Ovarian carcinoma can spread by local extension, lymphatic invasion, intraperitoneal implantation, hematogenous dissemination, and transdiaphragmatic passage.

Intraperitoneal dissemination is the most common and recognized characteristic of ovarian cancer. Malignant cells can implant anywhere in the peritoneal cavity but are more likely to implant in sites of stasis along the peritoneal fluid circulation. As discussed later, these mechanisms of dissemination represent the rationale to conduct surgical staging, debulking surgery, and intraperitoneal administration of chemotherapy. In contrast, hematogenous spread is clinically unusual early on in the disease process, although it is not infrequent in patients with advanced disease.

Epithelial ovarian cancer

Epithelial tumors represent the most common histology (90%) of ovarian tumors. Other histologies include the following:

Sex-cord stromal tumors Germ cell tumors Primary peritoneal carcinoma Metastatic tumors of the ovary

Epithelial ovarian cancer is thought to arise from epithelium covering the ovaries, which is derived from the coelomic epithelium in fetal development. This coelomic epithelium is also involved in formation of the Mllerian ducts, from which the Fallopian tubes, uterus, cervix, and upper vagina develop. Five main histologic subtypes, which are similar to carcinoma, arise in the epithelial lining of the cervix, uterus, and fallopian tube, as follows:

Serous (from fallopian tube) Endometrioid (endometrium) Mucinous (cervix) Clear cell (mesonephros) Brenner

Some variation is observed in the patterns of spread and disease distribution within the various histologic subtypes. Epithelial tumors are found as partially cystic lesions with solid components. The surface may be smooth or covered in papillary projections (see the image below), and the cysts contain fluid ranging from straw-colored to opaque brown or hemorrhagic.

An enlarged ovary with a papillary serous carcinoma on the surface. Epithelial ovarian cancer most often spreads initially within the peritoneal cavity (see the images below). Metastatic disease often is found on the peritoneal surfaces, particularly on the undersurface of the diaphragms, the paracolic gutters, the bladder, and the cul-de-sac. Other common sites are the surface of the liver, the mesentery and serosa of the large and small bowel, in the omentum, the uterus, and para-aortic and pelvic lymph nodes.

Laparotomy on a patient with intermittent small bowel obstruction. A loop of small bowel (bottom of frame) is adherent to a poorly differentiated primary epithelial ovarian carcinoma (left of frame) that has spread to involve the

pelvic sidewall, the bladder peritoneum, the serosa of the uterus, and the fallopian tube. Metastases from epithelial ovarian carcinoma involving the omentum. Outside the peritoneal cavity, epithelial ovarian cancer may spread to the pleural cavity, lungs, and groin lymph nodes. Presence of pleural effusion does not necessarily indicate disease in the chest, and malignancy can be diagnosed only cytologically. Mucinous

tumors tend to form large dominant masses, while papillary serous tumors have a more diffuse distribution and are more commonly bilateral. Endometrioid and clear-cell variants more commonly exhibit local invasion, retroperitoneal disease, and hepatic metastases. Li et al suggested a tubal origin of ovarian-serous cancers rather than through Mllerian metaplasia from ovarian surface epithelium.[1]

Etiology
The precise cause of ovarian cancer is unknown, but several risk and contributing factors have been identified. Hippisley-Cox and Coupland developed an algorithm to determine risk of breast cancer in women with and without symptoms.[2] , In their cohort study, 10% of women with the highest-predicted risk had 63% of all ovarian cancers diagnosed over the next 2 years.

Reproductive factors
Parity is an important risk factor. The risk of epithelial ovarian cancer is increased in women who have not had children and possibly those with early menarche or late menopause. Women who have been pregnant have a 50% decreased risk for developing ovarian cancer compared with nulliparous women. Multiple pregnancies offer an increasingly protective effect. Oral contraceptive use decreases the risk of ovarian cancer. These factors support the idea that risk for ovarian cancer is related to ovulation. Two theories regarding this relationship have been proposed. The incessant ovulation theory suggests that repeated ovarian epithelial trauma caused by follicular rupture and subsequent epithelial repair results in genetic alterations within the surface epithelium. The gonadotropin theory proposes that persistent stimulation of the ovaries by gonadotropins, coupled with local effects of endogenous hormones, increases surface epithelial proliferation and subsequent mitotic activity. Thus, the probability of ovarian cancer may be related to the number of ovulatory cycles, and conditions that suppress the ovulatory cycle may play a protective role. Ovulation suppression has been shown to decrease cancer incidence. Although treatment with agents that induce ovulation in women with infertility has been suggested to increase the incidence of epithelial ovarian cancer, this is unproven.

Genetic factors

Family history plays an important role in the risk of developing ovarian cancer. The lifetime risk for developing ovarian cancer is 1.6% in the general population. This compares with a 4-5% risk when 1 first-degree family member is affected, rising to 7% when 2 relatives are affected. From 5-10% of cases of ovarian cancer occur in an individual with a family history of the disease. Only a small percentage of these patients have an inherited genetic abnormality, and the risk of this occurrence increases with the strength of the family history. Hereditary epithelial ovarian cancer occurs at a younger age (approximately 10 years younger) than nonhereditary epithelial ovarian cancer, but the prognosis may be somewhat better. Integrated genomic analyses by the Cancer Genome Atlas Research Network have revealed high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumors. The findings also include the low prevalence but statistically recurrent somatic mutations in 9 further genes, including NF1, BRCA1, BRCA2, RB1, and CDK12, along with 113 significant focal DNA copy number aberrations and promoter methylation events involving 168 genes. Pathway analyses revealed defective homologous recombination in about half of all tumors, and that NOTCH and FOXM1 signaling are involved in serous ovarian cancer pathophysiology.[3] Evidence from the Cancer Genome Atlas Network showed that serous ovarian tumors and breast basal-like tumors shared a number of molecular characteristics such as the types and frequencies of genomic mutations, suggesting that ovarian and breast cancer may have a related etiology and potentially similar responsiveness to some of the sametherapies.[4] At least 2 syndromes of hereditary ovarian cancer are clearly identified, involving either (1) disorders of the genes associated with breast cancer, BRCA1 and BRCA2, or (2) more rarely, genes within the Lynch II syndrome complex. Breast/ovarian cancer syndrome is associated with early onset of breast or ovarian cancer. Inheritance follows an autosomal dominant transmission. It can be inherited from either parent. Most cases are related to the BRCA1 gene mutation. BRCA1 is a tumor suppressor gene that inhibits cell growth when functioning properly; the inheritance of mutant alleles of BRCA1 leads to a considerable increase in risk for developing ovarian cancer. Approximately 1 person in 4000 in the general population carries a mutation of BRCA1. Some populations have a much higher rate of BRCA1 and BRCA2 mutations, especially Ashkenazi Jews. In families with 2 first-degree relatives (mother, sister, or daughter) with premenopausal epithelial ovarian cancer, the likelihood of a female relative having an affected BRCA1 or BRCA2 gene is as high as 40%. The probability is much lower when the disease occurs in relatives postmenopausally. Individuals with a BRCA1 gene mutation have a 50-85% lifetime risk of developing breast cancer and a 15-45% risk of developing epithelial ovarian cancer. Those with a BRCA2 gene mutation have a 50-85% lifetime risk of developing breast cancer and a 1020% risk of developing epithelial ovarian cancer. Families with BRCA2 mutations are at risk for developing cancer of the prostate, larynx, pancreas, and male breast.

Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers; however, in an investigation of a common genetic variation at the 9p22.2 locus, a decreased risk of ovarian cancer was noted in carriers of a BRCA1 or BRCA2 mutation.[5] Families with Lynch II syndrome or hereditary nonpolyposis colorectal cancer are characterized by a high risk for developing colorectal, endometrial, stomach, small bowel, breast, pancreas, and ovarian cancers. This syndrome is caused by mutations in the mismatch repair genes. Mutations have been demonstrated in mismatch repair genes MSH2, MLH1, PMS1, and PMS2. Women with a history of breast cancer have an increased risk of epithelial ovarian cancer. In a study by Rafner et al, whole-genome sequencing identified a rare mutation in BRIP1, which behaves like a classical tumor suppressor gene in ovarian cancer.[6] This allele was also associated with breast cancer.

Previous hormone therapy

A nationwide prospective cohort study over 10 years that included all Danish women aged 50-79 years concluded that risk for ovarian cancer is increased with hormone therapy, regardless of duration of use, formulation, estrogen dose, regimen, progestin type, and administration route.[7] Nearly 1 million women without hormone-sensitive cancer or bilateral oophorectomy were followed. In an average of 8 years of follow-up, 3068 ovarian cancers were detected, of which 2681 were epithelial cancers. Current users of hormones had incidence rate ratios for all ovarian cancers of 1.38 (95% confidence interval [CI], 11.26-1.51) compared with women who never took hormone therapy. Risk declined as years since last hormone use increased. Incidence rates in current and never users of hormones were 0.52 and 0.40 per 1000 years, respectively. This translates to approximately 1 extra ovarian cancer for approximately 8300 women taking hormone therapy each year.

Other factors
Lactose consumption and the use of talcum powder on the vulva and perineum may be associated with increased risk of epithelial ovarian cancer.

Epidemiology
In the United States, the incidence of ovarian cancer is 33 cases per 100,000 women aged 50 years or older. The average patient age at diagnosis is 57 years. The estimated lifetime risk is 1 case in 70 women, which is a 1.4% lifetime incidence.

The American Cancer Society estimated that there would be 21,880 new cases of ovarian cancer in 2010 and 13,850 deaths from the disease.[8] The 2010 estimates are 21,880 cases and 13,850 deaths. Epithelial ovarian cancer is the eighth most common cancer in women, and uterine (corpus and endometrial) is fourth. The ovaries are the ninth most common site of cancer in women, accounting for approximately 3% of all new cases, but ovarian cancer causes 5% of cancer deathsmore than any other cancer of the female reproductive system. However, during 20012005, the incidence of ovarian cancer declined at a rate of 2.4% annually, and the death rate from ovarian cancer has been stable since 1998.[8] Ovarian cancer is more common among American women in the white population than it is among those in the black population. Epithelial ovarian cancer can occur in females as young as 15 years, but the mean age is 56 years. In the United States, incidence of ovarian carcinoma is approximately 15 cases per 100,000 women per year for women aged 50-54 years, rising to 35 cases per 100,000 women for women aged 70-74 years.

International statistics
Internationally, the incidence is 3.1 cases per 100,000 women in Japan and 21 cases per 100,000 women in Sweden. Around the world, more than 200,000 women are estimated to develop ovarian cancer every year and about 100,000 die from the disease. Epithelial ovarian cancer occurs most commonly in white women in the industrialized countries of northern and western Europe and North America and least commonly in India and Asia. Asian women have low risk unless they relocate to North America or Europe. Scandinavian and Norwegian women have the highest risk.

Prognosis
Although the 5-year survival rate for ovarian cancer has improved significantly in the past 30 years, the prognosis for ovarian cancer remains poor overall, with a 46% 5-year survival rate. The prognosis of ovarian cancer is closely related to the stage at diagnosis,[9, 10] as determined according to the staging system developed by the International Federation of Gynecology and Obstetrics (FIGO). (See Staging.) Approximately 20%, 5%, 58%, and 17% of women present with stage I, II, III, and IV, respectively. The 5-year survival rates (rounded to the nearest whole number) for epithelial ovarian carcinoma by FIGO stage are as follows:

Stage IA - 87% Stage IB - 71% Stage IC - 79% Stage IIA - 67% Stage IIB - 55%

Stage IIC - 57% Stage IIIA - 41% Stage IIIB - 25% Stage IIIC - 23% Stage IV - 11% Overall survival rate 46%

Bakhru et al found poorer survival among patients with ovarian cancer and diabetes. Although the underlying reason for this association is unknown, further studies are needed.[11] Among women with high-grade serous ovarian cancer, BRCA2 mutation but not BRCA1 deficiency was associated with improved survival, improved chemotherapy response, and genome instability compared with BRCA wild-type.[12] A study by Bolton et al found improved 5-year overall survival among carriers of BRCA1 or BRCA2, with BRCA1 having the best prognosis.[

Introduction
The ovary is the female Gonad homologous to the male Testes. It is usually a paired organ in domestic species, but in the bird only the left Ovary is present. The structures found within the ovary are undergoing constant changes throughout the oestrus cycle from the Follicles containing Oocytes, to the formation of Corpus Haemorrhagicum, Corpus Luteum, and finally Corpus Albicans. Ovaries are ellipsoidal in shape with an irregular surface due to the projection of dominant follicles and corpora lutea. These irregularities are absent in the mare due to the cortex and medulla being reversed with ovulation only occuring from the ovulation fossa. They are greatest in Polytocious animals such as the sow due to many dominant follicles, and so corpora lutea, developing at once.

Anatomical Location

In the dog and cat, ovaries do not migrate in development. They remain in the dorsal part of the abdomen, caudal to the kidneys at the tip of the uterine horns. In other domestic species, the ovaries migrate during development. The greatest degree of migration occurs in ruminants. Here, the ovaries come to lie close to the ventral abdominal wall, cranial to the pelvic inlet. In the pig, they descend to the middle of the abdomen.

In the mare, they are located ~8-10 cm ventral to the dorsal wall of the abdomen. In all domestic species except the horse, ovaries are ellipsoidal in shape and their surface has large follicles and corpora lutea. The ovaries of the mare are kidney shaped and the surface is smooth. The ovaries are suspended in the abdominal cavity by the Mesovarium of the Broad Ligament.

Structure

Outer Tunica Albuginea

Connective tissue layer covering the ovarian cortex. Overlying this structure is a single layered Germinal epithelium.

Ovarian Cortex

Contains: o Follicles in various stages of development o Corpus Luteum (includes Corpus Haemorrhagicum and Corpus Albicans)

Ovarian Medulla

The Medulla is made up of dense connective tissue. This is where all of the lymphatics, nerves and vasculature of the Ovary are found.

The Mare

The Ovaries of a Mare showing the Ovulation Fossa- Courtesy of A.Crook, Copyright RVC 2008

The structure of the ovary is reversed. The cortex is in the centre, follicles develop here. This layer is enclosed by a dense, richly vascularised connective tissue layer which is analagous to the medulla of other domestic mammals. The cortex reaches the surface of the ovary at the ovulation fossa, a deep indentation at the free margin. This is where mature follicles rupture in ovulation, as opposed to at various points on the surface in other domestic mammals. Follicles can be identified by transrectal palpation, but Corpora Lutea cannot. Identification of Corpora Lutea requires ultrasonography.

Histology

Histological Section of a Rabbit Ovary under Low Power- Courtesy of J.Bredl, Copyright RVC 2008

Stroma

The body of the ovary (ovarian stroma) consists of: o spindle-shaped cells o fine collagen fibres

o ground substance Stromal cells resemble fibroblasts, but some contain lipid droplets. Bundles of smooth muscle cells are scattered throughout the stroma.

Cortex

Follicles containing oocytes in various stages of development. Atretic Follicles Corpora lutea Corpora albicans The superficial cortex is more fibrotic than the deep, and is called the tunica albuginea. On the surface of the ovary is the germinal epithelium. This is a continuation of the peritoneum.

Medulla

Highly vascular Contains hilus cells, which are similar to the Leydig cells of the testes.

Vasculature

Arterial Supply

The ovarian artery (a branch of the Aorta) and ovarian branches of the Uterine artery form anastomoses in the mesovarium and the broad ligament. From this arterial plexus ~10 coiled Helicine arteries enter the hilus of the ovary. Smaller branches form a plexus at the corticomedullary junction, giving rise to straight Cortical arterioles, which radiate into the cortex. Here they branch and anastomose to form vascular arcades, which give rise to a rich capillary network around follicles.

Venous Drainage

Venous drainage follows the course of the arterial system. Medullary veins are large and tortuous.

The Ovarian Artery is closely associated with the Uterine Vein. This is important for the transfer of luteolytic PGF2 from the Uterus to the Ovary.

Lymphatics

Arise in the perifollicular stroma. Drain into larger vessels, which coil around the medullary veins.

Innervation

Sympathetic fibres of the autonomic nervous system supply blood vessels and terminate on smooth muscle cells in the stroma around follicles. May play a role in follicular maturation and ovulation, but the main control is via the endocrine system.

Function
It has two main functions:

Producing the female gametes oocytes via Gametogenesis. Producing the reproductive hormones Oestrogens and Progesterone, an endocrine function.

Processes Taking Place In The Ovary

Oogenesis Folliculogenesis Ovulation Corpus Luteum Formation Corpus Luteum Regression

Clinical Manifestations 1. Generalized or localized abdominal pain in the epigastric or periumbilical areas and upper right abdomen. Within 2 to 12 hours, the pain localizes in the right lower quadrant and intensity increases. 2. Anorexia, moderate malaise, mild fever, nausea and vomiting. 3. Usually constipation occurs ; occasionally diarrhea. 4. Rebound tenderness, involuntary guarding, generalized abdominal rigidity. Diagnostic Evaluation 1. 2. 3. 4. 5. Physical examination consistent with clinical manifestations. WBC count reveal moderate leukocytosis (10,000 to 16,000/mm3) with shift to the left (increased immature neutrophils). Urinalysis rule out urinary disorders. Abdominal x-ray may visualize shadow consistent with fecalith in appendix; perforation will reveal free air. Abdominal ultrasound or CT scan can visualize appendix and rule out other conditions, such as diverticulitis and crohns disease. Focused appendiceal CT can quickly evaluate for appendicitis.

Medications

Analgesics Intravenous fluids replacements Analgesics Introduction The appendix is a small fingerlike appendage about 10 cm (4 in) long, attached to the cecum just below the ileocecal valve. No definite functions can be assigned to it in humans. The appendix fills with food and empties as regularly as does the cecum, of which it is small, so that it is prone to become obstructed and is particularly vulnerable to infection (appendicitis). Appendicitis is the most common cause of acute inflammation in the right lower quadrant of the abdominal cavity. About 7% of the population will have appendicitis at some time in their lives, males are affected more than females, and teenagers more than adults. It occurs most frequently between the age of 10 and 30. The disease is more prevalent in countries in which people consume a diet low in fiber and high in refined carbohydrates. The lower quadrant pain is usually accompanied by a low-grade fever, nausea, and often vomiting. Loss of appetite is common. In up to 50% of presenting cases, local tenderness is elicited at Mc Burneys point applied located at halfway between the umbilicus and the anterior spine of the Ilium. Rebound tenderness (ex. Production or intensification of pain when pressure is released) may be present. The extent of tenderness and muscle spasm and the existence of the constipation or diarrhea depend not so much on the severity of the appendiceal infection as on the location of the appendix. If the appendix curls around behind the cecum, pain and tenderness may be felt in the lumbar region. Rovsings sign maybe elicited by palpating the left lower quadrant. If the appendix has ruptured, the pain become more diffuse, abdominal distention develops as a result of paralytic ileus, and the patient condition become worsens. Constipation can also occur with an acute process such as appendicitis. Laxative administered in the instance may result in perforation of the in flared appendix. In general a laxative should never be given when a persons has fever, nausea or pain. Anatomy and Physiology of Digestive System The mouth, or oral cavity, is the first part of the digestive tract. It is adapted to receive food by ingestion, break it into small particles by mastication, and mix it with saliva. The lips, cheeks, and palate form the boundaries. The oral cavity contains the teeth and tongue and receives the secretions from the salivary glands.

Lips and Cheeks The lips and cheeks help hold food in the mouth and keep it in place for chewing. They are also used in the formation of words for speech. The lips contain numerous sensory receptors that are useful for judging the temperature and texture of foods. Palate The palate is the roof of the oral cavity. It separates the oral cavity from the nasal cavity. The anterior portion, the hard palate, is supported by bone. The posterior portion, the soft palate, is skeletal muscle and connective tissue. Posteriorly, the soft palate ends in a projection called the uvula. During swallowing, the soft palate and uvula move upward to direct food away from the nasal cavity and into the oropharynx. Tongue The tongue manipulates food in the mouth and is used in speech. The surface is covered with papillae that provide friction and contain the taste buds. Teeth A complete set of deciduous (primary) teeth contains 20 teeth. There are 32 teeth in a complete permanent (secondary) set. The shape of each tooth type corresponds to the way it handles food. Pharynx The pharynx is a fibromuscular passageway that connects the nasal and oral cavities to the larynx and esophagus. It serves both the respiratory and digestive systems as a channel for air and food. The upper region, the nasopharynx, is posterior to the nasal cavity. It contains the pharyngeal tonsils, or adenoids, functions as a passageway for air, and has no function in the digestive system. The middle region posterior to the oral cavity is the oropharynx. This is the first region food enters when it is swallowed. The opening from the oral cavity into the oropharynx is called the fauces. Masses of lymphoid tissue, the palatine tonsils, are near the fauces. The lower region, posterior to the larynx, is the laryngopharynx, or hypopharynx. The laryngopharynx opens into both the esophagus and the larynx. Esophagus The esophagus is a collapsible muscular tube that serves as a passageway between the pharynx and stomach. As it descends, it is posterior to the trachea and anterior to the vertebral column. It passes through an opening in the diaphragm, called the esophageal hiatus, and then empties into the stomach. The mucosa has glands that secrete mucus to keep the lining moist and well lubricated to ease the passage of food. Upper and lower esophageal sphincters control the movement of food into and out of the esophagus. The lower esophageal sphincter is sometimes called the cardiac sphincter and resides at the esophagogastric junction

Stomach the stomach, which receives food from the esophagus, is located in the upper left quadrant of the abdomen. The stomach is divided into the fundic, cardiac, body, and pyloric regions. The lesser and greater curvatures are on the right and left sides, respectively, of the stomach. Small Intestine The small intestine extends from the pyloric sphincter to the ileocecal valve, where it empties into the large intestine. The small intestine finishes the process of digestion, absorbs the nutrients, and passes the residue on to the large intestine. The liver, gallbladder, and pancreas are accessory organs of the digestive system that are closely associated with the small intestine. The small intestine is divided into the duodenum, jejunum, and ileum. The small intestine follows the general structure of the digestive tract in that the wall has a mucosa with simple columnar epithelium, submucosa, smooth muscle with inner circular and outer longitudinal layers, and serosa. The absorptive surface area of the small intestine is increased by plicae circulares, villi, and microvilli. Exocrine cells in the mucosa of the small intestine secrete mucus, peptidase, sucrase, maltase, lactase, lipase, and enterokinase. Endocrine cells secrete cholecystokinin and secretin. The most important factor for regulating secretions in the small intestine is the presence of chyme. This is largely a local reflex action in response to chemical and mechanical irritation from the chyme and in response to distention of the intestinal wall. This is a direct reflex action, thus the greater the amount of chyme, the greater the secretion. Large Intestine The large intestine is larger in diameter than the small intestine. It begins at the ileocecal junction, where the ileum enters the large intestine, and ends at the anus. The large intestine consists of the colon, rectum, and anal canal. The wall of the large intestine has the same types of tissue that are found in other parts of the digestive tract but there are some distinguishing characteristics. The mucosa has a large number of goblet cells but does not have any villi. The longitudinal muscle layer, although present, is incomplete. The longitudinal muscle is limited to three distinct bands, called teniae coli, that run the entire length of the colon. Contraction of the teniae coli exerts pressure on the wall and creates a series of pouches, called haustra, along the colon. Epiploic appendages, pieces of fat-filled connective tissue, are attached to the outer surface of the colon. Unlike the small intestine, the large intestine produces no digestive enzymes. Chemical digestion is completed in the small intestine before the chyme reaches the large intestine. Functions of the large intestine include the absorption of water and electrolytes and the elimination of feces. Rectum and Anus The rectum continues from the signoid colon to the anal canal and has a thick muscular layer. It follows the curvature of the sacrum and is firmly attached to it by connective tissue. The rectum and ends about 5 cm below the tip of the coccyx, at the beginning of the anal canal. The last 2 to 3 cm of the digestive tract is the anal canal, which continues from the rectum

and opens to the outside at the anus. The mucosa of the rectum is folded to form longitudinal anal columns. The smooth muscle layer is thick and forms the internal anal sphincter at the superior end of the anal canal. This sphincter is under involuntary control. There is an external anal sphincter at the inferior end of the anal canal. This sphincter is composed of skeletal muscle and is under voluntary control

Background
Appendicitis is defined as an inflammation of the inner lining of the vermiform appendix that spreads to its other parts. This condition is a common and urgent surgical illness with protean manifestations, generous overlap with other clinical syndromes, and significant morbidity, which increases with diagnostic delay (see Clinical Presentation). In fact, despite diagnostic and therapeutic advancement in medicine, appendicitis remains a clinical emergency and is one of the more common causes of acute abdominal pain. No single sign, symptom, or diagnostic test accurately confirms the diagnosis of appendiceal inflammation in all cases, and the classic history of anorexia and periumbilical pain followed by nausea, right lower quadrant (RLQ) pain, and vomiting occurs in only 50% of cases (see Clinical Presentation). Appendicitis may occur for several reasons, such as an infection of the appendix, but the most important factor is the obstruction of the appendiceal lumen (see Pathogenesis and Etiology). Left untreated, appendicitis has the potential for severe complications, including perforation or sepsis, and may even cause death (see Prognosis and Complications). However, the differential diagnosis of appendicitis is often a clinical challenge because appendicitis can mimic several abdominal conditions (see Diagnostic Considerations and Differentials).[1] Appendectomy remains the only curative treatment of appendicitis (see Treatment and Management). The surgeon's goals are to evaluate a relatively small population of patients referred for suspected appendicitis and to minimize the negative appendectomy rate without increasing the incidence of perforation. The emergency department (ED) clinician must evaluate the larger group of patients who present to the ED with abdominal pain of all etiologies with the goal of approaching 100% sensitivity for the diagnosis in a time-, cost-, and consultation-efficient manner.

Anatomy
The appendix is a wormlike extension of the cecum and, for this reason, has been called the vermiform appendix. The average length of the appendix is 8-10 cm (ranging from 2-20 cm). The appendix appears during the fifth month of gestation, and several lymphoid follicles are scattered in its mucosa. Such follicles increase in number when individuals are aged 8-20 years. A normal appendix is seen below.
Normal appendix; barium enema radiographic examination. A complete contrast-filled appendix is observed (arrows), which effectively excludes the diagnosis of appendicitis.

The appendix is contained within the visceral peritoneum that forms the serosa, and its exterior layer is longitudinal and derived from the taenia coli; the deeper, interior muscle layer is circular. Beneath these layers lies the submucosal layer, which contains lymphoepithelial tissue. The mucosa consists of columnar epithelium with few glandular elements and neuroendocrine argentaffin cells. Taenia coli converge on the posteromedial area of the cecum, which is the site of the appendiceal base. The appendix runs into a serosal sheet of the peritoneum called the mesoappendix, within which courses the appendicular artery, which is derived from the ileocolic artery. Sometimes, an accessory appendicular artery (deriving from the posterior cecal artery) may be found.

Appendiceal vasculature
The vasculature of the appendix must be addressed to avoid intraoperative hemorrhages. The appendicular artery is contained within the mesenteric fold that arises from a peritoneal extension from the terminal ileum to the medial aspect of the cecum and appendix; it is a terminal branch of the ileocolic artery and runs adjacent to the appendicular wall. Venous drainage is via the ileocolic veins and the right colic vein into the portal vein; lymphatic drainage occurs via the ileocolic nodes along the course of the superior mesenteric artery to the celiac nodes and cisterna chyli.

Appendiceal location
The appendix has no fixed position. It originates 1.7-2.5 cm below the terminal ileum, either in a dorsomedial location (most common) from the cecal fundus, directly beside the ileal orifice, or as a funnel-shaped opening (2-3% of patients). The appendix has a retroperitoneal location in 65% of patients and may descend into the iliac fossa in 31%. In fact, many individuals may have an appendix located in the retroperitoneal space; in the pelvis; or behind the terminal ileum, cecum, ascending colon, or liver. Thus, the course of the appendix, the position of its tip, and the difference in appendiceal position considerably changes clinical findings, accounting for the nonspecific signs and symptoms of appendicitis.

Congenital appendiceal disorders

Appendiceal congenital disorders are extremely rare but occasionally reported (eg, agenesis, duplication, triplication).

Pathophysiology
Reportedly, appendicitis is caused by obstruction of the appendiceal lumen from a variety of causes (see Etiology). Independent of the etiology, obstruction is believed to cause an increase in pressure within the lumen. Such an increase is related to continuous

secretion of fluids and mucus from the mucosa and the stagnation of this material. At the same time, intestinal bacteria within the appendix multiply, leading to the recruitment of white blood cells (see the image below) and the formation of pus and subsequent higher intraluminal pressure.
Technetium-99m radionuclide scan of the abdomen shows focal uptake of labeled WBCs in the right lower quadrant consistent with acute appendicitis.

If appendiceal obstruction persists, intraluminal pressure rises ultimately above that of the appendiceal veins, leading to venous outflow obstruction. As a consequence, appendiceal wall ischemia begins, resulting in a loss of epithelial integrity and allowing bacterial invasion of the appendiceal wall. Within a few hours, this localized condition may worsen because of thrombosis of the appendicular artery and veins, leading to perforation and gangrene of the appendix. As this process continues, a periappendicular abscess or peritonitis may occur.

Etiology
Appendicitis is caused by obstruction of the appendiceal lumen. The most common causes of luminal obstruction include lymphoid hyperplasia secondary to inflammatory bowel disease (IBD) or infections (more common during childhood and in young adults), fecal stasis and fecaliths (more common in elderly patients), parasites (especially in Eastern countries), or, more rarely, foreign bodies and neoplasms. Fecaliths form when calcium salts and fecal debris become layered around a nidus of inspissated fecal material located within the appendix. Lymphoid hyperplasia is associated with various inflammatory and infectious disorders including Crohn disease, gastroenteritis, amebiasis, respiratory infections, measles, and mononucleosis. Obstruction of the appendiceal lumen has less commonly been associated with bacteria (Yersinia species, adenovirus, cytomegalovirus, actinomycosis, Mycobacteria species, Histoplasma species), parasites (eg, Schistosomes species, pinworms, Strongyloides stercoralis), foreign material (eg, shotgun pellet, intrauterine device, tongue stud, activated charcoal), tuberculosis, and tumors.

Epidemiology
Appendicitis is one of the more common surgical emergencies, and it is one of the most common causes of abdominal pain. In the United States, 250,000 cases of appendicitis are reported annually, representing 1 million patient-days of admission. The incidence of acute appendicitis has been declining steadily since the late 1940s, and the current annual incidence is 10 cases per 100,000

population. Appendicitis occurs in 7% of the US population, with an incidence of 1.1 cases per 1000 people per year. Some familial predisposition exists. In Asian and African countries, the incidence of acute appendicitis is probably lower because of the dietary habits of the inhabitants of these geographic areas. The incidence of appendicitis is lower in cultures with a higher intake of dietary fiber. Dietary fiber is thought to decrease the viscosity of feces, decrease bowel transit time, and discourage formation of fecaliths, which predispose individuals to obstructions of the appendiceal lumen. In the last few years, a decrease in frequency of appendicitis in Western countries has been reported, which may be related to changes in dietary fiber intake. In fact, the higher incidence of appendicitis is believed to be related to poor fiber intake in such countries. There is a slight male preponderance of 3:2 in teenagers and young adults; in adults, the incidence of appendicitis is approximately 1.4 times greater in men than in women. The incidence of primary appendectomy is approximately equal in both sexes. The incidence of appendicitis gradually rises from birth, peaks in the late teen years, and gradually declines in the geriatric years. The mean age when appendicitis occurs in the pediatric population is 6-10 years. Lymphoid hyperplasia is observed more often among infants and adults and is responsible for the increased incidence of appendicitis in these age groups. Younger children have a higher rate of perforation, with reported rates of 50-85%. The median age at appendectomy is 22 years. Although rare, neonatal and even prenatal appendicitis have been reported. Clinicians must maintain a high index of suspicion in all age groups.

Prognosis
Acute appendicitis is the most common reason for emergency abdominal surgery. Appendectomy carries a complication rate of 415%, as well as associated costs and the discomfort of hospitalization and surgery. Therefore, the goal of the surgeon is to make an accurate diagnosis as early as possible. Delayed diagnosis and treatment account for much of the mortality and morbidity associated with appendicitis. The overall mortality rate of 0.2-0.8% is attributable to complications of the disease rather than to surgical intervention. The mortality rate in children ranges from 0.1% to 1%; in patients older than 70 years, the rate rises above 20%, primarily because of diagnostic and therapeutic delay. Appendiceal perforation is associated with increased morbidity and mortality compared with nonperforating appendicitis. The mortality risk of acute but not gangrenous appendicitis is less than 0.1%, but the risk rises to 0.6% in gangrenous appendicitis. The rate of perforation varies from 16% to 40%, with a higher frequency occurring in younger age groups (40-57%) and in patients older than 50 years (55-70%), in whom misdiagnosis and delayed diagnosis are common. Complications occur in 1-5% of patients with appendicitis, and postoperative wound infections account for almost one third of the associated morbidity.

History
Variations in the position of the appendix, age of the patient, and degree of inflammation make the clinical presentation of appendicitis notoriously inconsistent. Statistics report that 1 of 5 cases of appendicitis is misdiagnosed; however, a normal appendix is found in 15-40% of patients who have an emergency appendectomy. Niwa et al reported an interesting case of a young woman with recurrent pain in who was referred for appendicitis, treated with antibiotics, and was found to have an appendiceal diverticulitis associated with a rare pelvic pseudocyst at laparotomy after 12 months.[2] Her condition was probably due to diverticular perforation of the pseudocyst.

Symptoms
The classic history of anorexia and periumbilical pain followed by nausea, right lower quadrant (RLQ) pain, and vomiting occurs in only 50% of cases. Nausea is present in 61-92% of patients; anorexia is present in 74-78% of patients. Neither finding is statistically different from findings in patients who present to the emergency department with other etiologies of abdominal pain. In addition, when vomiting occurs, it nearly always follows the onset of pain. Vomiting that precedes pain is suggestive of intestinal obstruction, and the diagnosis of appendicitis should be reconsidered. Diarrhea or constipation is noted in as many as 18% of patients and should not be used to discard the possibility of appendicitis. The most common symptom of appendicitis is abdominal pain. Typically, symptoms begin as periumbilical or epigastric pain migrating to the right lower quadrant (RLQ) of the abdomen. This pain migration is the most discriminating feature of the patient's history, with a sensitivity and specificity of approximately 80%, a positive likelihood ratio of 3.18, and a negative likelihood ratio of 0.5.[3] Patients usually lie down, flex their hips, and draw their knees up to reduce movements and to avoid worsening their pain. Later, a worsening progressive pain along with vomiting, nausea, and anorexia are described by the patient. Usually, a fever is not present at this stage. The duration of symptoms is less than 48 hours in approximately 80% of adults but tends to be longer in elderly persons and in those with perforation. Approximately 2% of patients report duration of pain in excess of 2 weeks. A history of similar pain is reported in as many as 23% of cases, but this history of similar pain, in and of itself, should not be used to rule out the possibility of appendicitis. In addition to recording the history of the abdominal pain, obtain a complete summary of the recent personal history surrounding gastroenterologic, genitourinary, and pneumologic conditions, as well as consider gynecologic history in female patients. An inflamed appendix near the urinary bladder or ureter can cause irritative voiding symptoms and hematuria or pyuria. Cystitis in male patients is rare in the absence of instrumentation. Consider the possibility of an inflamed pelvic appendix in male patients

with apparent cystitis. Also consider the possibility of appendicitis in pediatric or adult patients who present with acute urinary retention.[4]

Physical Examination
It is important to remember that the position of the appendix is variable. Of 100 patients undergoing 3-dimensional (3-D) multidetector computed tomography (MDCT) scanning, the base of the appendix was located at the McBurney point in only 4% of patients; in 36%, the base was within 3 cm of the point; in 28%, it was 3-5 cm from that point; and, in 36% of patients, the base of the appendix was more than 5 cm from the McBurney point.[5] The most specific physical findings in appendicitis are rebound tenderness, pain on percussion, rigidity, and guarding. Although RLQ tenderness is present in 96% of patients, this is a nonspecific finding. Rarely, left lower quadrant (LLQ) tenderness has been the major manifestation in patients with situs inversus or in patients with a lengthy appendix that extends into the LLQ. Tenderness on palpation in the RLQ over the McBurney point is the most important sign in these patients. A careful physical examination, not limited to the abdomen, must be performed in any patient with suspected appendicitis. Gastrointestinal (GI), genitourinary, and pulmonary systems must be studied. Male infants and children occasionally present with an inflamed hemiscrotum due to migration of an inflamed appendix or pus through a patent processus vaginalis. This is often initially misdiagnosed as acute testicular torsion. In addition, perform a rectal examination in any patient with an unclear clinical picture, and perform a pelvic examination in all women with abdominal pain. According to the American College of Emergency Physicians (ACEP) 2010 clinical policy update, clinical signs and symptoms should be used to stratify patient risk and to choose next steps for testing and management.[6, 7]

Accessory signs
In a minority of patients with acute appendicitis, some other signs may be noted. However, their absence never should be used to rule out appendiceal inflammation. The Rovsing sign (RLQ pain with palpation of the LLQ) suggests peritoneal irritation in the RLQ precipitated by palpation at a remote location. The obturator sign (RLQ pain with internal and external rotation of the flexed right hip) suggests that the inflamed appendix is located deep in the right hemipelvis. The psoas sign (RLQ pain with extension of the right hip or with flexion of the right hip against resistance) suggests that an inflamed appendix is located along the course of the right psoas muscle. The Dunphy sign (sharp pain in the RLQ elicited by a voluntary cough) may be helpful in making the clinical diagnosis of localized peritonitis. Similarly, RLQ pain in response to percussion of a remote quadrant of the abdomen, or to firm percussion of the patient's heel, suggests peritoneal inflammation.

The Markle sign, pain elicited in a certain area of the abdomen when the standing patient drops from standing on toes to the heels with a jarring landing, was studied in 190 patients undergoing appendectomy and found to have a sensitivity of 74%.[8]

Rectal examination
There is no evidence in the medical literature that the digital rectal examination (DRE) provides useful information in the evaluation of patients with suspected appendicitis; however, failure to perform a rectal examination is frequently cited in successful malpractice claims. In 2008, Sedlak et al studied 577 patients who underwent DRE as part of an evaluation for suspected appendicitis and found no value as a means of distinguishing patients with and without appendicitis.[9]

Approach Considerations
Appendectomy remains the only curative treatment of appendicitis, but management of patients with an appendiceal mass can usually be divided into the following 3 treatment categories:

Patients with a phlegmon or a small abscess: After intravenous (IV) antibiotic therapy, an interval appendectomy can be performed 4-6 weeks later. Patients with a larger well-defined abscess: After percutaneous drainage with IV antibiotics is performed, the patient can be discharged with the catheter in place. Interval appendectomy can be performed after the fistula is closed. Patients with a multicompartmental abscess: These patients require early surgical drainage.

Although many controversies exist over the nonoperative management of acute appendicitis, antibiotics have an important role in the treatment of patients with this condition. Antibiotics considered for patients with appendicitis must offer full aerobic and anaerobic coverage. The duration of the administration is closely related to the stage of appendicitis at the time of the diagnosis, considering either intraoperative findings or postoperative evolution. According to several studies, antibiotic prophylaxis should be administered before every appendectomy. When the patient becomes afebrile and the white blood cell (WBC) count normalizes, antibiotic treatment may be stopped. Cefotetan and cefoxitin seem to be the best choices of antibiotics. (See Medications).

Stages of Appendicitis
The stages of appendicitis can be divided into early, suppurative, gangrenous, perforated, phlegmonous, spontaneous resolving, recurrent, and chronic.

Early stage appendicitis

In the early stage of appendicitis, obstruction of the appendiceal lumen leads to mucosal edema, mucosal ulceration, bacterial diapedesis, appendiceal distention due to accumulated fluid, and increasing intraluminal pressure. The visceral afferent nerve fibers are stimulated, and the patient perceives mild visceral periumbilical or epigastric pain, which usually lasts 4-6 hours.

Suppurative appendicitis
Increasing intraluminal pressures eventually exceed capillary perfusion pressure, which is associated with obstructed lymphatic and venous drainage and allows bacterial and inflammatory fluid invasion of the tense appendiceal wall. Transmural spread of bacteria causes acute suppurative appendicitis. When the inflamed serosa of the appendix comes in contact with the parietal peritoneum, patients typically experience the classic shift of pain from the periumbilicus to the right lower abdominal quadrant (RLQ), which is continuous and more severe than the early visceral pain.

Gangrenous appendicitis
Intramural venous and arterial thromboses ensue, resulting in gangrenous appendicitis.

Perforated appendicitis
Persisting tissue ischemia results in appendiceal infarction and perforation. Perforation can cause localized or generalized peritonitis.

Phlegmonous appendicitis or abscess

An inflamed or perforated appendix can be walled off by the adjacent greater omentum or small-bowel loops, resulting in phlegmonous appendicitis or focal abscess.

Spontaneously resolving appendicitis

If the obstruction of the appendiceal lumen is relieved, acute appendicitis may resolve spontaneously.[13, 14] This occurs if the cause of the symptoms is lymphoid hyperplasia or when a fecalith is expelled from the lumen.

Recurrent appendicitis

The incidence of recurrent appendicitis is 10%. The diagnosis is accepted as such if the patient underwent similar occurrences of RLQ pain at different times that, after appendectomy, were histopathologically proven to be the result of an inflamed appendix.

Chronic appendicitis
Chronic appendicitis occurs with an incidence of 1% and is defined by the following: (1) the patient has a history of RLQ pain of at least 3 weeks duration without an alternative diagnosis; (2) after appendectomy, the patient experiences complete relief of symptoms; (3) histopathologically, the symptoms were proven to be the result of chronic active inflammation of the appendiceal wall or fibrosis of the appendix.