Krukenberg Tumor Related to Gallbladder Cancer in a Young Woman: A Case Report and Review of the Literature.

A gallbladder tumor is a rare condition, which usually spreads to the liver, lymph nodes, and other organs. A Krukenberg tumor, derived from the biliary tract and gallbladder cancers (GBCs), is an uncommon finding in routine clinical practice. Here, a case of a young woman with a Krukenberg tumor related to a previous diagnosis of GBC is reported. Differential diagnosis of an ovarian malignant lesion is challenging for both clinicians and pathologists. In order to provide a proper diagnosis, integrated multidisciplinary management is essential. The occurrence of Krukenberg tumors should be evaluated in the management of GBC, even if this is rare in clinical practice.

Perinatal environment and endometriosis.

BACKGROUND/AIMS: Perinatal environmental exposure may affect fetal development and reprogram the developing organism for adult-onset disease. In this case-control study, we aimed at assessing this pathogenetic model in endometriosis. METHODS: Consecutive patients with a first laparoscopic diagnosis of endometriosis were selected as cases. Controls were women who underwent laparoscopy during the same study period, but who were found to be free of the disease. Selected women and their mothers were interviewed. RESULTS: Ninety-one women with endometriosis and 82 controls were selected. Handedness, a variable believed to be determined prenatally by hormonal environment in utero significantly differed between the study groups. Women with the disease were less likely to be left- or mixed-handed (adjusted OR: 0.24, 95% CI: 0.08-0.71). In contrast, we failed to detect any association with birth order, maternal age, smoking, nausea, weight gain, prematurity, birth weight and breast-feeding. CONCLUSIONS: Our results generally do not support the view that in utero exposure may play a major role in the pathogenesis of endometriosis. The association with handedness, however, is intriguing in this regard and deserves further investigation.

Oral contraceptives and risk of endometriosis: a systematic review and meta-analysis.

BACKGROUND: Combined oral contraceptives (OCs) inhibit ovulation, substantially reduce the volume of menstrual flow and may hypothetically interfere with implantation of refluxed endometrial cells. The aim of this review is to establish if OC use influences the risk of endometriosis. METHODS: We performed a MEDLINE search to identify all studies published in the last four decades (January 1970 to January 2010) in the English language on the relationship between OC exposure and risk of endometriosis. Two authors abstracted data on standardized forms. RESULTS: We identified 608 potentially relevant studies and 18 studies (6 cross-sectional, 7 case-control and 5 cohort) were selected. Pooling of the results derived from all the included reports independently from study design, yielded a common relative risk of 0.63 [95% confidence interval (CI), 0.47-0.85] for current OC users, 1.21 (95% CI, 0.94-1.56) for past users and 1.19 (95% CI, 0.89-1.60) for ever users. Methodological drawbacks, such as uncertain temporal relationship between exposure and outcome in cross-sectional studies and suboptimal selection of controls in case-control studies, limit the quality of the available evidence. CONCLUSIONS: The risk of endometriosis appears reduced during OC use. However, it is not possible to exclude the possibility that the apparent protective effect of OC against endometriosis is the result of postponement of surgical evaluation due to temporary suppression of pain symptoms. Confounding by selection and indication biases may explain the trend towards an increase in risk of endometriosis observed after discontinuation, but further clarification is needed. To date, the hypothesis of recommending OCs for primary prevention of endometriosis does not seem sufficiently substantiated.

Endometriosis and estroprogestins: the chicken or the egg causality dilemma.

Dysmenorrhea as a reason to initiate estroprogestins is significantly more common in women with endometriosis than in women without the disease. This might explain the previously reported mild association between endometriosis and past use of oral contraceptives.

'Here comes the sun': pigmentary traits and sun habits in women with endometriosis.

BACKGROUND: There is limited but interesting evidence suggesting that endometriosis may be associated with specific pigmentary traits and sun habits. In this case-control study, we aimed to further clarify this point. MATERIALS AND METHODS: Consecutive patients with a first laparoscopic diagnosis of endometriosis according to Holt and Weiss criteria were selected as cases. Controls were women who underwent laparoscopy during the same study period, but who were found to be free of the disease. Selected women were interviewed and examined by two trained physicians. An unconditional logistic regression model that included age and baseline variables significantly differing between the two groups was used to estimate the adjusted odds ratios (OR). RESULTS: There were 98 women with endometriosis and 94 controls selected. Overall, women with the disease had a more photo-sensitive phenotype and were exposed less to sun or ultraviolet radiation. A statistically significant difference was documented for eye color, skin reaction to first sun exposure, freckles score and the use of tanning creams. The adjusted OR (95% CI) for the disease was 1.95 (1.02-3.72) for women with green/blue eyes, 2.19 (1.12-4.28) for those who frequently/always had skin burn reaction to first sun exposure, 5.67 (1.98-16.24) for those with a higher number of freckles and 0.35 (0.15-0.85) for the use of tanning creams. CONCLUSIONS: Women with endometriosis have a specific photo-sensitive phenotype and protect themselves more from the sun. This latter habit may be consequent to the former. We speculate that there is a shared genetic background between pigmentation and endometriosis.

Comparison of contraceptive ring and patch for the treatment of symptomatic endometriosis.

OBJECTIVE: To evaluate the efficacy and tolerability of a contraceptive vaginal ring and transdermal patch in the treatment of endometriosis-associated pain. DESIGN: Patient preference cohort study. SETTING: Academic center. PATIENT(S): Two-hundred and seven women with recurrent moderate or severe pelvic pain after conservative surgery for symptomatic endometriosis. INTERVENTION(S): Continuous, 12-month treatment with a vaginal ring supplying 15 mcg of ethinyl E and 120 mcg of etonogestrel per day or a transdermal system delivering 20 mcg of ethinyl E and 150 mcg norelgestromin per day. MAIN OUTCOME MEASURE(S): Satisfaction with treatment. RESULT(S): One-hundred and twenty-three women preferred the ring, and 84 preferred the patch. Forty-four ring users (36%) and 51 patch users (61%) withdrew. Thirty-six of 79 subjects (46%) in the ring group and 14 of 33 (42%) in the patch group shifted from continuous to cyclic use because of irregular bleeding. Pain symptoms were reduced by both treatments, with the ring being more effective than the patch in patients with rectovaginal lesions. According to an intention-to-treat analysis, 88 of 123 ring users (72%) and 40 of 84 patch users (48%) were satisfied with the treatment received. CONCLUSION(S): Patients who preferred the ring were significantly more likely to be satisfied and to comply with treatment than those who chose the patch. Both systems were associated with poor bleeding control when used continuously.

Repetitive surgery for recurrent symptomatic endometriosis: what to do?

In spite of the increasing number of operative laparoscopies performed for endometriosis associated pelvic pain, postoperative symptomatic recurrences are very common. Reoperation is often considered the best treatment option, but the extent and duration of the effect of second-line surgery is still unclear. The best available evidence has been reviewed in order to define the results of repetitive conservative surgery, the effects of pelvic denervating procedures and postoperative medical treatments, as well as the long-term outcome of definitive surgery. Because of the paucity of published data, estimating the real risk of symptomatic recurrence and need for reoperation after repetitive conservative surgery for endometriosis is very difficult. Based on the limited information available, the long-term outcome appears suboptimal, with a cumulative probability of pain recurrence between 20% and 40%, and of a further surgical procedure between 15% and 20%. These figures are probably an underestimate related to drawbacks in study design, exclusions of dropouts, and publication bias and should be considered with caution. Systematic complementary performance of denervating procedures in addition to reoperation cannot be recommended, as only a few symptomatic patients complain of predominantly midline, hypo-gastric pain. The outcome of hysterectomy for endometriosis-associated pain at medium-term follow-up seems quite satisfactory. Nevertheless, about 15% of patients had persistent symptoms, and 3-5% experienced worsening of pain. Concomitant bilateral oophorectomy reduced the risk of reoperation due to recurrent pelvic pain by six times. However, at least one gonad should be preserved in young women, especially in those with objections to the use of oestrogen-progestogens. Medical treatment appears to have limited and inconsistent effects when used for only a few months after conservative procedures. Data on the benefit of prolonged drug regimens with oral contraceptives or progestogen are lacking. The risk of recurrence of endometriosis during hormone replacement therapy seems marginal if combined preparations or tibolone are used and oestrogen-only treatments are avoided. The opportune surgical solution in women with recurrent symptoms after previous conservative procedures for endometriosis should be based on the desire for conception as well as on psychological characteristics. Studies on surgical management of recurrent rectovaginal endometriosis are warranted, due to the peculiar technical difficulties as well as the high risk of complications associated with this challenging disease form.

Endometriotic ovarian cysts negatively affect the rate of spontaneous ovulation.

BACKGROUND: A growing body of evidence suggests that ovarian reserve is damaged after excision of ovarian endometriomas. However, it may not be excluded that gonadal damage is at least partly caused by the very presence of an endometrioma per se, thus preceding surgery. To clarify this aspect, we set up a prospective study in women with monolateral endometriomas in order to assess the rate of ovulation in affected ovaries. MATERIALS AND METHODS: Seventy women with monolateral endometriomas who had not undergone previous adnexal surgery underwent serial ecographic examinations to determine the side of ovulation. RESULTS: Ovulation occurred in the affected ovary in 22 cases (31%; 95% CI: 22-43%). Assuming that the expected rate of ovulation in both ovaries in healthy women is similar, this difference is statistically significant (P = 0.002). CONCLUSION: The physiological mechanisms leading to ovulation are deranged in ovaries with endometriomas.

Surgery for deep endometriosis: a pathogenesis-oriented approach.

BACKGROUND: Deep endometriosis is usually associated with severe symptoms and constitutes a complex treatment challenge. METHODS: The available evidence has been revisited with the aim of defining an effective diagnostic workup and a safe surgical strategy based on pathogenetic findings. RESULTS: Vaginal, rectal, and bladder detrusor endometriosis appear to be caused by intraperitoneal seeding of regurgitated endometrial cells which implant in the posterior and anterior cul-de-sac and trigger an inflammatory process leading to adhesion of contiguous organs. Excision of posterior deep lesions implies removal of a fibrotic cast of the Douglas's pouch which may involve the posterior vaginal fornix and the rectal muscular layer, with a not negligible risk of major complications. Removal of full-thickness bladder detrusor endometriosis entails excision of the bladder dome or posterior wall, generally well above the trigone. Transurethral resection is contraindicated. A radical approach to obstructive uropathy is suggested, with resection of the stenotic ureteral tract and reimplantation with antireflux vesicoureteral plasty. CONCLUSION: Infiltrating endometriotic lesions appear to originate intraperitoneally sharing common pathogenetic mechanisms. Involvement of the intestinal and urologic apparatuses should be identified before surgery, in order to schedule intraoperative consultation and to inform the woman about the type of intervention required and its potential sequelae.

The second time around: reproductive performance after repetitive versus primary surgery for endometriosis.

After repetitive surgery for recurrent endometriosis, 20 of 89 (22%) women achieved spontaneous pregnancy, compared with 165 of 411 (40%) after first-line procedure (adjusted incidence rate ratio, 0.51; 95% confidence interval, 0.32 to 0.82), and the 12- and 24-month cumulative pregnancy rates were 14% and 26% in the former group compared with 32% and 38% in the latter. Among infertile patients at baseline, 13 of 67 (19%) conceived after reoperation compared with 98 of 290 (34%) after primary surgery (adjusted incidence rate ratio, 0.55; 95% confidence interval, 0.30 to 0.99), and the 12- and 24-month cumulative pregnancy rates were 13% and 22% in the former group and 25% and 30% in the latter.

Endometriosis: current therapies and new pharmacological developments.

Endometriosis is a chronic inflammatory condition that is responsive to management with steroids. The establishment of a steady hormonal environment and inhibition of ovulation can temporarily suppress ectopic implants and reduce inflammation as well as associated pain symptoms. In terms of pharmacological management, the currently available agents are not curative, and treatment often needs to be continued for years or until pregnancy is desired. Similar efficacy has been observed from the various therapies that have been investigated for endometriosis. Accordingly, combined oral contraceptives and progestins, based on their favourable safety profile, tolerability and cost, should be considered as first-line options, as an alternative to surgery and for post-operative adjuvant use. In situations where progestins and oral contraceptives prove ineffective, are poorly tolerated or are contraindicated, gonadotrophin-releasing hormone analogues, danazol or gestrinone may be used. Future therapeutic options for managing endometriosis must compare favourably against existing agents before they can be considered for inclusion into current practice. Finally, as reproductive prognosis is not ameliorated by medical treatment, it is not indicated for women seeking conception.

Chronic pelvic pain in women: etiology, pathogenesis and diagnostic approach.

Chronic pelvic pain (CPP), defined as non-cyclic pain of 6 or more months, is a frequent disorder that may negatively affect health-related quality of life. In women several causes are recognised, although in a not negligible proportion of patients a definite diagnosis cannot be made. Different neurophysiological mechanisms are involved in the pathophysiology of CPP. Pain may be classified as nociceptive or non-nociceptive. In the first case the symptom originates from stimulation of a pain-sensitive structure, whereas in the second pain is considered neuropatic or psychogenic. Patients history is crucial and is generally of utmost importance for a correct diagnosis, being sometimes more indicative than several diagnostic investigations. The main contributing factors in women with CPP can still be identified by history and physical examination in most cases. Many disorders of the reproductive tract, urological organs, gastrointestinal, musculoskeletal and psycho-neurological systems may be associated with CPP. Excluding endometriosis, the most frequent causes of CPP are: post-operative adhesions, pelvic varices, interstitial cystitis and irritable bowel syndrome. CPP is a symptom, not a disease, and rarely reflects a single pathologic process. Gaining women's trust and developing a strong patient-physician relationship is of utmost importance for the long-term outcome of care.

Medical, surgical and alternative treatments for chronic pelvic pain in women: a descriptive review.

Several causes of chronic pelvic pain (CPP) are recognised, but in many women a definite diagnosis cannot be made. Few randomised controlled trials on treatment of CPP have been conducted. In a Cochrane systematic review, only medroxy-progesterone acetate, counselling, a multidisciplinary approach and lysis of deep adhesions had a proven benefit. The aim of this descriptive review is to describe the management of CPP, which can focus on treating the pain itself, the underlying cause, or both. Combination drug therapy with medications with different mechanisms of action may improve therapeutic results. Pelvic denervating procedures should be indicated in selected circumstances, as the magnitude of the effect is undefined. Several alternative non-invasive treatments have been proposed including exercise programmes, cognitive and behavioural medicine, physical therapy, dietary modification, massage and acupuncture. When the woman has completed her family and particularly when pelvic varices have been demonstrated, hysterectomy can be considered after a careful pre-operative assessment. However, substantial pain relief may be achieved in no more than 60-70% of the cases. A minority of patients (3-5%) will experience worsening of pain or will develop new symptoms after surgery. Treatment of CPP, generally, requires acceptance of the concept of managing rather than curing symptoms.

Surgery for endometriosis-associated infertility: a pragmatic approach.

Laparoscopic treatment for endometriosis-associated infertility is gaining widespread popularity supported mostly by uncontrolled studies, but the purported benefit of surgery may be overvalued. We have therefore analysed the best available evidence with the aim of defining an approximate estimate of the effect size of conservative surgery for infertile women with endometriosis in various clinical conditions. The overall increase in post-operative likelihood of conception over background pregnancy rate may be estimated to be between 10 and 25%. The effect of surgery for peritoneal lesions is limited, and an estimate of benefit should be decreased by the fact that preoperative identification of the subjects actually with the condition is unfeasible. The benefit of excision of ovarian endometriomas is difficult to define due to multiple confounding factors and methodological drawbacks in the considered studies. Excision of rectovaginal endometriosis is of doubtful value and associated with worrying morbidity. The role of surgery before, after or as an alternative to IVF needs clarification. In conclusion, the absolute benefit increase of surgery for endometriosis-associated infertility appears smaller than previously believed. Complete and detailed information on risks and benefits of treatment alternatives must be offered to infertile patients to allow unbiased choices between possible options.

The role of myomectomy in fertility enhancement.

PURPOSE OF REVIEW: To review current available literature on the relationship between fibroids and infertility with particular emphasis on the benefits of myomectomy. Pregnancy complications related to the presence of these lesions and to their removal are also addressed. RECENT FINDINGS: There is a biological plausibility supporting a causal relationship between fibroids and infertility. From a clinical point of view, this association is mostly supported by studies comparing pregnancy rate following IVF in women with and without fibroids. The emerging view is that submucosal, intramural and subserosal fibroids interfere with fertility in decreasing order of importance. There is one randomized controlled trial supporting the benefits of myomectomy in infertile women with fibroids. The beneficial effects of surgery are further supported by insights from clinical series showing that the pregnancy rate following myomectomy is satisfactory and by the strong benefits documented in the few nonrandomized comparative studies. An increased rate of obstetric complications has been reported in women carrying fibroids. Data regarding the course of pregnancy in operated women are scanty. The most significant (although rare) complication is rupture of the uterus during pregnancy or labour. SUMMARY: At present, owing to the lack of adequately designed trials aimed to clearly establish that lesions benefit from surgery, a comprehensive and personalized approach should be adopted. The most important variables to be considered are the age of the woman, the characteristics of the fibroids, the concomitant presence of fibroids-related symptoms and the presence of other causes of infertility.

Endometriosis: current and future medical therapies.

Endometriosis is a chronic inflammatory disease that responds to steroidal manipulation. Creation of a steady hormonal environment with inhibition of ovulation temporarily suppresses the ectopic implants and reduces the inflammatory status as well as the associated pain symptoms. Pharmacological management of endometriosis must be set within the framework of long-term therapeutic strategies. As the available drugs are not curative, treatments will need to be administered for years or until women desire a pregnancy. The various therapies studied have shown similar efficacy. Consequently, based on a more favourable profile in terms of safety, tolerability and cost, combined oral contraceptives and progestins should be considered as the first-line option, both as an alternative to surgery and as a postoperative adjuvant measure. Gonadotrophin-releasing hormone analogues, danazol and gestrinone should be used when progestins and oral contraceptives fail, are not tolerated or are contra-indicated. Future therapies for endometriosis must compare favourably with existing drugs before hypothesizing their implementation in current practice. Medical treatment is not indicated in women seeking conception because reproductive prognosis is not ameliorated.

Adenomyosis: epidemiological factors.

Epidemiological studies of adenomyosis are difficult to interpret because the diagnostic criteria vary so widely that the disease may be easily over-diagnosed. This would severely hamper any attempt to define incidence and prevalence of the condition and the related risk factors, and would limit the possibility of clarifying to what extent adenomyosis contributes to clinical symptoms. There is a need for stringent and widely accepted diagnostic criteria in order to define not only the presence of adenomyosis but also depth of penetration and degree of spread of foci. Moreover, the evidence available on epidemiological characteristics of women with adenomyosis is greatly biased by the type of population studied, i.e. women undergoing hysterectomy. Therefore, a consensus on non-surgical diagnostic criteria at transvaginal ultrasonography and MRI is indispensable and urgently needed in order to be able to conduct epidemiological studies in women younger than those evaluated until now.

Molecular mechanisms and biological plausibility underlying the malignant transformation of endometriosis: a critical analysis.

Although population-based studies have unequivocally reported an increased risk of ovarian cancer in women with endometriosis, the biological evidence supporting the idea of endometriosis as a preneoplastic condition is scanty and not well substantiated. The fundamental features of human neoplasms (monoclonal growth, genetic changes, mutations in tumour suppressor genes and replicative advantage) have been evaluated in endometriotic lesions but results obtained are discordant. It is plausible that ectopic glands may expand monoclonally but the entity of this phenomenon is debated. According to some allelotyping studies, from one-third to one-half of endometriosis lesions would harbour somatic genetic changes in chromosomal regions supposed to contain genes involved in ovarian tumourigenesis, especially for the endometrioid histotype. These findings would be consistent with the progression model for carcinogenesis from the benign precursor to ovarian cancer but they could not be unequivocally replicated. Gene mutational studies are rare in this context. A single group has found missense mutations and deletions of PTEN gene in about 20% of ovarian endometriotic cysts. Moreover, in a model of genetically engineered mice harbouring an oncogenic allele of K-ras resulting in benign lesions reminiscent of endometriosis, a conditional deletion of PTEN caused the progression towards the endometrioid tumour. Based on these data, the causal link between endometriosis and ovarian endometrioid/clear cell carcinomas remains to be defined both in terms of entity of association and of underlying molecular mechanisms.

Variants of the CTLA4 gene that segregate with autoimmune diseases are not associated with endometriosis.

An autoimmune etiology has been suggested for endometriosis mostly on the basis of an increased prevalence of autoimmune diseases in affected women. Cytotoxic T lymphocyte antigen (CTLA) 4 gene is recognized as a primary determinant for autoimmunity since specific polymorphisms have been associated with predisposition to most autoimmune disorders. This study was aimed to evaluate whether two variants of CTLA4 gene might be associated with endometriosis in an Italian population. We examined the +49A/G polymorphism and the CT60A/G dimorphism in n = 146 endometriosis subjects classified according to Holt and Weiss criteria. Controls were represented by n = 165 women without laparoscopic evidence of the disease. We found no statistically significant difference in the genotype frequencies between women with and without endometriosis. The proportion of the mutant G allele of the +49A/G polymorphism in the former and in the latter group resulted 34 and 30%, respectively. The proportion of the susceptible G allele of the CT60 A/G dimorphism resulted 51% in both groups. No association was demonstrated between the polymorphisms and the clinical forms of the disease and no susceptibility haplotypes were found. These findings suggest that endometriosis aetiology is not primarily associated with the development of CTLA4-linked autoimmunity.

Overexpression of the Wnt5b gene in leiomyoma cells: implications for a role of the Wnt signaling pathway in the uterine benign tumor.

CONTEXT: Uterine leiomyomas are the most common tumors in the human female pelvis and the leading indication for pelvic surgery. The molecular causes of the disease remain unknown. OBJECTIVE: Using an oligonucleotide microarray-based hybridization analysis, we observed that a Wnt family member transcript, Wnt5b, was overexpressed in smooth muscle cells (SMC) derived from leiomyomas when compared with matched myometrial cells. Based on this finding and on previous observations, we have hypothesized that altered expression of specific Wnt family members might be involved in leiomyoma formation and/or growth. MAIN OUTCOME MEASURES: The expression patterns of two members of the Wnt pathway, Wnt5b and secreted frizzled related protein (sFRP)1, were evaluated in myometrial SMC (n = 22) and in leiomyoma cells (n = 27) by real-time quantitative PCR. In addition, regulation of expression of the two molecules was examined. RESULTS: Compared with myometrial SMC, cells derived from leiomyomas had significantly higher levels of both Wnt5b and sFRP1 transcripts. When the data were analyzed as a function of the phase of the menstrual cycle, no significant difference in sFRP1 mRNA levels could be detected, whereas levels of Wnt5b transcript were significantly higher in the secretory phase in myometrial cells. Treatment with 9-cis retinoic acid significantly inhibited Wnt5b expression in myometrial SMC but not in their leiomyoma counterparts. CONCLUSIONS: Specific Wnt signaling genes are overexpressed in leiomyoma cells. Moreover, in these cells, the regulation of Wnt5b expression by retinoids appears to be attenuated.