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Procainamide has been found to gastritis elimination diet esomeprazole 20 mg sale induce an increase in anti nuclear antibodies in A/J mice after eight months of exposure via the drinking-water (Layland et al gastritis diet in telugu generic 20mg esomeprazole. The disease is accompanied by a broad spectrum of au to gastritis symptoms nz buy 40 mg esomeprazole visa antibodies (rheuma to chronic gastritis medicine order 40 mg esomeprazole fast delivery id fac to r, anticollagen, antibodies to heat shock protein). Pristane-induced arthritis is clearly immune dependent, since it is not observed in nu/nu mice and + irradiated mice (Wooley & Whalen, 1991). It is controlled by multiple genes, identified as pristane-induced arthritis (pia) loci (Olofsson et al. The rationale behind using au to immune-prone animal strains for the purpose of studying and predicting the au to im munogenic potential of chemicals is that, apart from being probably very sensitive for adverse immune effects, exacerbation of disease is considered one of the possibilities by which chemicals may elicit au to immune phenomena (Pollard et al. As mentioned also, the Brown Norway rat is a sensitive rat strain for Th2-dependent phenomena, as is the Lewis rat for cyclosporin-induced au to im munity. In induced models, a susceptible animal strain is immunized with a mixture of an adjuvant and an au to antigen isolated from the target organ. Examples are adjuvant arthritis in the Lewis strain rat (Pearson, 1956) and experimental allergic encephalomyelitis, a model of multiple sclerosis (Ben-Nun & Cohen, 1982). Induced models are often used to study the pathogenesis of and therapeutic venues for relevant au to immune diseases. These models have been proposed as means to evaluate the immunomodula to ry effects of chemicals on ongoing au to immune diseases in a second tier of immuno to xicity testing. Although drug-induced lupus differs from systemic lupus erythema to sus in certain aspects (Pollard et al. Experience with any of these strains is scarce and is restricted mainly to salts of heavy metals such as mercury. In a study examining the immuno to xic effects of diphenyl hydan to in (Bloksma et al. Future studies should include more au to immunogenic pharmaceu ticals and negative controls in order to determine the extent to which systemic lupus erythema to sus-prone models are useful to study or predict chemical-induced au to immunity. However, there are only few reports in the open literature on dog studies with respect to chemical or drug-induced hypersensitivity reactions or au to immune effects, and studies are also often contradic to ry. For instance, procainamide has been shown to induce mainly an increase in antinuclear antibodies in one study (Balazs & Robinson, 1983), but not in another study with younger dogs (Dubois & Strain, 1972). Similar discrepancies were observed for hydralazine-induced effects in mice (Kammuller et al. More recent reports show clear sulfonamide-induced idiosyn cratic responses in dog. The syndrome induced by sulfonamides in dogs (mostly Dobermans) encompasses fever, arthropathy blood dyscrasias (neutropenia, thrombocy to penia, or haemolytic anaemia), hepa to pathy, skin eruptions, uveitis, and kera to conjunctivitis sicca (Trepanier, 2004). These symp to ms start to occur on average as soon as 12 days after start of exposure. The incidence in dogs (and cats) is as expected from idiosyncrasy, estimated to be around 0. Experiments with cats showed that propylthiouracil induces systemic lupus erythema to sus-like phenomena (au to antibodies against nuclear antigen, Smith [Sm] antigen, red blood cells, and cy to plasmic components, lymphoadenopathy, weight loss) (Aucoin, 1989). The model could also not be reproduced in more recent years for yet unknown reasons, shedding doubt on the usefulness of the propylthiouracil-induced cat model at this moment (Shen to n et al. Chemical-induced (including diet-mediated) au to immune effects in other species have also been documented; in most, if not all, cases, however, they are limited to isolated cases (for review, see Kosuda & Bigazzi, 1996). For instance, monkeys fed alfalfa seeds developed antibody-induced anaemia, chickens (Cornell C strain) receiving excess of iodine developed antibodies against thyroid hormones and lymphocytic thyroiditis, halothane-treated rabbits displayed antibodies against a set of five endogenous antigens, and drug-specific antibodies to a number of drugs (including isoniazid and procainamide) were detected in guinea-pigs (upon injection of drug in combination with complete Freund’s adjuvant) (Katsutani & Shionoya, 1992; Aida et al. The local lymph node assay is widely used in regula to ry to xicology in the testing of contact sensitizing properties of chemicals. The popliteal lymph node assay could also be used to identify sensitizing properties of chemicals involved in either systemic allergy or au to immunity. In particular, the popliteal lymph node assay has been extensively used to evaluate the potential of certain drugs to stimulate the immune system, and, when proper immunologically relevant parameters are assessed, the popliteal lymph node assay may also identify immunosensitizing potential (Pieters & Albers, 1999). The popliteal lymph node assay is mostly performed in mice (Gleich mann, 1981; Bloksma et al. The response, which can be assessed by detecting lymphocyte prolif eration or changes in the distribution of leukocyte subsets, cy to kine production, or immunohis to logy, is determined 6–8 days after injection (Ravel & Descotes, 2005). In the secondary popliteal lymph node assay, pretreated animals are re-exposed to the same chemical or to a metabolite in a dose that itself is incapable of stimulating naive T cells. A measured response to this low dose strongly indicates, but does not formally prove, that memory T cells are present. Proof for the formation of memory T cells can be obtained with the adoptive transfer popliteal lymph node assay in which purified T cells obtained from systemically treated mice are transferred to naive recipients that subsequently receive an injection in to the paw of a non-sensitizing dose of the same chemical or a relevant metabolite. Recently, an inven to ry study was carried out to evaluate the predictive value of local lymph node approaches for the immuno sensitizing potential of drugs (Weaver et al. Since the footpad injection raises ethical concerns, in some instances, head injection and ear injection with the auricular lymph node as read-out organ were used instead. The head injection pro to col, designated the lymph node proliferation assay, showed that 6 out of 10 drugs tested were adequately identified as positive and that negative compounds were supposed to be so, known to require metabolic activation, or to o to xic to use in sufficiently high doses. Depending on the antigen used, the reporter antigen response can provide information about the way the drug stimulates the immune system. Thus, the use of immunology-based read-out parameters improves the predictability of the popliteal lymph node assay; in addition, such parameters allow the further study of fundamental aspects of chemical-induced sensitization (Albers et al. Interestingly, the popliteal lymph node assay technique can be used in combination with relevant route of exposure models. Basically, T cell activation in the popliteal lymph node in response to a subcutaneous injection of a non-immunogenic dose of an appropriate chemical (hapten, relevant metabolite, native au to antigen, or reporter antigen) may allow the assessment of systemic T cell memory and hence systemic immunosensitization in animals that have been exposed to the chemical for a certain period. Those chemicals with known immunostimulating activity in humans were predicted correctly (Kammuller et al. This number includes a substantial number of structural homologues of diphenylhydan to in (Kammuller & Seinen, 1988) and zimeldine (Thomas et al. However, only about 20 compounds have been tested using the reporter antigen–popliteal lymph node assay (Albers et al. As indicated already, a recent inven to ry study using a different sub cutaneous route of exposure (the lymph node proliferation assay) showed that 6 out of 10 compounds were identified correctly as positive, whereas compounds that were not identified correctly either required metabolic activation or were to o to xic (Weaver et al. In addition, outliers are usually discarded from the experiment, whereas it is these outliers that may give an indication of unexpected and idio syncratic immune effects. Because of the multifac to rial nature of many of the chemical induced au to immune diseases, achieving one standard model for the prediction of these side-effects may be a difficult task. Rather, one might try to design a to olbox approach with a number of models that fit to a two or multiple-tiered approach. Based on the knowledge that the process leading to hyperreactivity responses or au to immune diseases may start in many cases with an initial phase of sensi tization, the first tier may include one of the local lymph node approaches, such as the popliteal lymph node assay (possibly in combination with a metabolizing system, but preferably with an immunological read-out parameter such as the reporter antigen approach). This first tier would then allow screening for a chem ical’s potential to stimulate the immune system. It is important to note that the popliteal lymph node assay in any of its forms is a hazard identification test and belongs to the qualitative stage of the risk assessment paradigm. So, at best, although the popliteal lymph node assay (in any of its forms) could be predictive of a sensitizing potential, it is not indicative of the au to immunogenic potential of a compound as such. The recent studies using the reporter antigen approach in combination with oral exposures (in particular with penicillamine) might serve as an example of com bining straightforward local lymph node approaches and oral route of exposure (see above). In summary, high priority has to be given to the validation of the popliteal lymph node assay (or other local lymph node approaches) and to the further development of predictive animal assays using routes of exposure that are more directly relevant to the human experience. These advancements would significantly enhance the usefulness of animal models and testing strategies for au to immunity and au to immune diseases. In order to make a diagnosis of a particular au to immune disease, characteristic clinical features of the disease must be present. Early clinical manifestations in some diseases, however, are nonspecific, and in such patients the presence of au to antibodies may be used as a diagnostic marker. In the majority of patients, the diagnosis, how ever, is reasonably clear after a thorough clinical assessment, and in such patients antibody testing is used to confirm the diagnosis or to make an alternative diagnosis. In many au to immune diseases, signs of tissue inflammation are present, reflected by elevated levels of c reactive protein. Positive predictive values of these antibodies for certain au to immune diseases, when tested in a general population, are low, since the diseases are uncommon. In the context of characteristic clinical features, however, the positive predictive value may be sufficiently high. Despite low positive predictive values for diagnosis in an individual patient, au to antibody testing in a population that is exposed to a certain environmental fac to r may be useful to provide preliminary information for detailed studies of the fac to r. Many hundreds of different au to antibodies have been described to date (Peter & Shoenfeld, 1996).

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It is a mul tisystem disease affecting many organs of the body gastritis diet 30 buy esomeprazole 20mg amex, and this makes it diffi cult to gastritis que hacer cheap 40mg esomeprazole otc diagnose unless the vasculitis is recognized by biopsy gastritis diet őîđîńęîď 20mg esomeprazole with mastercard. Symp to gastritis gagging order 20mg esomeprazole with visa ms include fever, weight loss, malaise, abdominal pain, headache, and myal gia. This pattern is seen in patients with Wegener’s granuloma to sis or Churg-Strauss syndrome. Henoch-Schonlein pur pura is a disorder of children who present with hemorrhagic urticaria and hematuria following an upper respira to ry infection. The pathology of this disease involves the deposition of immunoglobulin A (IgA) immune com plexes in small vessels of the skin. Because the antibody is IgA, the alter nate complement pathway is activated in these patients. His to logically there is fibrinoid necrosis of small arteries, early infiltration by neutrophils, and granuloma formation with giant cells. The disease is highly fatal, with death occurring within 1 year, unless recognized and treated with immunosuppressive agents. Churg-Strauss syndrome (allergic vasculitis) is a form of necrotizing vasculitis with granulomas of the respira to ry tract and asthma. It used to be found exclusively in men, but recently there has been an increase in the number of reported cases in women. The vessels primarily affected are in the extremities, and this leads to painful ischemia and gangrene of the legs and arms due to thrombosis. His to logic sections reveal an acute inflamma to ry infiltrate involving the entire wall of the vessel. In contrast to atherosclerosis, 214 Pathology small microabscesses may be seen within thrombi. The inflammation leads to intimal proliferation that obliterates the lumen and causes pain. In contrast, granuloma to us inflammation with giant cells involving blood vessels can be seen with tem poral arteritis or Takayasu’s arteritis. The causes of aneurysms are many, but the two most important ones are atherosclerosis and cystic medial necrosis. Atherosclerotic aneurysms, the most common type of aor tic aneurysms, usually occur distal to the renal arteries and proximal to the bifurcation of the aorta. Many atherosclerotic aneurysms are asymp to matic, but if they rupture they produce sudden, severe abdominal pain, shock, and a risk of death. Cystic medial necrosis refers to the focal loss of elastic and muscle fibers in the media of vessels and is seen in patients with hypertension, dissecting aneurysms, and Marfan’s syndrome. Berry aneurysms, found at the bifurcation of arteries in the circle of Willis, are due to congenital defects in the vascular wall. Syphilitic (luetic) aneurysms are caused by obliterative endarteritis of the vasa vasorum of the aorta. These aneurysms are part of the tertiary manifestation of syphilis and become evident 15 to 20 years after persons have contracted the initial infection with Treponema pallidum. Elastic tissue and smooth-muscle cells of the media undergo ischemic destruction as a result of the treponemal infection (obliterative endarteritis). As a consequence of ischemia in the media, musculoelastic support is lost and fibrosis occurs. Luetic aneurysms almost always occur in the thoracic aorta and may lead to luetic heart disease by producing insuffi ciency of the aortic valve (aortic regurgitation). This abnormality results from loss of elastic tissue in the media and is asso ciated with hypertension and Marfan’s syndrome. Most cases of dissecting Cardiovascular System Answers 215 aneurysms involve a transverse tear in the intima and are located in the ascending aorta, just above the aortic ring. The pain caused by a dissecting aneurysm is similar to the pain caused by a myocardial infarction, but it extends in to the abdomen as the dissection progresses. Additionally, the blood pressure is not decreased with a dissecting aneurysm unless the aorta itself has ruptured. In contrast, berry aneurysms, found at the bifurcation of arteries in the circle of Willis, are due to congenital defects in the vascular wall. Berry aneurysms have been noted in about one-sixth of patients with adult poly cystic renal disease and account for death in about 10% of patients with this type of polycystic renal disease. Syphilitic (luetic) aneurysms occur in the thoracic aorta and may lead to luetic heart disease by producing insuf ficiency of the aortic valve. Mycotic (infectious) aneurysms result from microbial infection during septicemia, usually secondary to bacterial endo carditis. His to logically they reveal dilated vessels lined by endothelial cells, but they lack red blood cells in their lumen. The absence of red blood cells helps to dis tinguish these lesions from hemangiomas. Cystic hygromas are cystic lym phangiomas that typically occur in the neck or axilla. These lesions may be found in patients with Turner’s syndrome, an abnormality that results from complete or partial monosomy for the X chromosome. Swelling of the neck in these individuals occurs because of dilated lymphatic vessels. With time the swelling decreases, but patients may develop bilateral neck webbing and loose skin on the back of the neck. In contrast, dilated blood vessels (vascular ectasia) may be congenital or acquired. Spider angiomas are acquired vascular ectasias that are the result of increased estrogen levels. His to logically, there are proliferating capillaries that are lined by protuberant endothelial cells. Additionally, numerous neutrophils are present along with nuclear dust and purple granules. These latter gran ules are Rickettsia-like bacteria that are the cause of this lesion, which responds to erythromycin. The juvenile (strawberry) hemangioma is a fast-growing lesion that appears in the first few months of life, but most completely regresses by the age of 5 years. Unless near the eye, definitive therapy is usually not indicated, as the possible techniques, such as surgery, cryotherapy, laser therapy, and injection of sclerosing drugs, all cause more scarring than is produced by spontaneous resolution. It occurs in older men of Eastern European or Mediterranean origin (predominantly Italian or Jewish) and is characterized by purple maculopapular skin lesions of the lower extremities and visceral involvement in only 10% of cases. The African form occurs in younger peo ple and is more aggressive; it often involves lymph nodes in children. The rare form in immunosuppressed recipients of renal transplants often regresses when immunosuppression s to ps. His to logic determination is difficult, but all four clinical types appear similar. In the early stages, irregular, dilated epidermal vascular spaces, extravasated red cells, and hemosiderin are characteristic. This his to logic appearance is very similar to that of granulation tissue or stasis dermatitis. Later in the dis ease process, more characteristic lesions show spindle cells around slit spaces with extravasation of erythrocytes. In contrast, irregular vascular Cardiovascular System Answers 217 spaces lined by nests of uniform cells describe the his to logic appearance of a glomus tumor, while multiple dilated endothelial-lined vessels that lack red blood cells describe the his to logic appearance of lymphangiomas. Numerous neutrophils, nuclear dust, and purple granules characterize bacillary angioma to sis, while proliferating blood vessels, endothelial cells, and fibroblasts suggest granulation tissue. This is the pattern arising in the liver from chronic passive congestion as a result of right heart failure (“nutmeg liver”). Mitral stenosis with consequent pulmonary hypertension leads to right heart failure, as does any cause of pulmonary hypertension, such as emphysema (cor pulmonale). Right heart failure also leads to congestion of the spleen and transudation of fluid in to the abdomen (ascites) and lower extremity soft tissues (pitting ankle edema) as a result of venous congestion. The symp to ms produced by congestive heart failure relate to whether the failure involves the left side of the heart or the right side of the heart. Symp to ms of acute left ventricu lar failure include pulmonary edema, pulmonary hemorrhage, and hypoxia, while chronic left ventricular failure will produce dyspnea on exertion, orthopnea (trouble breathing when lying down), paroxysmal nocturnal dyspnea, and eventually right heart failure. There are many causes of congestive heart failure, but basically they pro duce either sys to lic dysfunction or dias to lic dysfunction. Sys to lic dysfunc tion may result from increased preload, increased afterload, or decreased contractility.

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Serati M gastritis hiv symptom order esomeprazole 20 mg, Bogani G gastritis yoga cheap esomeprazole 40 mg with mastercard, Sorice P chronic gastritis message boards generic esomeprazole 40mg line, Braga A chronic gastritis fever buy esomeprazole 20 mg otc, Torella M, Salva to re S, Uccella S, Cromi A, Ghezzi F. Robot-assisted Sacrocolpopexy for Pelvic Organ Prolapse: A Systematic Review and Meta-analysis of Comparative Studies. Male Urinary Incontinence: Prevalence, Risk Fac to rs, and Preventive Interventions Rev Urol. An Acellular Biologic Scaffold Promotes Skeletal Muscle Formation in Mice and Humans with Volumetric Muscle Loss. A standardized description of graft containing meshes and recommended steps before the introduction of medical devices for prolapse surgery. Symp to matic pelvic organ prolapse and possible risk fac to rs in a general population. The prevalence of pelvic organ prolapse symp to ms and signs and their relation with bladder and bowel disorders in a general female population. Synthetic or biological mesh use in laparoscopic ventral mesh rec to pexy—a systematic review. Risk fac to rs of treatment failure after retrourethral transobtura to r male sling, World Journal of Urology 2012; vol. Tensile strength and host response to wards silk and type I polypropylene implants used for augmentation of fascial repair in a rat model. The tensile properties of tension-free vaginal tape and cadaveric fascia lata in an in vivo rat model. Bupivacaine enhanced small intestinal submucosa biomaterial as a hernia repair device. Effect of patient age on increasing morbidity and mortality following urogynecologic surgery. A summary of the evidence on the benefits and risks of vaginal mesh implants, avaialable from. A stereological analysis of fibrosis and inflamma to ry reaction induced by four different synthetic slings. Toozs-Hobson P, Freeman R, Barber M, Maher C, Haylen B, Athanasiou S, Swift S, Whitmore K, Ghoniem G, de Ridder D. A comparison of 30-day surgical outcomes for minimally invasive and open sacrocolpopexy. Public Health Notification: Serious Complications Associated with Transvaginal Placement of Surgical Mesh in Repair of Pelvic Organ Prolapse and Stress Urinary Incontinence; 20 Oc to ber 2008. Urogynecologic Surgical Mesh: Update on the Safety and Effectiveness of Transvaginal Placement for Pelvic Organ Prolapse; 13 July 2011. A Comparative Study Evaluating the In Vivo Incorporation of Biological Sling Materials. Allograft transplantation in the knee: Tissue regulation, procurement, processing, and sterilization. Changes in tensile strength of cadaveric human fascia lata after implantation in a rabbit vagina model. A his to logic and immunohis to chemical analysis of defective vaginal heating after continence taping procedures: A prospective case controlled pilot study. Post-operative catheterization, urinary retention, and permanent voiding dysfunction after polytetrafluroethylene suburethral sling placement. Small intestinal submucosa for pubourethral sling suspension for the treatment of stress incontinence: First his to pathological results in humans. Effect of Weight Loss on Urinary Incontinence in Overweight and Obese Women: Results at 12 and 18 Months. Credentialing for transvaginal mesh placement-a case for "added qualification" in competency. Risk fac to rs for exposure, pain, and dyspareunia after tension-free vaginal mesh procedure. Development of de novo prolapse in untreated vaginal compartments after prolapse repair with and without mesh: a 103 the safety of surgical meshes used in urogynecological surgery secondary analysis of a randomised controlled trial. Tissue reactions of 5 sling materials and tissue material detachment strength of 4 synthetic mesh materials in a rabbit model. Medicines and Healthcare Products Regula to ry Agency: Summaries of the Safety/Adverse Effects of Vaginal Tapes/Slings/Meshes for Stress Urinary Incontinence and Prolapse. Host response after reconstruction of abdominal wall defects with porcine dermal collagen in a rat model. The guidance material dealing with medical assessment is intended for the use of medical examiners and medical assessors at the discretion of the Licensing Authorities. Those engaged in multicrew operations, where there has been effective incapacitation training, may be considered less stringently. In many such cases flight safety may be adequately protected by an operational condition or limitation applied to the licence. They may also have the consequence of licence holders being reluctant to report illness to the medical examiner or the Licensing Authority, and this is important from the flight safety viewpoint since the value of the medical examination relies to a large extent upon an accurate medical his to ry. Any specification for physical characteristics, configuration, materiel, performance, personnel or procedure, the uniform application of which is recognized as desirable in the interest of safety, regularity or efficiency of international air navigation, and to which Contracting States will endeavour to conform in accordance with the Convention. This category includes all operations conducted with large and sophisticated aircraft which used to be piloted by several crew members. The operations are not conducted for remuneration and generally involve small aircraft. There is a real gap between the bush pilot flying a rugged aircraft solo in a deserted area and the pilot-in-command of a complex aeroplane on one of the major air routes with comprehensive ground support. This difference, which also affects licensed ground personnel, used to increase as technological progress became more involved in airline operations than in other categories, but is now decreasing somewhat as advanced and sophisticated electronics and computer-based equipment are becoming available even to the private pilot. This concept has remained valid throughout the years, and the whole of Annex 1 may be considered as an evolution of this basic idea. However, these licences have no medical fitness requirements due to the nature of duties. In some States, the Medical Assessment itself, when issued as a certificate, functions as the student pilot’s licence. Therefore the medical examiner should be prepared to counsel the applicant against further time and expense in pursuance of piloting ambitions if a medical condition is established which might prevent his acquisition of a more senior pilot licence, if this is his ambition. The most commonly held licence permitting the holder to fly an aeroplane other than professionally. The senior pilot licence, permitting the holder to operate any aircraft either as pilot-in-command or co-pilot. The larger aircraft (usually those with a maximum take-off mass of more than 5 700 kg) need a specific rating. The smallest aircraft are grouped in to classes (single-engine and multi-engine) and the holder of a licence endorsed with a class rating is permitted to fly all the aircraft of the relevant class. The licence permitting the holder to perform the duty of a flight engineer when required by aircraft certification or operational regulation. These licences, especially the latter two, are becoming obsolete and are seldom issued. Rules concerning licences I-1-5 the basic ratings for this licence are: a) Aerodrome control rating, permitting the holder to provide or to supervise the provision of aerodrome control service for the aerodrome for which he is rated. When a radar is used to perform the duty, the air traffic controller must hold a radar rating in addition to the relevant basic rating. Other States endorse aviation licences with the date of the medical examination and the word “passed”, thus rendering the licence valid again for a limited period until the next medical examination is due. When such a licence expires, a new one is issued, provided the holder still meets the medical requirements. A minimum level of experience depending on the licence is required for all personnel to be licensed. Contracting States generally use a written examination and a practical test to check the competency of an applicant. Some other methods are also used concurrently, such as acceptance of a military licence. The other type of licence (continuous type) is not limited to a defined period of currency. The holder is allowed to exercise licence privileges as long as he holds a current Medical Assessment and complies with the regulations detailing the actions necessary to ensure maintenance of competency. This is an effective way to promote the medical examiner’s understanding of the practical demands, both physiological and psychological, that the licence holder’s task and duties impose. Also the audit of medical reports by designated medical examiners and refresher training of medical examiners will usually fall within the remit of the medical assessor.

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Although some attributed these rates to atrophic gastritis symptoms webmd buy generic esomeprazole 20 mg online a relative resistance to gastritis bile reflux diet buy esomeprazole 40 mg radiation gastritis diet ăóăë generic 20mg esomeprazole mastercard, they are more likely a reflection of the tendency of adenocarcinomas to gastritis exercise buy discount esomeprazole 20mg line grow endophytically and to be undetected until a large volume of tumor is present. When adjusted for tumor size, it appears that there is no difference in prognosis between the two his to logic subtypes. Adenocarcinoma may be detected by cervical sampling, but less reliably so than squamous carcinomas. These studies identified size of tumor, depth of invasion, grade of tumor, and age of the patient as significant correlates of lymph node metastasis and survival. When matched with squamous carcinomas for lesion size, age, and depth of invasion, the incidence of lymph node metastases and the survival rate appear to be the same (38,39). Patients with stage I adenocarcinomas can be selected for treatment according to the same criteria as for those with squamous cancers (39). Some advocated treatment with radiation alone, whereas others support radiation plus extrafascial hysterec to my (40–42). A subsequent report revealed no significant difference in survival among patients treated with radiation alone or radiation plus extrafascial hysterec to my (43). Within the category of pure adenocarcinoma, the tumors are quite heterogeneous, with a wide range of cell types, growth patterns, and differentiation (30). About 80% of cervical adenocarcinomas consist predominantly of the endocervical type cells with mucin production. The remaining tumors are populated by endometrioid cells, clear cells, intestinal cells, or a mixture of more than one cell type. By his to logic examination alone, some of these tumors are indistinguishable from those arising elsewhere in the endometrium or ovary. Within each cell type, the growth patterns and nuclear abnormalities vary according to the degree of differentiation. In well-differentiated tumors, tall columnar cells line the well-formed branching glands and papillary structures, whereas pleomorphic cells tend to form irregular nests and solid sheets in poorly differentiated neoplasms. Irregular glands are lined with tall columnar cells with vacuolated mucinous cy to plasm resembling endocervical cells. Nuclear stratification, mild nuclear atypism, and mi to tic figures are evident in higher power. Minimal deviation adenocarcinoma (adenoma malignum) is an extremely well-differentiated form of adenocarcinoma in which the branching glandular pattern strongly simulates that of the normal endocervical glands. Because of this, the tumor may not be recognized as malignant in small biopsy specimens, thereby causing considerable delay in diagnosis. Earlier studies reported a dismal outcome for women with this tumor, but more recent studies found a favorable prognosis if the disease is detected early (46). Although rare, similar tumors were reported in association with endometrioid, clear, and mesonephric cell types (47). An entity described as villoglandular papillary adenocarcinoma deserves special attention (48). It primarily affects young women, some of whom are pregnant or users of oral contraceptives. His to logically, the tumors have smooth, well-defined borders, are well differentiated, and are either in situ or superficially invasive. None of these tumors recurred after cervical conization or hysterec to my, and no metastasis was detected among women undergoing pelvic lymphadenec to my. Adenosquamous Carcinoma Carcinomas with a mixture of malignant glandular and squamous components are known as adenosquamous carcinomas. Patients with adenosquamous carcinoma of the cervix were reported to have a poorer prognosis than those with pure adenocarcinoma or squamous carcinoma (49). In mature adenosquamous carcinomas, the glandular and squamous carcinomas are readily identified on routine his to logic evaluation and do not cause diagnostic problems. In one study, 30% of squamous cell carcinomas demonstrated mucin secretion when stained with mucicarmine (47). These squamous cell carcinomas with mucin secretion have a higher incidence of pelvic lymph node metastases than do squamous cell carcinomas without mucin secretion, and they are similar to the signet-ring variant of adenosquamous carcinoma (47,50). Glassy cell carcinoma is recognized as a poorly differentiated form of adenosquamous carcinoma (51). Individual cells have abundant eosinophilic, granular, ground-glass cy to plasm, large round to oval nuclei, and prominent nucleoli. Approximately half of these tumors contain glandular structures or stain positive for mucin. The poor diagnosis of this tumor is linked to understaging and resistance to radiotherapy. Other variants of adenosquamous carcinoma include adenoid basal carcinoma and adenoid cystic carcinoma. Nests of basaloid cells extend from the surface epithelium deep in to the underlying tissue. Cells at the periphery of tumor nests form a distinct parallel nuclear arrangement, so-called peripheral palisading. Adenoid cystic carcinoma of the cervix behaves much like such lesions elsewhere in the body. The tumors tend to invade in to the adjacent tissues and metastasize late, often 8 to 10 years after the primary tumor was removed. The pattern simulates that of the adenoid basal tumor, but there is a cystic component, and the glands of the cervix are involved (51). Sarcoma the most important sarcoma of the cervix is embryonal rhabdomyosarcoma, which occurs in children and young adults. The tumor has grapelike polypoid nodules, known as botryoid sarcoma, and the diagnosis depends on the recognition of rhabdomyoblasts. Leiomyosarcomas and mixed mesodermal tumors involving the cervix may be primary but are more likely to be secondary to uterine tumors. Cervical adenosarcoma is described as a low-grade tumor with a good prognosis (52). If recurrence develops, it is generally a central recurrence that may be treated with resection and hormonal therapy. His to pathologically, it simulates melanoma elsewhere, and the prognosis depends on the depth of invasion in to the cervical stroma. Neuroendocrine Carcinoma the classification of neuroendocrine cervical carcinoma includes four his to logic subtypes: (i) small cell, (ii) large cell, (iii) classical carcinoid, and (iv) atypical carcinoid (53). Neuroendocrine tumors of the cervix are rare, and treatment regimens are based on small case series of patients. Small cell (neuroendocrine type) carcinoma of the cervix is aggressive in nature and is similar to cancer arising from the bronchus (54). The hallmark of neuroendocrine tumors is their aggressive malignant behavior with the propensity to metastasize. At the time of diagnosis, it is usually disseminated, with bone, brain, liver, and bone marrow being the most common sites of metastases. In one study of 11 patients with disease apparently confined to the cervix, a high rate of lymph node metastasis was noted (55). In addition to the traditional staging for cancer of the cervix, these patients should undergo bone, liver and brain scanning and bone marrow aspiration and biopsy to evaluate the possibility of metastatic disease. Because patients with early-stage disease have distant metastases, multimodal therapy is recommended. Regimens of combination chemotherapy improved the median survival rates in small cell bronchogenic carcinoma, and these regimens are used for treatment of small cell carcinoma of the cervix. Patients must be moni to red carefully because they are at high risk for developing recurrent metastatic disease (57). Patterns of Spread Cancer of the cervix spreads by (i) direct invasion in to the cervical stroma, corpus, vagina, and parametrium; (ii) lymphatic metastasis; (iii) blood-borne metastasis; and (iv) intraperi to neal implantation. The latter is rare, and most lesions that involve the cervix and vagina are designated cervical primaries. Consequently, the clinical classification is that of cervical neoplasia extending to the vagina, rather than vice versa. Endometrial cancer may extend in to the cervix by three modes: direct extension from the endometrium, submucosal involvement by lymph vascular extension, and multifocal disease.


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