the RER+ phenotype of ECs. Only 1 of 8 endometrial carcinomas showing MI was associated with mutant p53 expression, while the majority of RER+ tumors were positive for estrogen and progesterone receptors. Our findings suggest that MI plays an early role in endometrial tumorigenesis and is significantly correlated with adenocarcinomas showing endometrioid features (EAs). The frequent involvement of the telomeric region of chromosome 6 in the MI of EA is an indication that this region may be crucial in the process of EA tumorigenesis.

OBJECTIVE Height and weight changes during the first 3 years of diabetes were prospectively followed in 152 diabetic children and adolescents. RESEARCH DESIGN AND METHODS The study sample consisted of 152 Caucasian diabetic patients (84 boys; 68 girls) followed from diabetes onset in the Paediatric Diabetes Unit and 80 Caucasian normal subjects (49 boys; 31 girls) assessed in the Outpatient General Paediatric Clinic of the same hospital for routine examination and not affected by problems that might influence growth. Diabetic patients and control subjects were consecutively enrolled in the study between 1989 and 1992; diabetic patients with positive markers for celiac disease (positive antiendomysial antibodies) and thyroid disease (positive antimicrosomial antibodies) or any other chronic disease were not considered in the study. Mean age of diabetic patients (8.9 ± 4.1 years) and control subjects (8.5 ± 4.2 years) at recruitment in the study was similar. RESULTS At onset of diabetes, the mean height expressed as the height standard deviation score (HSDS) was significantly greater than the expected values (P < 0.0001) and was independent of sex and pubertal stage. During the first 3 years of diabetes, HSDS decreased significantly (F = 6.9; P < 0.001). Meanwhile, growth velocity as standard deviation score (SDS) decreased significantly between the 1st and 2nd year (−0.12 ± 2.1; −0.76 ± 2.6, respectively; P < 0.05), but it was similar between the 2nd and 3rd year of diabetes. Weight expressed as SDS increased significantly during the first 2 years of diabetes but not thereafter. Height changes during the study period were independent from pubertal stage and sex. Metabolic control and insulin requirement, in our series, were not clearly related to height and weight changes. CONCLUSIONS Diabetic patients at onset of diabetes are taller than age- and sex-matched nondiabetic subjects. During the first years of the disease, linear growth decreases independently of metabolic control and weight changes.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated transcription factor. In addition to its canonical role in lipid and glucose metabolism, PPAR-gamma controls cell proliferation, death, and differentiation in several tissues. Here we have examined the expression of PPAR-gamma in ovarian tumors and the cellular and molecular consequences of its activation in ovarian cancer cells. PPAR-gamma was expressed in a large number of epithelial ovarian tumors and cell lines. The PPAR-gamma ligand ciglitazone inhibited the growth and clonogenic survival of ovarian cancer cells, inducing cell cycle arrest and cell death. Growth inhibition by ciglitazone was reversed by the PPAR-gamma antagonist GW9662, indicating the involvement of PPAR-gamma-dependent mechanisms. Microarray-based gene profiling revealed complex changes in the transcriptional program of ovarian cancer cells on treatment with ciglitazone and identified multiple pathways that may contribute to PPAR-gamma ligands' antitumor activity. Genes upregulated by ciglitazone were predominantly associated with metabolic, differentiation, and tumor-suppressor pathways, whereas downregulated genes were involved in cell proliferation, cell cycle, cell organization, and steroid biosynthesis. Collectively, our data indicate that PPAR-gamma activation by selective agonists is a valid strategy for ovarian cancer therapy and prevention, and should be tested alone and in combination with other anticancer drugs.

We investigated whether endometrial cancer (EC) cells can express fibrinogen. Consecutive patients treated for EC were enrolled (cases). A control group of women who had hysterectomy for benign conditions was identified in a case:control ratio of 4:1. Immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) were performed to identify the presence of fibrinogen and the mRNA of its three chains (α, β, γ) in the tissue specimens from both cases and controls. Sixteen EC cases and 4 benign controls were included. Immunohistochemistry failed in one case of EC. In 12/15 (80%) cases versus 0 controls, a moderate-to-intense positivity for fibrinogen was observed (p = 0.09; OR: 32.1; 95%CI: 1.4-752.9). Six (37.5%) women among the cases versus 0 controls expressed RNA for at least one chain of fibrinogen (p = 0.25). All the cases (6/6, 100%) with positive RT-PCR had moderate-to-intense positive immunohistochemistry. Molecular and immunohistochemistry show that some cases of EC have the capability to express fibrinogen and the mRNA of at least one of its chains.