GI Cancer

A gastrointestinal stromal tumor (GIST) is one of the most common mesenchymal tumors of the gastrointestinal tract (1-3% of all gastrointestinal malignancies). They are typically defined as tumors whose behavior is driven by mutations in the Kit gene or PDGFRA gene, and may or may not stain positively for Kit.

 

Signs and symptoms

 

Patients present with trouble swallowing, gastrointestinal hemorrhage or metastases (mainly in the liver). Intestinal obstruction is rare, due to the tumor’s outward pattern of growth. Often, there is a history of vague abdominal pain or discomfort, and the tumor has become rather large by time the diagnosis is made.

 

Generally, the definitive diagnosis is made with a biopsy, which can be obtained endoscopically, percutaneously with CT or ultrasound guidance or at the time of surgery.

 

Diagnosis

 

As part of the analysis, blood tests and CT scanning are often undertaken.

A biopsy sample will be investigated under the microscope. The histopathologist identifies the characteristics of GISTs (spindle cells in 70-80%, epitheloid aspect in 20-30%). Smaller tumors can usually be found to the muscularis propria layer of the intestinal wall. Large ones grow, mainly outward, from the bowel wall until the point where they outstrip their blood supply and necrose (die) on the inside, forming a cavity that may eventually come to communicate with the bowel lumen.

 

When GIST is suspected—as opposed to other causes for similar tumors—the pathologist can use immunohistochemistry (specific antibodies that stain the molecule CD117 (also known as c-kit) —see below). 95% of all GISTs are CD117-positive (other possible markers include CD34, desmin, vimentin and others). Other cells that show CD117 positivity are mast cells.

 

If the CD117 stain is negative and suspicion remains that the tumor is a GIST, the newer antibody DOG-1 (Discovered On GIST-1) can be used. Also sequencing of Kit and PDGFRA can be used to prove the diagnosis.

 

Radiology

 

Barium fluoroscopic examinations (upper GI series and small bowel series (small bowel follow-through)) and CT are commonly used to evaluate the patient with upper abdominal pain. Both are adequate to make the diagnosis of GIST, although small tumors may be missed, especially in cases of a suboptimal examination.

 

Small GISTs appear as intramural masses. When large (> 5 cm), they most commonly grow outward from the bowel. Internal calcifications may be present. As the tumor outstrips its blood supply, it can necrose internally, creating a central fluid-filled cavity that can eventually ulcerate into the lumen of the bowel or stomach.

 

The tumor can directly invade adjacent structures in the abdomen. The most common site of spread is to the liver. Spread to the peritoneum may be seen. In distinction to gastric adenocarcinoma or gastric/small bowel lymphoma, malignant adenopathy (swollen lymph nodes) is uncommon (<10%).

 

Pathophysiology

 

GISTs are tumors of connective tissue, i.e. sarcomas; unlike most gastrointestinal tumors, they are non-epithelial. 70% occur in the stomach, 20% in the small intestine and less than 10% in the esophagus. Small tumors are generally benign, especially when cell division rate is slow, but large tumors disseminate to the liver, omentum and peritoneal cavity. They rarely occur in other abdominal organs.

 

Some tumors of the stomach and small bowel referred to as leiomyosarcomas (malignant tumor of smooth muscle) would most likely be reclassified as GISTs today on the basis of immunohistochemical staining.

 

GISTs are thought to arise from interstitial cells of Cajal (ICC), that are normally part of the autonomic nervous system of the intestine. They serve a pacemaker function in controlling motility.

 

Most (50-80%) GISTs arise because of a mutation in a gene called c-kit. This gene encodes a transmembrane receptor for a growth factor termed scf (stem cell factor). The c-kit/CD117 receptor is expressed on ICCs and a large number of other cells, mainly bone marrow cells, mast cells, melanocytes and several others. In the gut, however, a mass staining positive for CD117 is likely to be a GIST, arising from ICC cells.

 

The c-kit molecule comprises a long extracellular domain, a transmembrane segment, and an intracellular part. Mutations generally occur in the DNA encoding the intracellular part (exon 11), which acts as a tyrosine kinase to activate other enzymes. Mutations make c-kit function independent of activation by scf, leading to a high cell division rate and possibly genomic instability. It is likely that additional mutations are “required” for a cell with a c-kit mutation to develop into a GIST, but the c-kit mutation is probably the first step of this process. The tyrosine kinase function of c-kit is vital in the therapy for GISTs, as described below.

 

Genetics

 

Although some families with hereditary GISTs have been described, most cases are sporadic. In GIST cells, the c-kit gene is mutated approximately 85% to 90% of the time. 35% of the GIST cells that do not have a mutated c-kit (“wild-type”) do have a mutation in another gene, PDGFR-α (platelet derived growth factor receptor alpha), which is a related tyrosine kinase. Mutations in the exons 11, 9 and rarely 13 and 17 of the c-kit gene are known to occur in GIST. D816V point mutations in c-kit exon 17 are responsible for resistance to targeted therapy drugs like imatinib mesylate. Mutations in c-kit and PDGFrA are mutually exclusive.

 

Therapy

 

Tumor size, mitotic rate, and location can be used to predict the risk of recurrence in GIST patients. Tumors

Surgery is the mainstay of therapy for non-metastatic GISTs. Lymph node metastases are rare and routine removal of lymph nodes is typically not necessary. Wide margins are not necessary. Laparoscopic surgery, a minimally invasive type of abdominal surgery using telescopes and specialized instruments, has been shown to be effective for removal of these tumors without needing large incisions.

 

Until recently, GISTs were notorious for being resistant to chemotherapy, with a success rate of <5%. Recently, the c-kit tyrosine kinase inhibitor imatinib, a drug initially marketed for chronic myelogenous leukemia, was found to be useful in treating GISTs, leading to a 40-70% response rate in metastatic or inoperable cases.

 

Data presented at the 2007 ASCO meeting showed that adjuvant treatment with imatinib following surgical resection of GIST tumors can significantly reduce the risk of disease recurrence (6% recurrence on imatinib vs. 17% without therapy at 12 months). The optimal duration of adjuvant therapy is currently unknown; trials are ongoing evaluating treatment durations of 1, 2, and 3 years.

 

Patients who develop resistance to imatinib may respond to the multiple tyrosine kinase inhibitor sunitinib (marketed as Sutent).

 

The effectiveness of imatinib and sunitinib depend on the genotype.

 

Therapy for GIST is best directed by physicians familiar with the disease. Such doctors, specifically surgeons and medical oncologists, are found at major cancer centers.

Esophageal cancer is malignancy of the esophagus. There are various subtypes, primarily adenocarcinoma (approx. 50-80% of all Esophageal cancer) and squamous cell cancer. Squamous cell cancer arises from the cells that line the upper part of the esophagus. Adenocarcinoma arises from glandular cells that are present at the junction of the esophagus and stomach. Esophageal tumors usually lead to dysphagia (difficulty swallowing), pain and other symptoms, and are diagnosed with biopsy. Small and localized tumors are treated surgically with curative intent. Larger tumors tend not to be operable and hence are treated with Palliative care; their growth can still be delayed with chemotherapy, radiotherapy or a combination of the two. In some cases chemo- and radiotherapy can render these larger tumors operable. Prognosis depends on the extent of the disease and other medical problems, but is fairly poor.

 

Esophageal cancers are typically carcinomas which arise from the epithelium, or surface lining, of the esophagus. Most esophageal cancers fall into one of two classes: squamous cell carcinomas, which are similar to head and neck cancer in their appearance and association with tobacco and alcohol consumption, and adenocarcinomas, which are often associated with a history of gastroesophageal reflux disease and Barrett’s esophagus.

 

Signs and symptoms

 

Dysphagia and Odynophagia are the most common symptoms of esophageal cancer. Dysphagia (difficulty swallowing) is the first symptom in most patients. Odynophagia (painful swallowing) may be present. Fluids and soft foods are usually tolerated, while hard or bulky substances (such as bread or meat) cause much more difficulty. Substantial weight loss is characteristic as a result of poor nutrition and the active cancer. Pain, often of a burning nature, may be severe and worsened by swallowing, and can be spasmodic in character. An early sign may be an unusually husky or raspy voice.

 

The presence of the tumor may disrupt normal peristalsis (the organised swallowing reflex), leading to nausea and vomiting, regurgitation of food, coughing and an increased risk of aspiration pneumonia. The tumor surface may be fragile and bleed, causing hematemesis (vomiting up blood). Compression of local structures occurs in advanced disease, leading to such problems as upper airway obstruction and superior vena cava syndrome. Fistulas may develop between the esophagus and the trachea, increasing the pneumonia risk; this condition is usually heralded by cough, fever or aspiration.

 

If the disease has spread elsewhere, this may lead to symptoms related to this: liver metastasis could cause jaundice and ascites, lung metastasis could cause shortness of breath, pleural effusions, etc.

 

Causes

 

Increased risk

 

Barrett’s esophagus is considered to be a risk factor for esophageal adenocarcinoma.

 

• There are a number of risk factors for esophageal cancer. Some subtypes of cancer are linked to particular risk factors:

• Age. Most patients are over 60, and the median in US patients is 67.

• Sex. It is more common in men.

• Heredity. It is more likely in people who have close relatives with cancer.

• Tobacco smoking and heavy alcohol use increase the risk, and together appear to increase the risk more than either individually.

• Gastroesophageal reflux disease (GERD) and its resultant Barrett’s esophagus increase esophageal cancer risk due to the chronic irritation of the mucosal lining (adenocarcinoma is more common in this condition, while all other risk factors predispose more for squamous cell carcinoma).

• Human papillomavirus (HPV)

• Corrosive injury to esophagus by swallowing strong alkalines (lye) or acids.

• Particular dietary substances, such as nitrosamine.

• A medical history of other head and neck cancers increases the chance of developing a second cancer in the head and neck area, including esophageal cancer.

• Plummer-Vinson syndrome (anemia and esophageal webbing)

• Tylosis and Howel-Evans syndrome (hereditary thickening of the skin of the palms and soles).

• Radiation therapy for other conditions in the mediastinum.

• Celiac disease predisposes towards squamous cell carcinoma.

• Obesity increases the risk of adenocarcinoma fourfold. It is suspected that increased risk of reflux may be behind this association.

• Drinking large quantities of hot beverages, especially hot brewed teas

• Alcohol consumption in individuals predisposed to alcohol flush reaction.

• Achalasia

Decreased risk

 

• Risk appears to be less in patients using aspirin or related drugs (NSAIDs).

• The role of Helicobacter pylori in progression to esophageal adenocarcinoma is still uncertain, but, on the basis of population data, it may carry a protective effect. It is postulated that H. pylori prevents chronic gastritis, which is a risk factor for reflux, which in turn is a risk factor for esophageal adenocarcinoma.

• According to the National Cancer Institute, “diets high in cruciferous (cabbage, broccoli, cauliflower) and green and yellow vegetables and fruits are associated with a decreased risk of esophageal cancer.”

• Moderate coffee consumption is associated with a decreased risk.

• According to one Italian study of “diet surveys completed by 5,500 Italians”—a study which has raised debates questioning its claims among cancer researchers cited in news reports about it—eating pizza more than once a week appears “to be a favorable indicator of risk for digestive tract neoplasms in this population.”

 

Diagnosis

 

Endoscopy and radial endoscopic ultrasound images of submucosal tumour in mid-esophagus.

Clinical evaluation

 

Although an occlusive tumor may be suspected on a barium swallow or barium meal, the diagnosis is best made with esophagogastroduodenoscopy (EGD, endoscopy); this involves the passing of a flexible tube down the esophagus and visualising the wall. Biopsies taken of suspicious lesions are then examined histologically for signs of malignancy.

 

Additional testing is usually performed to estimate the tumor stage. Computed tomography (CT) of the chest, abdomen and pelvis, can evaluate whether the cancer has spread to adjacent tissues or distant organs (especially liver and lymph nodes). The sensitivity of CT scan is limited by its ability to detect masses (e.g. enlarged lymph nodes or involved organs) generally larger than 1 cm. FDG-PET (positron emission tomography) scan is also being used to estimate whether enlarged masses are metabolically active, indicating faster-growing cells that might be expected in cancer. Esophageal endoscopic ultrasound (EUS) can provide staging information regarding the level of tumor invasion, and possible spread to regional lymph nodes.

 

The location of the tumor is generally measured by the distance from the teeth. The esophagus (25 cm or 10 inches long) is commonly divided into three parts for purposes of determining the location. Adenocarcinomas tend to occur distally and squamous cell carcinomas proximally, but the converse may also be the case.

 

Histopathology

 

Most tumors of the esophagus are malignant, only about 0.5% are benign. A very small proportion (under 10%) is leiomyoma (smooth muscle tumor) or gastrointestinal stromal tumor (GIST). Malignant tumors are generally adenocarcinomas, squamous cell carcinomas, and occasionally small-cell carcinomas. The latter share many properties with small-cell lung cancer, and are relatively sensitive to chemotherapy compared to the other types.

 

Management

Self-expandable metallic stents are used for the palliation of esophageal cancer.

General approaches

 

Esophageal cancer affecting the lower esophageus. Insets show the tumor in more detail both before and after placement of a stent.

The treatment is determined by the cellular type of cancer (adenocarcinoma or squamous cell carcinoma vs other types), the stage of the disease, the general condition of the patient and other diseases present. On the whole, adequate nutrition needs to be assured, and adequate dental care is vital.

 

If the patient cannot swallow at all, a stent may be inserted to keep the esophagus patent; stents may also assist in occluding fistulas. A nasogastric tube may be necessary to continue feeding while treatment for the tumor is given, and some patients require a gastrostomy (feeding hole in the skin that gives direct access to the stomach). The latter two are especially important if the patient tends to aspirate food or saliva into the airways, predisposing for aspiration pneumonia.

 

Tumor treatments

 

Surgery is possible if the disease is localised, which is the case in 20–30% of all patients. If the tumor is larger but localised, chemotherapy and/or radiotherapy may occasionally shrink the tumor to the extent that it becomes “operable”; however, this combination of treatments (referred to as neoadjuvant chemoradiation) is still somewhat controversial in most medical circles. Esophagectomy is the removal of a segment of the esophagus; as this shortens the length of the remaining esophagus, some other segment of the digestive tract (typically the stomach or part of the Colon or jejunum]) is pulled up to the chest cavity and interposed. If the tumor is unresectable or the patient is not fit for surgery, palliative esophageal stenting can allow the patient to tolerate soft diet.

 

Endoscopic Therapy for Localized Disease There is accumulating data that endoscopic therapy is a safe, less invasive, and effective therapy for very early esophageal cancer. The candidates for endoscopic therapy are Stage 1 patients with tumors invading into the lamina propria (T1 mucosal) or submucosa (T1 submucosal) that do not have regional or distant metastasis. Patients with carcinoma in-situ or high-grade dysplasia can also be treated with endoscopic therapy. Submucosa cancers with increased risk of nodal metastases may not be as amenable to curative therapy.

 

The two forms of endoscopic therapy that have been used for Stage 0 and I disease are endoscopic mucosal resection (EMR) and mucosal ablation using photodynamic therapy, Nd-YAG laser, or argon plasma coagulation.

 

EMR Endoscopic Mucosal Resection has been advocated for early cancers (that is, those that are superficial and confined to the mucosa only) and has been shown to be a less invasive, safe, and highly effective nonsurgical therapy for early squamous cell esophageal cancer. Preliminary reports also suggest its safety and efficacy for early adenocarcinoma arising in Barrett’s esophagus. The prognosis after treatment with endoscopic mucosal resection is comparable to surgical resection. This technique can be attempted in patients, without evidence of nodal or distant metastases, with differentiated tumors that are slightly raised and less than 2 cm in diameter, or in differentiated tumors that are ulcerated and less than 1 cm in diameter. The most commonly employed modalities of endoscopic mucosal resection include strip biopsy, double-snare polypectomy, resection with combined use of highly concentrated saline and epinephrine, and resection using a cap.

 

The strip biopsy method for endoscopic mucosal resection of esophageal cancer is performed with a double-channel endoscope equipped with grasping forceps and snare. After marking the lesion border with an electric coagulator, saline is injected into the submucosa below the lesion to separate the lesion from the muscle layer and to force its protrusion. The grasping forceps are passed through the snare loop. The mucosa surrounding the lesion is grasped, lifted, and strangulated and resected by electrocautery. The endoscopic double-snare polypectomy method is indicated for protruding lesions. Using a double-channel scope, the lesion is grasped and lifted by the first snare and strangulated with the second snare for complete resection.

 

Endoscopic resection with injection of concentrated saline and epinephrine is carried out using a double-channel scope. The lesion borders are marked with a coagulator. Highly concentrated saline and epinephrine are injected (15–20 ml) into the submucosal layer to swell the area containing the lesion and elucidate the markings. The mucosa outside the demarcated border is excised using a high-frequency scalpel to the depth of the submucosal layer. The resected mucosa is lifted and grasped with forceps, trapping and strangulating the lesion with a snare, and then resected by electrocautery.

 

A fourth method of endoscopic mucosal resection employs the use of a clear cap and prelooped snare inside the cap. After insertion, the cap is placed on the lesion and the mucosa containing the lesion is drawn up inside the cap by aspiration. The mucosa is caught by the snare and strangulated, and finally resected by electrocautery. This is called the “band and snare” or “suck and cut” technique. The resected specimen is retrieved and submitted for microscopic examination for determination of tumor invasion depth, resection margin, and possible vascular involvement. The resulting “ulcer” heals within 3 weeks.

 

Although most lesions treated in the esophagus have been early squamous cell cancers, endoscopic snare resection can also be used to debulk or completely treat polypoid dysplastic or malignant lesions in Barrett’s esophagus. In a preliminary report from Germany, EMR was performed as primary treatment or adjunctive therapy following photodynamic therapy for early adenocarcinomas in Barrett’s esophagus. The “suck and cut” technique (with and without prior saline injection) was used as well as the “band and cut” technique. Although all tumors were resected without difficulty, 12.5% developed bleeding (which was managed successfully by endoscopic therapy). Eighty-one percent of the lesions were completely resected. The other lesions were also treated with other endoscopic techniques. While this report suggests it is feasible to completely resect local, circumscribed, early adenocarcinomas arising in Barrett’s esophagus, the relative safety and efficacy of EMR in conjunction with photodynamic therapy is unknown.

 

The major complications of endoscopic mucosal resection include postoperative bleeding and perforation and stricture formation. During the procedure, an injection of 100,000 times diluted epinephrine into the muscular wall, along with high frequency coagulation or clipping can be applied to the bleeding point for hemostasis. It is important to administer acid-reducing medications to prevent postoperative hemorrhage. Perforation may be prevented with sufficient saline injection to raise the mucosa containing the lesion. The “non-lifting sign” and complaints of pain when the snare strangulates the lesion are contrainidications of EMR. When perforation is recognized immediately after a procedure, the perforation should be closed by clips. Surgery should be considered in cases of endoscopic closure failure. The incidence of complication range from 0–50% and squamous cell recurrence rates range from 0–8%.

 

Laser therapy is the use of high-intensity light to destroy tumor cells; it affects only the treated area. This is typically done if the cancer cannot be removed by surgery. The relief of a blockage can help to reduce dysphagia and pain. Photodynamic therapy (PDT), a type of laser therapy, involves the use of drugs that are absorbed by cancer cells; when exposed to a special light, the drugs become active and destroy the cancer cells.

 

Chemotherapy depends on the tumor type, but tends to be cisplatin-based (or carboplatin or oxaliplatin) every three weeks with fluorouracil (5-FU) either continuously or every three weeks. In more recent studies, addition of epirubicin (ECF) was better than other comparable regimens in advanced nonresectable cancer. Chemotherapy may be given after surgery (adjuvant, i.e. to reduce risk of recurrence), before surgery (neoadjuvant) or if surgery is not possible; in this case, cisplatin and 5-FU are used. Ongoing trials compare various combinations of chemotherapy; the phase II/III REAL-2 trial – for example – compares four regimens containing epirubicin and either cisplatin or oxaliplatin and either continuously infused fluorouracil or capecitabine.

 

Radiotherapy is given before, during or after chemotherapy or surgery, and sometimes on its own to control symptoms. In patients with localised disease but contraindications to surgery, “radical radiotherapy” may be used with curative intent.

 

Follow-up

 

Patients are followed up frequently after a treatment regimen has been completed. Frequently, other treatments are necessary to improve symptoms and maximize nutrition.

 

Prognosis

 

In general, the prognosis of esophageal cancer is quite poor, because so many patients present with advanced disease: The overall five-year survival rate (5YSR) is less than 5%. Individualized prognosis depends largely on stage. Those with cancer restricted entirely to the esophageal mucosa have about an 80% 5YSR, but submucosal involvement brings this down to less than 50%. Extension into the muscularis propria (muscular layer of the esophageus) has meant a 20% 5YSR and extension to the structures adjacent to the esophagus results in a 7% 5YSR. Patients with distant metastases (who are not candidates for curative surgery) have a less than 3% 5YSR. Of all patients undergoing surgery with curative intent, the 5YSR is only about 25%.[citation needed] But these statistics are getting better, as more patients are getting diagnosis earlier because of the awareness of Barrett’s Esophagus.

Stomach or gastric cancer can develop in any part of the stomach and may spread throughout the stomach and to other organs; particularly the esophagus, lungs and the liver. Stomach cancer causes about 800,000 deaths worldwide per year.”

 

Signs and symptoms

 

Endoscopic image of linitis plastica, a type of stomach cancer where the entire stomach is invaded, leading to a leather bottle-like appearance with blood coming out of it.

 

Stomach cancer is often asymptomatic or causes only nonspecific symptoms in its early stages. By the time symptoms occur, the cancer has generally metastasized to other parts of the body, one of the main reasons for its poor prognosis.

 

Stomach cancer can cause the following signs and symptoms:

 

Early

 

• Indigestion or a burning sensation (heartburn)

• Loss of appetite, especially for meat

 

Late

 

• Abdominal pain or discomfort in the upper abdomen

• Nausea and vomiting

• Diarrhea or constipation

• Bloating of the stomach after meals

• Weight loss

• Weakness and fatigue

 

Bleeding (vomiting blood or having blood in the stool) which will appear as black. This can lead to anemia.

 

Dysphagia; this feature suggests a tumor in the cardia or extension of the gastric tumor in to the esophagus.

 

These can be symptoms of other problems such as a stomach virus, gastric ulcer or tropical sprue and diagnosis should be done by a gastroenterologist or an oncologist.

 

Causes

 

Infection by Helicobacter pylori is believed to be the cause of most stomach cancer while autoimmune atrophic gastritis, intestinal metaplasia and various genetic factors are associated with increased risk levels. It is not currently believed that diet has any role to play.

 

In more detail, H. pylori is the main risk factor in 65–80% of gastric cancers, but in only 2% of such infections. Approximately ten percent of cases show a genetic component. In Japan and other countries bracken consumption and spores are correlated with incidence of stomach cancer, though causality has yet to be established.

 

Gastric cancer shows a male predominance in its incidence as up to three males are affected for every female. Estrogen may protect women against the development of this cancer form.[6] A very small percentage of diffuse-type gastric cancers (see Histopathology below) are thought to be genetic. Hereditary Diffuse Gastric Cancer (HDGC) has recently been identified and research is ongoing. However, genetic testing and treatment options are already available for families at risk.

 

Some researchers showed a correlation between Iodine deficiency or excess, iodine-deficient goitre and gastric cancer; a decrease of the incidence of death rate from stomach cancer after implementation of the effective I-prophylaxis was reported too. The proposed mechanism of action is that iodide ion can function in gastric mucosa as an antioxidant reducing species that can detoxify poisonous reactive oxygen species, such as hydrogen peroxide. China being member of International Cancer Genome Consortium is leading efforts to map stomach cancer’s complete genome.

 

Diagnosis

 

To find the cause of symptoms, the doctor asks about the patient’s medical history, does a physical exam, and may order laboratory studies.

 

The patient may also have one or all of the following exams:

• Gastroscopic exam is the diagnostic method of choice. This involves insertion of a fibre optic camera into the stomach to visualize it.

• Upper GI series (may be called barium roentgenogram)

• Computed tomography or CT scanning of the abdomen may reveal gastric cancer, but is more useful to determine invasion into adjacent tissues, or the presence of spread to local lymph nodes.

 

Abnormal tissue seen in a gastroscope examination will be biopsied by the surgeon or gastroenterologist. This tissue is then sent to a pathologist for histological examination under a microscope to check for the presence of cancerous cells. A biopsy, with subsequent histological analysis, is the only sure way to confirm the presence of cancer cells.

 

Various gastroscopic modalities have been developed to increased yield of detect mucosa with a dye that accentuates the cell structure and can identify areas of dysplasia. Endocytoscopy involves ultra-high magnification to visualize cellular structure to better determine areas of dysplasia. Other gastroscopic modalities such as optical coherence tomography are also being tested investigationally for similar applications.

 

A number of cutaneous conditions are associated with gastric cancer. A condition of darkened hyperplasia of the skin, frequently of the axilla and groin, known as acanthosis nigricans, is associated with intra-abdominal cancers such as gastric cancer. Other cutaneous manifestations of gastric cancer include tripe palms (a similar darkening hyperplasia of the skin of the palms) and the sign of Leser-Trelat, which is the rapid development of skin lesions known as seborrheic keratoses.

 

Histopathology

 

• Gastric adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the gastric mucosa. It invades the gastric wall, infiltrating the muscularis mucosae, the submucosa and thence the muscularis propria. Histologically, there are two major types of gastric cancer (Lauren classification): intestinal type and diffuse type.

• Intestinal type adenocarcinoma: tumor cells describe irregular tubular structures, harboring pluristratification, multiple lumens, reduced stroma (“back to back” aspect). Often, it associates intestinal metaplasia in neighboring mucosa. Depending on glandular architecture, cellular pleomorphism and mucosecretion, adenocarcinoma may present 3 degrees of differentiation: well, moderate and poorly differentiate.

• Diffuse type adenocarcinoma (mucinous, colloid): Tumor cells are discohesive and secrete mucus which is delivered in the interstitium producing large pools of mucus/colloid (optically “empty” spaces). It is poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery – “signet-ring cell”.

 

Staging

 

If cancer cells are found in the tissue sample, the next step is to stage, or find out the extent of the disease. Various tests determine whether the cancer has spread and, if so, what parts of the body are affected. Because stomach cancer can spread to the liver, the pancreas, and other organs near the stomach as well as to the lungs, the doctor may order a CT scan, a PET scan, an endoscopic ultrasound exam, or other tests to check these areas. Blood tests for tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) may be ordered, as their levels correlate to extent of metastasis, especially to the liver, and the cure rate.

 

Staging may not be complete until after surgery. The surgeon removes nearby lymph nodes and possibly samples of tissue from other areas in the abdomen for examination by a pathologist. TNM staging is used.

 

Management

 

Like any cancer, treatment is adapted to fit each person’s individual needs and depends on the size, location, and extent of the tumor, the stage of the disease, and general health. Cancer of the stomach is difficult to cure unless it is found in an early stage (before it has begun to spread). Unfortunately, because early stomach cancer causes few symptoms, the disease is usually advanced when the diagnosis is made. Treatment for stomach cancer may include surgery, chemotherapy, and/or radiation therapy. New treatment approaches such as biological therapy and improved ways of using current methods are being studied in clinical trials.

 

Surgery

 

Surgery is the most common treatment and is the only hope of cure for stomach cancer. The surgeon removes part or all of the stomach, as well as the surrounding lymph nodes, with the basic goal of removing all cancer and a margin of normal tissue. Depending on the extent of invasion and the location of the tumor, surgery may also include removal of part of the intestine or pancreas. Tumors in the lower part of the stomach may call for a Billroth I or Billroth II procedure. Endoscopic mucosal resection (EMR) is a treatment for early gastric cancer (tumor only involves the mucosa) that has been pioneered in Japan, but is also available in the United States at some centers. In this procedure, the tumor, together with the inner lining of stomach (mucosa), is removed from the wall of the stomach using an electrical wire loop through the endoscope. The advantage is that it is a much smaller operation than removing the stomach. Endoscopic submucosal dissection (ESD) is a similar technique pioneered in Japan, used to resect a large area of mucosa in one piece. If the pathologic examination of the resected specimen shows incomplete resection or deep invasion by tumor, the patient would need a formal stomach resection.

 

Surgical interventions are currently curative in less than 40% of cases, and, in cases of metastasis, may only be palliative.

 

Chemotherapy

 

The use of chemotherapy to treat stomach cancer has no established standard of care. Unfortunately, stomach cancer has not been especially sensitive to these drugs until recently, and historically served to palliatively reduce the size of the tumor and increase survival time. Some drugs used in stomach cancer treatment include: 5-FU (fluorouracil), BCNU (carmustine), methyl-CCNU (Semustine), and doxorubicin (Adriamycin), as well as Mitomycin C, and more recently cisplatin and taxotere in various combinations. The relative benefits of these drugs, alone and in combination, are unclear.[12] Scientists are exploring the benefits of giving chemotherapy before surgery to shrink the tumor, or as adjuvant therapy after surgery to destroy remaining cancer cells. Combination treatment with chemotherapy and radiation therapy is also under study. Doctors are testing a treatment in which anticancer drugs are put directly into the abdomen (intraperitoneal hyperthermic chemoperfusion). Chemotherapy also is being studied as a treatment for cancer that has spread, and as a way to relieve symptoms of the disease. The side effects of chemotherapy depend mainly on the drugs the patient receives.

 

Radiation therapy

 

Radiation therapy (also called radiotherapy) is the use of high-energy rays to damage cancer cells and stop them from growing. When used, it is generally in combination with surgery and chemotherapy, or used only with chemotherapy in cases where the individual is unable to undergo surgery. Radiation therapy may be used to relieve pain or blockage by shrinking the tumor for palliation of incurable disease

 

Multimodality therapy

 

While previous studies of multimodality therapy (combinations of surgery, chemotherapy and radiation therapy) gave mixed results, the Intergroup 0116 (SWOG 9008) study showed a survival benefit to the combination of chemotherapy and radiation therapy in patients with nonmetastatic, completely resected gastric cancer. Patients were randomized after surgery to the standard group of observation alone, or the study arm of combination chemotherapy and radiation therapy. Those in the study arm receiving chemotherapy and radiation therapy survived on average 36 months; compared to 27 months with observation.

Hepatocellular carcinoma (HCC, also called malignant hepatoma) is a primary malignancy (cancer) of the liver. Most cases of HCC are secondary to either a viral hepatitide infection (hepatitis B or C) or cirrhosis (alcoholism being the most common cause of hepatic cirrhosis). In countries where hepatitis is not endemic, most malignant cancers in the liver are not primary HCC but metastasis (spread) of cancer from elsewhere in the body, e.g., the colon. Treatment options of HCC and prognosis are dependent on many factors but especially on tumor size and staging. Tumor grade is also important. High-grade tumors will have a poor prognosis, while low-grade tumors may go unnoticed for many years, as is the case in many other organs, such as the breast, where a ductal carcinoma in situ (or a lobular carcinoma in situ) may be present without any clinical signs and without correlate on routine imaging tests, although in some occasions it may be detected on more specialized imaging studies like MR mammography.

 

The usual outcome is poor, because only 10 – 20% of hepatocellular carcinomas can be removed completely using surgery. If the cancer cannot be completely removed, the disease is usually deadly within 3 to 6 months. This is partially due to late presentation with large tumours, but also the lack of medical expertise and facilities. This is a rare tumor in the United States. A new receptor tyrosine kinase inhibitor, sorafenib has been shown in a Spanish phase III clinical trial to add two months to the lifespan of late stage HCC patients with well preserved liver function.

 

Signs and symptoms

 

HCC may present with jaundice, bloating from ascites, easy bruising from blood cloting abnormalies.

 

Cause

 

Hepatitis and excessive alcohol are the leading causes of HCC.

 

Pathogenesis

 

Hepatocellular carcinoma, like any other cancer, develops when there is a mutation to the cellular machinery that causes the cell to replicate at a higher rate and/or results in the cell avoiding apoptosis. In particular, chronic infections of hepatitis B and/or C can aid the development of hepatocellular carcinoma by repeatedly causing the body’s own immune system to attack the liver cells, some of which are infected by the virus, others merely bystanders. While this constant cycle of damage followed by repair can lead to mistakes during repair which in turn lead to carcinogenesis, this hypothesis is more applicable, at present, to hepatitis C. Chronic hepatitis C causes HCC through the stage of cirrhosis. In chronic hepatitis B, however, the integration of the viral genome into infected cells can directly induce a non-cirrhotic liver to develop HCC. Alternatively, repeated consumption of large amounts of ethanol can have a similar effect. Besides, cirrhosis is commonly caused by alcoholism, chronic hepatitis B and chronic hepatitis C. The toxin aflatoxin from certain Aspergillus species of fungus is a carcinogen and aids carcinogenesis of hepatocellular cancer by building up in the liver. The combined high prevalence of rates of aflatoxin and hepatitis B in settings like China and West Africa has led to relatively high rates of heptatocellular carcinoma in these regions. Other viral hepatitides such as hepatitis A have no potential to become a chronic infection and thus are not related to hepatocellular carcinoma.

 

Diagnosis

 

Hepatocellular carcinoma (HCC) most commonly appears in a patient with chronic viral hepatitis (hepatitis B or hepatitis C, 20%) or with cirrhosis (about 80%). These patients commonly undergo surveillance with ultrasound due to the cost-effectiveness.

In patients with a higher suspicion of HCC (such as rising alpha-fetoprotein and des-gamma carboxyprothrombin levels), the best method of diagnosis involves a CT scan of the abdomen using intravenous contrast agent and three-phase scanning (before contrast administration, immediately after contrast administration, and again after a delay) to increase the ability of the radiologist to detect small or subtle tumors. It is important to optimize the parameters of the CT examination, because the underlying liver disease that most HCC patients have can make the findings more difficult to appreciate.

 

On CT, HCC can have three distinct patterns of growth:

• A single large tumor

• Multiple tumors

• Poorly defined tumor with an infiltrative growth pattern

A biopsy is not needed to confirm the diagnosis of HCC if certain imaging criteria are met.

 

The key characteristics on CT are hypervascularity in the arterial phase scans, washout or de-enhancement in the portal and delayed phase studies, a pseudocapsule and a mosaic pattern. Both calcifications and intralesional fat may be appreciated.

 

CT scans use contrast agents, which are typically iodine or barium based. Some patients are allergic to one or both of these contrast agents, most often iodine. Usually the allergic reaction is manageable and not life threatening.

 

An alternative to a CT imaging study would be the MRI. MRI’s are more expensive and not as available because fewer facilities have MRI machines. More important MRI are just beginning to be used in tumor detection and fewer radiologists are skilled at finding tumors with MRI studies when it is used as a screening device. Mostly the radiologists are using MRIs to do a secondary study to look at an area where a tumor has already been detected. MRI’s also use contrast agents. One of the best for showing details of liver tumors is very new: iron oxide nano-particles appears to give better results. The latter are absorbed by normal liver tissue, but not tumors or scar tissue.

 

In a review article of the screening, diagnosis and treatment of hepatocellular carcinoma, 4 articles were selected for comparing the accuracy of CT and MRI in diagnosing this malignancy.[3] Radiographic diagnosis was verified against post-transplantation biopsy as the gold standard. With the exception of one instance of specificity, it was discovered that MRI was more sensitive and specific than CT in all four studies.

 

Pathology

 

Macroscopically, liver cancer appears as a nodular or infiltrative tumor. The nodular type may be solitary (large mass) or multiple (when developed as a complication of cirrhosis). Tumor nodules are round to oval, grey or green (if the tumor produces bile), well circumscribed but not encapsulated. The diffuse type is poorly circumscribed and infiltrates the portal veins, or the hepatic veins (rarely).

 

Microscopically, there are four architectural and cytological types (patterns) of hepatocellular carcinoma: fibrolamellar, pseudoglandular (adenoid), pleomorphic (giant cell) and clear cell. In well differentiated forms, tumor cells resemble hepatocytes, form trabeculae, cords and nests, and may contain bile pigment in cytoplasm. In poorly differentiated forms, malignant epithelial cells are discohesive, pleomorphic, anaplastic, giant. The tumor has a scant stroma and central necrosis because of the poor vascularization.

 

Staging

 

Important features that guide treatment include: –

• size

• spread (stage)

• involvement of liver vessels

• presence of a tumor capsule

• presence of extrahepatic metastases

• presence of daughter nodules

• vascularity of the tumor

 

MRI is the best imaging method to detect the presence of a tumor capsule.

 

Management

 

• Surgical resection to remove a tumor together with surrounding liver tissue while preserving enough liver remnant for normal body function. This treatment offers the best prognosis for long-term survival, but unfortunately only 10-15% of patients are suitable for surgical resection. This is often due to extensive disease or poor liver function. Resection in cirrhotic patients carries high morbidity and mortality. The expected liver remnant should be more than 25% of the total size for a non-cirrhotic liver, while that should be more than 40% of the total size for a cirrhotic liver. The overall recurrent rate after resection is 50-60%.

• Liver transplantation to replace the diseased liver with a cadaveric liver or a living donor graft. Historically low survival rates (20%-36%). Recentimprovement (61.1%; 1996-2001), likely related to adoption of the Milan criteria at US transplantation centers. If the liver tumor has metastasized, the immuno-suppressant post-transplant drugs decrease the chance of survival.

• Percutaneous ethanol injection (PEI) well tolerated, high RR in small (8 cm), presence of portal vein thrombus, tumors with portal-systemic shunt and patients with poor liver function.

• Radiofrequency ablation (RFA) uses high frequency radio-waves to destroy tumor by local heating. The electrodes are inserted into the liver tumor under ultrasound image guidance using percutaneous, laparoscopic or open surgical approach. It is suitable for small tumors(<5 cm). A large randomised trial comparing surgical resection and RFA for small HCC showed similar 4 years-survival and less morbidities for patients treated with RFA.

• Selective Internal Radiation Therapy can be used to destroy the tumor from within (thus minimizing exposure to healthy tissue). There are currently two products available, SIR-Spheres and TheraSphere The latter is an FDA approved treatment for primary liver cancer (HCC) which has been shown in clinical trials to increase survival rate of low-risk patients. SIR-Spheres are FDA approved for the treatment of metastatic colorectal cancer but outside the US SIR-Spheres are approved for the treatment of any non-resectable liver cancer including primary liver cancer. This method uses a catheter (inserted by a radiologist) to deposit radioactive particles to the area of interest.

• Intra-arterial iodine-131–lipiodol administration Efficacy demonstrated in unresectable patients, those with portal vein thrombus. This treatment is also used as adjuvant therapy in resected patients (Lau at et, 1999). It is believed to raise the 3-year survival rate from 46 to 86%. This adjuvant therapy is in phase III clinical trials in Singapore and is available as a standard medical treatment to qualified patients in Hong Kong.

• Combined PEI and TACE can be used for tumors larger than 4 cm in diameter, although some Italian groups have had success with larger tumours using TACE alone.

• High intensity focused ultrasound (HIFU) (not to be confused with normal diagnostic ultrasound) is a new technique which uses much more powerful ultrasound to treat the tumour. Still at a very experimental stage. Most of the work has been done in China. Some early work is being done in Oxford and London in the UK.

• Hormonal therapy Antiestrogen therapy with tamoxifen studied in several trials, mixed results across studies, but generally considered ineffective Octreotide (somatostatin analogue) showed 13-month MS v 4-month MS in untreated patients in a small randomized study; results not reproduced.

• Adjuvant chemotherapy: No randomized trials showing benefit of neoadjuvant or adjuvant systemic therapy in HCC; single trial showed decrease in new tumors in patients receiving oral synthetic retinoid for 12 months after resection/ablation; results not reproduced. Clinical trials have varying results.

• Palliative: Regimens that included doxorubicin, cisplatin, fluorouracil, interferon, epirubicin, or taxol, as single agents or in combination, have not shown any survival benefit (RR, 0%-25%); a few isolated major responses allowed patients to undergo partial hepatectomy; no published results from any randomized trial of systemic chemotherapy.

• Cryosurgery: Cryosurgery is a new technique that can destroy tumors in a variety of sites (brain, breast, kidney, prostate, liver). Cryosurgery is the destruction of abnormal tissue using sub-zero temperatures. The tumor is not removed and the destroyed cancer is left to be reabsorbed by the body. Initial results in properly selected patients with unresectable liver tumors are equivalent to those of resection. Cryosurgery involves the placement of a stainless steel probe into the center of the tumor. Liquid nitrogen is circulated through the end of this device. The tumor and a half inch margin of normal liver are frozen to -190°C for 15 minutes, which is lethal to all tissues. The area is thawed for 10 minutes and then re-frozen to -190°C for another 15 minutes. After the tumor has thawed, the probe is removed, bleeding is controlled, and the procedure is complete. The patient will spend the first post-operative night in the intensive care unit and typically is discharged in 3 – 5 days. Proper selection of patients and attention to detail in performing the cryosurgical procedure are mandatory in order to achieve good results and outcomes. Frequently, cryosurgery is used in conjunction with liver resection as some of the tumors are removed while others are treated with cryosurgery. Patients may also have insertion of a hepatic intra-arterial artery catheter for post-operative chemotherapy. As with liver resection, your surgeon should have experience with cryosurgical techniques in order to provide the best treatment possible.

 

There is a new drug Sorafenib which was originally used for Renal Cell Cancer that has shown promising results when used with Hepatocellular Cancer

• Interventional radiology
  Agaricus blazei mushrooms inhibited abnormal collagen fiber formation in human hepatocarcinoma cells in an in vitro experiment.

• Abbreviations: HCC, hepatocellular carcinoma; TACE, transarterial embolization/chemoembolization; PFS, progression-free survival; PS, performance status; HBV, hepatitis B virus; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation; RR, response rate; MS, median survival.

 

A systematic review assessed 12 articles involving a total of 318 patients with hepatocellular carcinoma treated with Yttrium-90 radioembolization.[8] Excluding a study of only one patient, post-treatment CT evaluation of the tumor showed a response ranging from 29 to 100 % of patients evaluated, with all but two studies showing a response of 71 % or greater.

 

Prognosis

 

The usual outcome is poor, because only 10 – 20% of hepatocellular carcinomas can be removed completely using surgery. If the cancer cannot be completely removed, the disease is usually fatal within 3 – 6 months. However, survival can vary, and occasionally people will survive much longer than 6 months.

Gallbladder cancer is a relatively uncommon cancer. It has peculiar geographical distribution being common in central and south America, central and eastern Europe, Japan and northern India; it is also common in certain ethnic groups e.g. Native American Indians and Hispanics. If it is diagnosed early enough, it can be cured by removing the gallbladder, part of liver and lymph nodes. Most often it is found after symptoms such as abdominal pain, jaundice and vomiting occur, and it has spread to other organs such as the liver.

 

It is a rare cancer that is still being studied and thought to be related to gallstones building up, which also can lead to calcification of the gallbladder, a condition known as Porcelain gallbladder. Porcelain gallbladder is also rare. Some studies indicate that people with porcelain gallbladder have a high risk of developing gallbladder cancer, but other studies question this. The outlook is poor for recovery if the cancer is found after symptoms have started to occur.

 

Risk factors

 

• Gender: Approx. twice more common in women than men, mostly between the ages of 50 and 60.

• Obesity increases the risk for gallbladder cancer. It is common in north India and indigenous peoples of the Americas.

• Primary carcinoma is linked to chronic cholecystitis and cholelithiasis.

 

Signs and Symptoms

 

• Steady pain in the upper right abdomen

• Weakness

• Loss of appetite

• Weight loss

• Jaundice and vomiting due to obstruction

• Early symptoms mimic gallbladder inflammation due to gallstones. Later, the symptoms may be that of biliary and stomach obstruction.

 

Disease Course

 

Most tumors are adenocarcinomas, with a small percent being squamous cell carcinomas. The cancer commonly spreads to the liver, bile duct, stomach,and duodenum.

 

Diagnosis

 

Early diagnosis is not generally possible. People at high risk, such as women or Native Americans with gallstones, are evaluated closely. Transabdominal ultrasound, CT scan, endoscopic ultrasound, MRI, and MR cholangio-pancreatography (MRCP) can be used to diagnose.

 

Treatment

 

The most common and most effective treatment is surgical removal of the gallbladder (cholecystectomy) with part of liver and lymph node dissection. However, with gallbladder cancer’s extremely poor prognosis, most patients will die by one year following the surgery. If surgery is not possible, endoscopic stenting of the biliary tree can reduce jaundice and a stent in stomach may relieve vomiting. Chemotherapy and radiation may also be used with surgery. If gall bladder cancer is diagnosed after cholecystectomy for stone disease (incidental cancer), reoperation to remove part of liver and lymph nodes is required in most cases – this should be done as early as possible as these patients have the best chance of long term survival and even cure

Pancreatic cancer is a malignant neoplasm of the pancreas. Each year in the United States, about 42,470 individuals are diagnosed with this condition and 35,240 die from the disease. The prognosis is relatively poor but has improved; the three-year survival rate is now about thirty percent (according to the Washington University School of Medicine), but less than 5 percent of those diagnosed are still alive five years after diagnosis. Complete remission is still rather rare.

 

About 95% of exocrine pancreatic cancers are adenocarcinomas (M8140/3). The remaining 5% include adenosquamous carcinomas, signet ring cell carcinomas, hepatoid carcinomas, colloid carcinomas, undifferentiated carcinomas, and undifferentiated carcinomas with osteoclast-like giant cells. Exocrine pancreatic cancers are far more common than endocrine pancreatic cancers (also known as islet cell carcinomas), which make up about 1% of total cases.

 

Signs and symptoms

 

Presentation

 

Pancreatic cancer is sometimes called a “silent killer” because early pancreatic cancer often does not cause symptoms, and the later symptoms are usually non-specific and varied. Therefore, pancreatic cancer is often not diagnosed until it is advanced.

 

Common symptoms include:

• Pain in the upper abdomen that typically radiates to the back (seen in carcinoma of the body or tail of the pancreas)

• Loss of appetite and/or nausea and vomiting

• Significant weight loss

• Painless jaundice (yellow skin/eyes, dark urine) when a cancer of the head of the pancreas (about 60% of cases) obstructs the common bile duct as it runs through the pancreas. This may also cause pale-colored stool and steatorrhea.

• Trousseau sign, in which blood clots form spontaneously in the portal blood vessels, the deep veins of the extremities, or the superficial veins anywhere on the body, is sometimes associated with pancreatic cancer.

• Diabetes mellitus, or elevated blood sugar levels. Many patients with pancreatic cancer develop diabetes months to even years before they are diagnosed with pancreatic cancer, suggesting that new onset diabetes in an elderly individual may be an early warning sign of pancreatic cancer.

• Clinical depression has been reported in association with pancreatic cancer, sometimes presenting before the cancer is diagnosed. However, the mechanism for this association is not known.

 

Causes

 

Risk factors for pancreatic cancer include:

• Age (particularly over 60)

• Male gender

• African-American ethnicity

• Smoking. Cigarette smoking has a risk ratio of 1.74 with regard to pancreatic cancer; a decade of non-smoking after heavy smoking is associated with a risk ratio of 1.2.

• Diets low in vegetables and fruits

• Diets high in red meat

• Obesity

• Diabetes mellitus is both risk factor for pancreatic cancer, and, as noted earlier, new onset diabetes can be an early sign of the disease.

• Chronic pancreatitis has been linked, but is not known to be causal. The risk of pancreatic cancer in individuals with familial pancreatitis is particularly high.

• Helicobacter pylori infection

• Family history, 5–10% of pancreatic cancer patients have a family history of pancreatic cancer. The genes responsible for most of this clustering in families have yet to be identified. Pancreatic cancer has been associated with the following syndromes; autosomal recessive ataxia-telangiectasia and autosomal dominantly inherited mutations in the BRCA2 gene and PALB2 gene, Peutz-Jeghers syndrome due to mutations in the STK11 tumor suppressor gene, hereditary non-polyposis colon cancer (Lynch syndrome), familial adenomatous polyposis, and the familial atypical multiple mole melanoma-pancreatic cancer syndrome (FAMMM-PC) due to mutations in the CDKN2A tumor suppressor gene.

• Gingivitis or periodontal disease

• Australia and Canada being members of International Cancer Genome Consortium are leading efforts to map pancreatic cancer’s complete genome.

 

Alcohol

It is controversial whether alcohol consumption is a risk factor for pancreatic cancer. Drinking alcohol excessively is a major cause of chronic pancreatitis, which in turn predisposes to pancreatic cancer, but “chronic pancreatitis that is due to alcohol doesn’t increase risk as much as other types of chronic pancreatitis.” Overall, the association is consistently weak and the majority of studies have found no association.

 

Some studies suggest a relationship, with risk increasing with increasing amount of alcohol intake. Risk is greatest in heavy drinkers mostly on the order of four or more drinks per day. But there appears to be no increased risk for people consuming up to 30g of alcohol a day, so most of the U.S. consumes alcohol at a level that “is probably not a risk factor for pancreatic cancer.”

 

Several studies caution that their findings could be due to confounding factors. Even if a link exists, it “could be due to the contents of some alcoholic beverages” other than the alcohol itself. One Dutch study even found that drinkers of white wine had lower risk.

 

A pooled analysis concluded, “Our findings are consistent with a modest increase in risk of pancreatic cancer with consumption of 30 or more grams of alcohol per day.”

 

Diagnosis

 

Most patients with pancreatic cancer experience pain, weight loss, or jaundice.

 

Pain is present in 80 to 85 percent of patients with locally advanced or advanced metastatic disease. The pain is usually felt in the upper abdomen as a dull ache that radiates straight through to the back. It may be intermittent and made worse by eating. Weight loss can be profound; it can be associated with anorexia, early satiety, diarrhea, or steatorrhea. Jaundice is often accompanied by pruritus and dark urine. Painful jaundice is present in approximately one-half of patients with locally unresectable disease, while painless jaundice is present in approximately one-half of patients with a potentially resectable and curable lesion.

 

The initial presentation varies according to location of the cancer. Malignancies in the pancreatic body or tail usually present with pain and weight loss, while those in the head of the gland typically present with steatorrhea, weight loss, and jaundice. The recent onset of atypical diabetes mellitus, a history of recent but unexplained thrombophlebitis (Trousseau sign), or a previous attack of pancreatitis are sometimes noted.

 

Courvoisier sign defines the presence of jaundice and a painlessly distended gallbladder as strongly indicative of pancreatic cancer, and may be used to distinguish pancreatic cancer from gallstones.

 

Tiredness, irritability and difficulty eating due to pain also exist. Pancreatic cancer is usually discovered during the course of the evaluation of aforementioned symptoms.

 

Liver function tests can show a combination of results indicative of bile duct obstruction (raised conjugated bilirubin, γ-glutamyl transpeptidase and alkaline phosphatase levels). CA19-9 (carbohydrate antigen 19.9) is a tumor marker that is frequently elevated in pancreatic cancer. However, it lacks sensitivity and specificity. When a cutoff above 37 U/mL is used, this marker has a sensitivity of 77% and specificity of 87% in discerning benign from malignant disease. CA 19-9 might be normal early in the course, and could be elevated due to benign causes of biliary obstruction.

 

Imaging studies, such as computed tomography (CT scan) and Endoscopic ultrasound (EUS) can be used to identify the location and form of the cancer. However, percutaneous needle biopsy of the cancerous pancreatic tissue is necessary to establish a definitive diagnosis. Endoscopic ultrasound is often used to visually guide the needle biopsy procedure.

 

In the September 2009 issue of the journal Cancer Prevention Research, scientists from the University of Texas M.D. Anderson Cancer Center identified microRNAs associated with pancreatic cancer from blood samples of pancreatic cancer patients, leading to a new and minimally invasive approach to early detection. Expression of higher levels of miR-155 circulating in blood was identified as a potential early stage biomarker, and expression of miR196a was shown to increase during disease progression. Using a panel of 4 miRNA biomarkers, miR-21, miR-210, miR-155, and miR-196a, the study achieved 64% sensitivity and 89% specificity in a sample of 28 pancreatic cancer patients and 19 healthy controls.

 

Prevention

 

According to the American Cancer Society, there are no established guidelines for preventing pancreatic cancer, although cigarette smoking has been reported as responsible for 20–30% of pancreatic cancers.

 

The ACS recommends keeping a healthy weight, and increasing consumption of fruits, vegetables, and whole grains while decreasing red meat intake, although there is no consistent evidence that this will prevent or reduce pancreatic cancer specifically. In 2006 a large prospective cohort study of over 80,000 subjects failed to prove a definite association. The evidence in support of this lies mostly in small case-control studies.

 

In September 2006, a long-term study concluded that taking Vitamin D can substantially cut the risk of pancreatic cancer (as well as other cancers) by up to 50%, but this study needs to evaluate fully the risks, costs and potential benefits of taking Vitamin D.

 

Several studies, including one published on 1 June 2007, indicate that B vitamins such as B12, B6, and folate, can reduce the risk of pancreatic cancer when consumed in food, but not when ingested in vitamin tablet form.

 

Treatment

 

Surgery

 

Treatment of pancreatic cancer depends on the stage of the cancer. The Whipple procedure is the most common surgical treatment for cancers involving the head of the pancreas. This procedure involves removing the pancreatic head and the curve of the duodenum together (pancreato-duodenectomy), making a bypass for food from stomach to jejunum (gasto-jejunostomy) and attaching a loop of jejunum to the cystic duct to drain bile (cholecysto-jejunostomy). It can only be performed if the patient is likely to survive major surgery and if the cancer is localized without invading local structures or metastasizing. It can therefore only be performed in the minority of cases.

 

Spleen-preserving distal pancreatectomy can also be used as a method to remove a cancer running through centre of pancreas; this is invasive surgery, resulting in loss of body and tail.Cancers of the tail of the pancreas can be resected using a procedure known as a distal pancreatectomy. Recently, localized cancers of the pancreas have been resected using minimally invasive (laparoscopic) approaches.

 

After surgery, adjuvant chemotherapy with gemcitabine has in several large randomized studies been shown to significantly increase the 5-year survival (from approximately 10 to 20%), and should be offered if the patient is fit after surgery(Oettler et al. JAMA 2007, Neoptolemos et al. NEJM 2004, Oettler et al. ASCO proc 2007) . There is a study being done currently by Washington University that is using interferon to treat the cancer, and it has boosted survival times somewhat further. Addition of radiation therapy is a hotly debated topic, with groups in the US often favoring the use of adjuvant radiation therapy, while groups in Europe do not, due to the lack of any large randomized studies to show any survival benefit of this strategy.

 

Surgery can be performed for palliation, if the malignancy is invading or compressing the duodenum or colon. In that case, bypass surgery might overcome the obstruction and improve quality of life, but it is not intended as a cure.

 

Chemotherapy

In patients not suitable for resection with curative intent, palliative chemotherapy may be used to improve quality of life and gain a modest survival benefit. Gemcitabine was approved by the United States Food and Drug Administration in 1998 after a clinical trial reported improvements in quality of life in patients with advanced pancreatic cancer. This marked the first FDA approval of a chemotherapy drug for a non-survival clinical trial endpoint. Gemcitabine is administered intravenously on a weekly basis. Addition of oxaliplatin (Gem/Ox) conferred benefit in small trials, but is not yet standard therapy., a recently published study ECOG 6201 failed to show superiority of GEMOX over gemcitabine alone (Poplin et al, JCO 2009, Louvet et al. JCO 2005). Fluorouracil (5FU) may also be included, however no large randomized study has shown significant survival benefit from this addition(Berlin et al. JCO 2002). One sofar unpublished trial has shown a significant benefit from adding capecitabine to gemcitabine (Cunningham et al. ASCO proc 2005),

 

On the basis of a Canadian led Phase III Randomised Controlled trial involving 569 patients with advanced pancreatic cancer, the US FDA has licensed the use of erlotinib in combination with gemcitabine as a palliative regimen for pancreatic cancer. This trial compared the action of gemcitabine/erlotinib vs gemcitabine/placebo and demonstrated improved survival rates, improved tumor response and improved progression-free survival rates(Moore et al. JCO 2005). The survival improvement with the combination is on the order of less than four weeks, leading some cancer experts to question the incremental value of adding erlotinib to gemcitabine treatment. New trials are now investigating the effect of the above combination in the adjuvant and neoadjuvant setting. A trial of anti-angiogenesis agent bevacizumab as an addition to chemotherapy has shown no improvement in survival of patients with advanced pancreatic cancer(Kindler et al.). It may cause higher rates of high blood pressure, bleeding in the stomach and intestine, and intestinal perforations.

 

Prognosis

 

Patients diagnosed with pancreatic cancer typically have a poor prognosis partly because the cancer usually causes no symptoms early on, leading to locally advanced or metastatic disease at time of diagnosis. Median survival from diagnosis is around 3 to 6 months; 5-year survival is less than 5%. With 37,170 cases diagnosed in the United States in 2007, and 33,700 deaths, pancreatic cancer has one of the highest fatality rates of all cancers and is the fourth highest cancer killer in the United States among both men and women. Although it accounts for only 2.5% of new cases, pancreatic cancer is responsible for 6% of cancer deaths each year.

 

Pancreatic cancer may occasionally result in diabetes. Insulin production is hampered and it has been suggested that the cancer can also prompt the onset of diabetes and vice versa.[53] Thus diabetes is both a risk factor for the development of pancreatic cancer and diabetes can be an early sign of the disease in the elderly.

Colorectal cancer, also called colon cancer or large bowel cancer, includes cancerous growths in the colon, rectum and appendix. With 655,000 deaths worldwide per year, it is the fourth most common form of cancer in the United States and the third leading cause of cancer-related death in the Western world. Colorectal cancers arise from adenomatous polyps in the colon. These mushroom-shaped growths are usually benign, but some develop into cancer over time. Localized colon cancer is usually diagnosed through colonoscopy.

 

Invasive cancers that are confined within the wall of the colon (TNM stages I and II) are curable with surgery. If untreated, they spread to regional lymph nodes (stage III), where up to 73% are curable by surgery and chemotherapy. Cancer that metastasizes to distant sites (stage IV) is not curable, although chemotherapy can extend survival. Radiation is used with rectal cancer.

 

On the cellular and molecular level, colorectal cancer starts with a mutation to the Wnt signaling pathway. When Wnt binds to a receptor on the cell, that sets in motion a chain of molecular events that ends with β-catenin moving into the nucleus and activating a gene on DNA. In colorectal cancer, genes along this chain are damaged. Usually, a gene called APC, which is a “brake” on the Wnt pathway, is damaged. Without a working APC brake, the Wnt pathway is stuck in the “on” position.

 

Signs and symptoms

 

The symptoms of colorectal cancer depend on the location of tumor in bowel and whether it has spread to elsewhere in the body (metastasis). Most of the symptoms may occur in other diseases as well, and hence none of the symptoms mentioned here is diagnostic of colorectal cancer. Symptoms and signs are divided into local, constitutional (affecting the whole body) and metastatic (caused by spread to other organs).

 

Local

 

Local symptoms are more likely if the tumor is located closer to the anus. There may be a change in bowel habit (new-onset constipation or diarrhea in the absence of another cause), and a feeling of incomplete defecation (tenesmus) and reduction in diameter of stool; tenesmus and change in stool shape are both characteristic of rectal cancer. Lower gastrointestinal bleeding, including the passage of bright red blood in the stool, may indicate colorectal cancer, as may the increased presence of mucus. Melena, black stool with a tarry appearance, normally occurs in upper gastrointestinal bleeding (such as from a duodenal ulcer) but is sometimes encountered in colorectal cancer when the disease is located in the beginning of the large bowel.

 

A tumor that is large enough to fill the entire lumen of the bowel may cause bowel obstruction. This situation is characterized by constipation, abdominal pain, abdominal distension and vomiting. This occasionally leads to the obstructed and distended bowel perforating and causing peritonitis.

 

Certain local effects of colorectal cancer occur when the disease has become more advanced. A large tumor is more likely to be noticed on feeling the abdomen, and it may be noticed by a doctor on physical examination. The disease may invade other organs, and may cause blood or air in the urine (invasion of the bladder) or vaginal discharge (invasion of the female reproductive tract).

 

Constitutional

 

If a tumor has caused chronic occult bleeding, iron deficiency anemia may occur; this may be experienced as fatigue, palpitations and noticed as pallor (pale appearance of the skin). Colorectal cancer may also lead to weight loss, generally due to a decreased appetite.

 

More unusual constitutational symptoms are an unexplained fever and one of several paraneoplastic syndrome. The most common paraneoplastic syndrome is thrombosis, usually deep vein thrombosis.

 

Metastatic

Colorectal cancer most commonly spreads to the liver. This may go unnoticed, but large deposits in the liver may cause jaundice and abdominal pain (due to stretching of the capsule). If the tumor deposit obstructs the bile duct, the jaundice may be accompanied by other features of biliary obstruction, such as pale stools.

 

Risk factors

 

Micrograph of a tubular adenoma (left of image), a type of colonic polyp and a precursor of colorectal cancer. Normal colorectal mucosa is seen on the right. H&E stain.

 

The lifetime risk of developing colon cancer in the United States is about 7%. Certain factors increase a person’s risk of developing the disease.

 

These include:

• Age. The risk of developing colorectal cancer increases with age. Most cases occur in the 60s and 70s, while cases before age 50 are uncommon unless a family history of early colon cancer is present.

• Polyps of the colon, particularly adenomatous polyps, are a risk factor for colon cancer. The removal of colon polyps at the time of colonoscopy reduces the subsequent risk of colon cancer.

• History of cancer. Individuals who have previously been diagnosed and treated for colon cancer are at risk for developing colon cancer in the future. Women who have had cancer of the ovary, uterus, or breast are at higher risk of developing colorectal cancer.

• Heredity:
  • Family history of colon cancer, especially in a close relative before the age of 55 or multiple relatives.
  • Familial adenomatous polyposis (FAP) carries a near 100% risk of developing colorectal cancer by the age of 40 if untreated
  • Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome

 

• Smoking. Smokers are more likely to die of colorectal cancer than non-smokers. An American Cancer Society study found that “Women who smoked were more than 40% more likely to die from colorectal cancer than women who never had smoked. Male smokers had more than a 30% increase in risk of dying from the disease compared to men who never had smoked.”

• Diet. Studies show that a diet high in red meat and low in fresh fruit, vegetables, poultry and fish increases the risk of colorectal cancer. In June 2005, a study by the European Prospective Investigation into Cancer and Nutrition suggested that diets high in red and processed meat, as well as those low in fiber, are associated with an increased risk of colorectal cancer. Individuals who frequently eat fish showed a decreased risk. However, other studies have cast doubt on the claim that diets high in fiber decrease the risk of colorectal cancer; rather, low-fiber diet was associated with other risk factors, leading to confounding. The nature of the relationship between dietary fiber and risk of colorectal cancer remains controversial.

• Physical inactivity. People who are physically active are at lower risk of developing colorectal cancer.

• Virus. Exposure to some viruses (such as particular strains of human papilloma virus) may be associated with colorectal cancer.

• Primary sclerosing cholangitis offers a risk independent to ulcerative colitis

• Low levels of selenium.

• Inflammatory bowel disease. About one percent of colorectal cancer patients have a history of chronic ulcerative colitis. The risk of developing colorectal cancer varies inversely with the age of onset of the colitis and directly with the extent of colonic involvement and the duration of active disease. Patients with colorectal Crohn’s disease have a more than average risk of colorectal cancer, but less than that of patients with ulcerative colitis.

• Environmental factors. Industrialized countries are at a relatively increased risk compared to less developed countries that traditionally had high-fiber/low-fat diets. Studies of migrant populations have revealed a role for environmental factors, particularly dietary, in the etiology of colorectal cancers.

• Exogenous hormones. The differences in the time trends in colorectal cancer in males and females could be explained by cohort effects in exposure to some gender-specific risk factor; one possibility that has been suggested is exposure to estrogens. There is, however, little evidence of an influence of endogenous hormones on the risk of colorectal cancer. In contrast, there is evidence that exogenous estrogens such as hormone replacement therapy (HRT), tamoxifen, or oral contraceptives might be associated with colorectal tumors.

• Alcohol. Drinking, especially heavily, may be a risk factor.

Alcohol

 

The WCRF panel report Food, Nutrition, Physical Activity and the Prevention of Cancer: a Global Perspective finds the evidence “convincing” that alcoholic drinks increase the risk of colorectal cancer in men.

 

The NIAAA reports that: “Epidemiologic studies have found a small but consistent dose-dependent association between alcohol consumption and colorectal cancer even when controlling for fiber and other dietary factors. Despite the large number of studies, however, causality cannot be determined from the available data.”

 

“Heavy alcohol use may also increase the risk of colorectal cancer” (NCI). One study found that “People who drink more than 30 grams of alcohol per day (and especially those who drink more than 45 grams per day) appear to have a slightly higher risk for colorectal cancer.” Another found that “The consumption of one or more alcoholic beverages a day at baseline was associated with approximately a 70% greater risk of colon cancer.”

 

One study found that “While there was a more than twofold increased risk of significant colorectal neoplasia in people who drink spirits and beer, people who drank wine had a lower risk. In our sample, people who drank more than eight servings of beer or spirits per week had at least a one in five chance of having significant colorectal neoplasia detected by screening colonoscopy.”

 

Other research suggests that “to minimize your risk of developing colorectal cancer, it’s best to drink in moderation.”

 

On its colorectal cancer page, the National Cancer Institute does not list alcohol as a risk factor: however, on another page it states, “Heavy alcohol use may also increase the risk of colorectal cancer”

 

Drinking may be a cause of earlier onset of colorectal cancer.

 

Pathogenesis

 

Colorectal cancer is a disease originating from the epithelial cells lining the colon or rectum of the gastrointestinal tract, as a result of mutations along the ‘Wnt signaling pathway. Some of the mutations are inherited, and others are acquired.[33][34] The most commonly mutated gene in all colorectal cancer is the APC gene, which produces the APC protein. The APC protein is the “brake” on the β-catenin protein. Without APC, β-catinin moves into the nucleus, binds to DNA, and activates more proteins. (If APC isn’t mutated in colorectal cancer, then β-catinin itself is.)

 

But it’s not enough for the Wnt-APC-beta-catinin signaling pathway to get stuck in the “on” position. Other mutations must occur for the cell to become cancerous. The TP53 protein, produced by the p53 gene, normally monitors cell division and kills cells if they have Wnt pathway defects. But eventually, a clone of cells gets a second mutation, in the p53 gene, and it transforms from a large adenoma into an invasive carcenoma. (Sometimes p53 isn’t mutated, but another protective protein named BAX is.)

 

Another protein that’s supposed to kill cells when they become cancerous is TGF-β. But in at least half of colorectal cancers, TGF-β also has a deactivating mutation. (Sometimes TGF-β isn’t deactivated, but a downstream protein named SMAD is.)

 

Some genes are oncogenes — they are overexpressed in colorectal cancer. For example, RAS, RAF, and PI3K, which normally encourage the cell to divide in response to growth factors, can become mutated with mutations that make them oversignal the cell. PTEN normally inhibits PI3K, but sometimes PTEN gets mutated.

 

Diagnosis

 

Endoscopic image of colon cancer identified in sigmoid colon on screening colonoscopy in the setting of Crohn’s disease.

 

Colorectal cancer can take many years to develop and early detection of colorectal cancer greatly improves the chances of a cure. The National Cancer Policy Board of the Institute of Medicine estimated in 2003 that even modest efforts to implement colorectal cancer screening methods would result in a 29 percent drop in cancer deaths in 20 years. Despite this, colorectal cancer screening rates remain low.[35] Therefore, screening for the disease is recommended in individuals who are at increased risk. There are several different tests available for this purpose.

• Digital rectal exam (DRE): The doctor inserts a lubricated, gloved finger into the rectum to feel for abnormal areas. It only detects tumors large enough to be felt in the distal part of the rectum but is useful as an initial screening test.

• Fecal occult blood test (FOBT): a test for blood in the stool. Two types of tests can be used for detecting occult blood in stools i.e. guaiac based (chemical test) and immunochemical. The sensitivity of immunochemical testing is superior to that of chemical testing without an unacceptable reduction in specifity.

• Endoscopy:
  • Sigmoidoscopy: A lighted probe (sigmoidoscope) is inserted into the rectum and lower colon to check for polyps and other abnormalities.
  • Colonoscopy: A lighted probe called a colonoscope is inserted into the rectum and the entire colon to look for polyps and other abnormalities that may be caused by cancer. A colonoscopy has the advantage that if polyps are found during the procedure they can be immediately removed. Tissue can also be taken for biopsy.

 

In the United States, colonoscopy or FOBT plus sigmoidoscopy are the preferred screening options

 

Other screening methods

• Double contrast barium enema (DCBE): First, an overnight preparation is taken to cleanse the colon. An enema containing barium sulfate is administered, then air is insufflated into the colon, distending it. The result is a thin layer of barium over the inner lining of the colon which is visible on X-ray films. A cancer or a precancerous polyp can be detected this way. This technique can miss the (less common) flat polyp.

• Virtual colonoscopy replaces X-ray films in the double contrast barium enema (above) with a special computed tomography scan and requires special workstation software in order for the radiologist to interpret. This technique is approaching colonoscopy in sensitivity for polyps. However, any polyps found must still be removed by standard colonoscopy.

• Standard computed axial tomography is an x-ray method that can be used to determine the degree of spread of cancer, but is not sensitive enough to use for screening. Some cancers are found in CAT scans performed for other reasons.

• Blood tests: Measurement of the patient’s blood for elevated levels of certain proteins can give an indication of tumor load. In particular, high levels of carcinoembryonic antigen (CEA) in the blood can indicate metastasis of adenocarcinoma. These tests are frequently false positive or false negative, and are not recommended for screening, it can be useful to assess disease recurrence.

• Genetic counseling and genetic testing for families who may have a hereditary form of colon cancer, such as hereditary nonpolyposis colorectal cancer (HNPCC) or familial adenomatous polyposis (FAP).

• Positron emission tomography (PET) is a 3-dimensional scanning technology where a radioactive sugar is injected into the patient, the sugar collects in tissues with high metabolic activity, and an image is formed by measuring the emission of radiation from the sugar. Because cancer cells often have very high metabolic rate, this can be used to differentiate benign and malignant tumors. PET is not used for screening and does not (yet) have a place in routine workup of colorectal cancer cases.

• Whole-Body PET imaging is the most accurate diagnostic test for detection of recurrent colorectal cancer, and is a cost-effective way to differentiate resectable from non-resectable disease. A PET scan is indicated whenever a major management decision depends upon accurate evaluation of tumour presence and extent.

• Stool DNA testing is an emerging technology in screening for colorectal cancer. Pre-malignant adenomas and cancers shed DNA markers from their cells which are not degraded during the digestive process and remain stable in the stool. Capture, followed by PCR amplifies the DNA to detectable levels for assay. Clinical studies have shown a cancer detection sensitivity of 71%–91%.

 

Monitoring

 

Carcinoembryonic antigen (CEA) is a protein found on virtually all colorectal tumors. CEA may be used to monitor and assess response to treatment in patients with metastatic disease. CEA can also be used to monitor recurrence in patients post-operatively.

 

Pathology

Gross appearance of a colectomy specimen containing two adenomatous polyps (the brownish oval tumors above the labels, attached to the normal beige lining by a stalk) and one invasive colorectal carcinoma (the crater-like, reddish, irregularly-shaped tumor located above the label).

 

Gross appearance of a colectomy specimen containing one invasive colorectal carcinoma (the crater-like, reddish, irregularly-shaped tumor).

 

Micrograph of an invasive adenocarcinoma (the most common type of colorectal cancer). The cancerous cells are seen in the center and at the bottom right of the image (blue). Near normal colon-lining cells are seen at the top right of the image.

 

Histopathologic image of colonic carcinoid stained by hematoxylin and eosin.

 

The pathology of the tumor is usually reported from the analysis of tissue taken from a biopsy or surgery. A pathology report will usually contain a description of cell type and grade. The most common colon cancer cell type is adenocarcinoma which accounts for 95% of cases. Other, rarer types include lymphoma and squamous cell carcinoma.

 

Cancers on the right side (ascending colon and cecum) tend to be exophytic, that is, the tumour grows outwards from one location in the bowel wall. This very rarely causes obstruction of feces, and presents with symptoms such as anemia. Left-sided tumours tend to be circumferential, and can obstruct the bowel much like a napkin ring.

 

Adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the colorectal mucosa. It invades the wall, infiltrating the muscularis mucosae, the submucosa and thence the muscularis propria. Tumor cells describe irregular tubular structures, harboring pluristratification, multiple lumens, reduced stroma (“back to back” aspect). Sometimes, tumor cells are discohesive and secrete mucus, which invades the interstitium producing large pools of mucus/colloid (optically “empty” spaces) – mucinous (colloid) adenocarcinoma, poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery – “signet-ring cell.” Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present three degrees of differentiation: well, moderately, and poorly differentiated.

 

Most colorectal cancer tumors are thought to be cyclooxygenase-2 (COX-2) positive. This enzyme is generally not found in healthy colon tissue, but is thought to fuel abnormal cell growth.

 

Staging

 

Colon cancer staging is an estimate of the amount of penetration of a particular cancer. It is performed for diagnostic and research purposes, and to determine the best method of treatment. The systems for staging colorectal cancers depend on the extent of local invasion, the degree of lymph node involvement and whether there is distant metastasis.

 

Definitive staging can only be done after surgery has been performed and pathology reports reviewed. An exception to this principle would be after a colonoscopic polypectomy of a malignant pedunculated polyp with minimal invasion. Preoperative staging of rectal cancers may be done with endoscopic ultrasound. Adjunct staging of metastasis include Abdominal Ultrasound, CT, PET Scanning, and other imaging studies.

 

The most common staging system is the TNM (for tumors/nodes/metastases) system, from the American Joint Committee on Cancer (AJCC). The TNM system assigns a number based on three categories. “T” denotes the degree of invasion of the intestinal wall, “N” the degree of lymphatic node involvement, and “M” the degree of metastasis. The broader stage of a cancer is usually quoted as a number I, II, III, IV derived from the TNM value grouped by prognosis; a higher number indicates a more advanced cancer and likely a worse outcome. Details of this system are in the graph below:

 

AJCC stage	TNM stage	TNM stage criteria for colorectal cancer
Stage 0	Tis N0 M0	Tis: Tumor confined to mucosa; cancer-in-situ
Stage I	T1 N0 M0	T1: Tumor invades submucosa
Stage I	T2 N0 M0	Stage I T2 N0 M0 T2: Tumor invades muscularis propria
Stage II-A	T3 N0 M0	T3: Tumor invades subserosa or beyond (without other organs involved)
Stage II-B	T4 N0 M0	T4: Tumor invades adjacent organs or perforates the visceral peritoneum
Stage III-A	T1-2 N1 M0	N1: Metastasis to 1 to 3 regional lymph nodes. T1 or T2.
Stage III-B	T3-4 N1 M0	N1: Metastasis to 1 to 3 regional lymph nodes. T3 or T4.
Stage III-C	any T, N2 M0	N2: Metastasis to 4 or more regional lymph nodes. Any T.
Stage IV	any T, any N, M1	M1: Distant metastases present. Any T, any N.

 

Dukes system

 

Micrograph of a colorectal adenocarcinoma metastasis to a lymph node. The cancerous cells are at the top center-left of the image, in glands (circular/ovoid structures) and eosinophilic (bright pink). H&E stain.

 

Dukes classification is an older and less complicated staging system, that predates the TMN system, and was first proposed by Dr. Cuthbert Dukes in 1932;

 

it identifies the stages as:

• A – Tumour confined to the intestinal wall

• B – Tumour invading through the intestinal wall

• C – With lymph node(s) involvement (this is further subdivided into C1 lymph node involvement where the apical node is not involved and C2 where the apical lymph node is involved)

• D – With distant metastasis

 

A few cancer centers still use this staging system.

 

Prevention

 

Most colorectal cancers should be preventable, through increased surveillance, improved lifestyle, and, probably, the use of dietary chemopreventative agents.

 

Surveillance

Most colorectal cancer arise from adenomatous polyps. These lesions can be detected and removed during colonoscopy. Studies show this procedure would decrease by > 80% the risk of cancer death, provided it is started by the age of 50, and repeated every 5 or 10 years.[41]

 

As per current guidelines under National Comprehensive Cancer Network, in average risk individuals with negative family history of colon cancer and personal history negative for adenomas or Inflammatory Bowel diseases, flexible sigmoidoscopy every 5 years with fecal occult blood testing annually or double contrast barium enema are other options acceptable for screening rather than colonoscopy every 10 years (which is currently the Gold-Standard of care).

 

Lifestyle and nutrition

 

The comparison of colorectal cancer incidence in various countries strongly suggests that sedentarity, overeating (i.e., high caloric intake), and perhaps a diet high in meat (red or processed) could increase the risk of colorectal cancer. In contrast, a healthy body weight, physical fitness, and good nutrition decreases cancer risk in general. Accordingly, lifestyle changes could decrease the risk of colorectal cancer as much as 60-80%.

 

A high intake of dietary fiber (from eating fruits, vegetables, cereals, and other high fiber food products) has, until recently, been thought to reduce the risk of colorectal cancer and adenoma. In the largest study ever to examine this theory (88,757 subjects tracked over 16 years), it has been found that a fiber rich diet does not reduce the risk of colon cancer.[43] A 2005 meta-analysis study further supports these findings.

 

The Harvard School of Public Health states: “Health Effects of Eating Fiber: Long heralded as part of a healthy diet, fiber appears to reduce the risk of developing various conditions, including heart disease, diabetes, diverticular disease, and constipation. Despite what many people may think, however, fiber probably has little, if any effect on colon cancer risk.”

 

Chemoprevention

 

More than 200 agents, including the above cited phytochemicals, and other food components like calcium or folic acid (a B vitamin), and NSAIDs like aspirin, are able to decrease carcinogenesis in pre-clinical development models: Some studies show full inhibition of carcinogen-induced tumours in the colon of rats. Other studies show strong inhibition of spontaneous intestinal polyps in mutated mice (Min mice). Chemoprevention clinical trials in human volunteers have shown smaller prevention, but few intervention studies have been completed today. The “chemoprevention database” shows the results of all published scientific studies of chemopreventive agents, in people and in animals.

 

Aspirin chemoprophylaxis

 

Aspirin should not be taken routinely to prevent colorectal cancer, even in people with a family history of the disease, because the risk of bleeding and kidney failure from high dose aspirin (300 mg or more) outweigh the possible benefits.

 

A clinical practice guideline of the U.S. Preventive Services Task Force (USPSTF) recommended against taking aspirin (grade D recommendation). The Task Force acknowledged that aspirin may reduce the incidence of colorectal cancer, but “concluded that harms outweigh the benefits of aspirin and NSAID use for the prevention of colorectal cancer”. A subsequent meta-analysis concluded “300 mg or more of aspirin a day for about 5 years is effective in primary prevention of colorectal cancer in randomised controlled trials, with a latency of about 10 years”. However, long-term doses over 81 mg per day may increase bleeding events.

 

Calcium

 

The meta-analysis by the Cochrane Collaboration of randomized controlled trials published through 2002 concluded “Although the evidence from two RCTs suggests that calcium supplementation might contribute to a moderate degree to the prevention of colorectal adenomatous polyps, this does not constitute sufficient evidence to recommend the general use of calcium supplements to prevent colorectal cancer.”.[51] Subsequently, one randomized controlled trial by the Women’s Health Initiative (WHI) reported negative results.[52] A second randomized controlled trial reported reduction in all cancers, but had insufficient colorectal cancers for analysis

 

Vitamin D

 

A scientific review undertaken by the National Cancer Institute found that vitamin D was beneficial in preventing colorectal cancer, which showed an inverse relationship with blood levels of 80 nmol/L or higher associated with a 72% risk reduction compared with lower than 50 nmol/L.

 

Management

 

The treatment depends on the staging of the cancer. When colorectal cancer is caught at early stages (with little spread) it can be curable. However, when it is detected at later stages (when distant metastases are present) it is less likely to be curable.

 

Surgery remains the primary treatment while chemotherapy and/or radiotherapy may be recommended depending on the individual patient’s staging and other medical factors.

 

Because colon cancer primarily affects the elderly, it can be a challenge to determine how aggressively to treat a particular patient, especially after surgery. Clinical trials suggest that “otherwise fit” elderly patients fare well if they have adjuvant chemotherapy after surgery, so chronological age alone should not be a contraindication to aggressive management.

 

Surgery

 

Surgeries can be categorised into curative, palliative, bypass, fecal diversion, or open-and-close.

 

Curative Surgical treatment can be offered if the tumor is localized.

• Very early cancer that develops within a polyp can often be cured by removing the polyp (i.e., polypectomy) at the time of colonoscopy.

• In colon cancer, a more advanced tumor typically requires surgical removal of the section of colon containing the tumor with sufficient margins, and radical en-bloc resection of mesentery and lymph nodes to reduce local recurrence (i.e., colectomy). If possible, the remaining parts of colon are anastomosed together to create a functioning colon. In cases when anastomosis is not possible, a stoma (artificial orifice) is created.

• Curative surgery on rectal cancer includes total mesorectal excision (lower anterior resection) or abdominoperineal excision.

 

In case of multiple metastases, palliative (non curative) resection of the primary tumor is still offered in order to reduce further morbidity caused by tumor bleeding, invasion, and its catabolic effect. Surgical removal of isolated liver metastases is, however, common and may be curative in selected patients; improved chemotherapy has increased the number of patients who are offered surgical removal of isolated liver metastases.

 

If the tumor invaded into adjacent vital structures which makes excision technically difficult, the surgeons may prefer to bypass the tumor (ileotransverse bypass) or to do a proximal fecal diversion through a stoma.

 

The worst case would be an open-and-close surgery, when surgeons find the tumor unresectable and the small bowel involved; any more procedures would do more harm than good to the patient. This is uncommon with the advent of laparoscopy and better radiological imaging. Most of these cases formerly subjected to “open and close” procedures are now diagnosed in advance and surgery avoided.

 

Laparoscopic-assisted colectomy is a minimally-invasive technique that can reduce the size of the incision and may reduce post-operative pain.

 

As with any surgical procedure, colorectal surgery may result in complications including

• wound infection, Dehiscence (bursting of wound) or hernia

• anastomosis breakdown, leading to abscess or fistula formation, and/or peritonitis

• bleeding with or without hematoma formation

• adhesions resulting in bowel obstruction. A 5-year study of patients who had surgery in 1997 found the risk of hospital readmission to be 15% after panproctocolectomy, 9% after total colectomy, and 11% after ileostomy

• adjacent organ injury; most commonly to the small intestine, ureters, spleen, or bladder

• Cardiorespiratory complications such as myocardial infarction, pneumonia, arrythmia, pulmonary embolism etc

 

Chemotherapy

 

Chemotherapy is used to reduce the likelihood of metastasis developing, shrink tumor size, or slow tumor growth. Chemotherapy is often applied after surgery (adjuvant), before surgery (neo-adjuvant), or as the primary therapy (palliative). The treatments listed here have been shown in clinical trials to improve survival and/or reduce mortality rate and have been approved for use by the US Food and Drug Administration. In colon cancer, chemotherapy after surgery is usually only given if the cancer has spread to the lymph nodes (Stage III).

 

At the 2008 annual meeting of the American Society of Clinical Oncology, researchers announced that colorectal cancer patients that have a mutation in the KRAS gene do not respond to certain therapies, those that inhibit the epidermal growth factor receptor (EGFR)–namely Erbitux (cetuximab) and Vectibix (panitumumab).[57] Following recommendations by ASCO, patients should now be tested for the KRAS gene mutation before being offered these EGFR-inhibiting drugs.[58] In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs (panitumumab (Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations.

 

However, having the normal KRAS version does not guarantee that these drugs will benefit the patient.

 

“The trouble with the KRAS mutation is that it’s downstream of EGFR,” says Richard Goldberg, MD, director of oncology at the Lineberger Comprehensive Cancer Center at the University of North Carolina. “It doesn’t matter if you plug the socket if there’s a short downstream of the plug. The mutation turns [EGFR] into a switch that’s always on.” But this doesn’t mean that having normal, or wild-type, KRAS is a fail-safe. “It isn’t foolproof,” cautions Goldberg. “If you have wild-type KRAS, you’re more likely to respond, but it’s not a guarantee.” Tumors shrink in response to these drugs in up to 40 percent of patients with wild-type KRAS, and progression-free and overall survival is increased.

 

The cost benefit of testing patients for the KRAS gene could potentially save about $740 million a year by not providing EGFR-inhibiting drugs to patients who would not benefit from the drugs. “With the assumption that patients with mutated Kras (35.6% of all patients) would not receive cetuximab (other studies have found Kras mutation in up to 46% of patients), theoretical drug cost savings would be $753 million; considering the cost of Kras testing, net savings would be $740 million.”

 

• Adjuvant (after surgery) chemotherapy. One regimen involves the combination of infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX)
  • 5-fluorouracil (5-FU) or Capecitabine
  • Leucovorin (LV, Folinic Acid)
  • Oxaliplatin

• Chemotherapy for metastatic disease. Commonly used first line chemotherapy regimens involve the combination of infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) with bevacizumab or infusional 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with bevacizumab or the same chemotherapy drug combinations with cetuximab in KRAS wild type tumors

• 5-fluorouracil (5-FU) or Capecitabine
  • UFT or Tegafur-uracil
  • Leucovorin (LV, Folinic Acid)
  • Irinotecan
  • Oxaliplatin
  • Bevacizumab
  • Cetuximab
  • Panitumumab

 

• In clinical trials for treated/untreated metastatic disease.

• Bortezomib
  • Oblimersen
  • Gefitinib and Erlotinib
  • Topotecan

 

Radiation therapy

Radiotherapy is not used routinely in colon cancer, as it could lead to radiation enteritis, and it is difficult to target specific portions of the colon. It is more common for radiation to be used in rectal cancer, since the rectum does not move as much as the colon and is thus easier to target. Indications include:

 

• Colon cancer
  • pain relief and palliation – targeted at metastatic tumor deposits if they compress vital structures and/or cause pain

• Rectal cancer
  • neoadjuvant – given before surgery in patients with tumors that extend outside the rectum or have spread to regional lymph nodes, in order to decrease the risk of recurrence following surgery or to allow for less invasive surgical approaches (such as a low anterior resection instead of an abdomino-perineal resection)
  • adjuvant – where a tumor perforates the rectum or involves regional lymph nodes (AJCC T3 or T4 tumors or Duke’s B or C tumors)
  • palliative – to decrease the tumor burden in order to relieve or prevent symptoms
  • Sometimes chemotherapy agents are used to increase the effectiveness of radiation by sensitizing tumor cells if present.

 

Immunotherapy

 

Bacillus Calmette-Guérin (BCG) is being investigated as an adjuvant mixed with autologous tumor cells in immunotherapy for colorectal cancer

 

Cancer Vaccine

 

TroVax, a cancer vaccine,[63] produced by Oxford BioMedica [64], is in Phase III trials for renal cancers, and phase III trials are planned for colon cancers.

 

Treatment of liver metastases

 

According to the American Cancer Society statistics in 2006, over 20% of patients present with metastatic (stage IV) colorectal cancer at the time of diagnosis, and up to 25% of this group will have isolated liver metastasis that is potentially resectable. Lesions which undergo curative resection have demonstrated 5-year survival outcomes now exceeding 50%.

 

Resectability of a liver metastasis is determined using preoperative imaging studies (CT or MRI), intraoperative ultrasound, and by direct palpation and visualization during resection. Lesions confined to the right lobe are amenable to en bloc removal with a right hepatectomy (liver resection) surgery. Smaller lesions of the central or left liver lobe may sometimes be resected in anatomic “segments”, while large lesions of left hepatic lobe are resected by a procedure called hepatic trisegmentectomy. Treatment of lesions by smaller, non-anatomic “wedge” resections is associated with higher recurrence rates. Some lesions which are not initially amenable to surgical resection may become candidates if they have significant responses to preoperative chemotherapy or immunotherapy regimens. Lesions which are not amenable to surgical resection for cure can be treated with modalities including radio-frequency ablation (RFA), cryoablation, and chemoembolization.

 

Patients with colon cancer and metastatic disease to the liver may be treated in either a single surgery or in staged surgeries (with the colon tumor traditionally removed first) depending upon the fitness of the patient for prolonged surgery, the difficulty expected with the procedure with either the colon or liver resection, and the comfort of the surgery performing potentially complex hepatic surgery.

 

Aspirin

 

A study published in 2009 found that Aspirin reduces risk of colorectal neoplasia in randomized trials and inhibits tumor growth and metastases in animal models. The influence of aspirin on survival after diagnosis of colorectal cancer is unknown. Several reports including a prospective cohort of 1,279 people diagnosed with stages I-III (non-metastatic) colorectal cancer have suggested a significant improvement in cancer-specific survival in a subset of patients using aspirin.

 

Support therapies

 

Cancer diagnosis very often results in an enormous change in the patient’s psychological wellbeing. Various support resources are available from hospitals and other agencies which provide counseling, social service support, cancer support groups, and other services. These services help to mitigate some of the difficulties of integrating a patient’s

 

medical complications into other parts of their life.

 

Prognosis

 

Survival is directly related to detection and the type of cancer involved. Survival rates for early stage detection is about 5 times that of late stage cancers. CEA level is also directly related to the prognosis of disease, since its level correlates with the bulk of tumor tissue.

 

Follow-up

 

Micrograph of a colorectal villous adenoma. These lesions are considered pre-cancerous. H&E stain.

 

The aims of follow-up are to diagnose in the earliest possible stage any metastasis or tumors that develop later but did not originate from the original cancer (metachronous lesions).

 

The U.S. National Comprehensive Cancer Network and American Society of Clinical Oncology provide guidelines for the follow-up of colon cancer. A medical history and physical examination are recommended every 3 to 6 months for 2 years, then every 6 months for 5 years. Carcinoembryonic antigen blood level measurements follow the same timing, but are only advised for patients with T2 or greater lesions who are candidates for intervention. A CT-scan of the chest, abdomen and pelvis can be considered annually for the first 3 years for patients who are at high risk of recurrence (for example, patients who had poorly differentiated tumors or venous or lymphatic invasion) and are candidates for curative surgery (with the aim to cure). A colonoscopy can be done after 1 year, except if it could not be done during the initial staging because of an obstructing mass, in which case it should be performed after 3 to 6 months. If a villous polyp, polyp >1 centimeter or high grade dysplasia is found, it can be repeated after 3 years, then every 5 years. For other abnormalities, the colonoscopy can be repeated after 1 year.

 

Routine PET or ultrasound scanning, chest X-rays, complete blood count or liver function tests are not recommended. These guidelines are based on recent meta-analyses showing that intensive surveillance and close follow-up can reduce the 5-year mortality rate from 37% to 30%.

Anal cancer is a type of cancer which arises from the anus, the distal orifice of the gastrointestinal tract. It is a distinct entity from the more common colorectal cancer. The etiology, risk factors, clinical progression, staging, and treatment are all different. Anal cancer is typically a squamous cell carcinoma that arises near the squamocolumnar junction.

 

Prevalence

 

The American Cancer Society estimates that in 2009 about 5,290 new cases of anal cancer will be diagnosed in the United States (about 3,000 in women and 2,000 in men). It is typically found in adults, average age early 60s.

 

In the United States, an estimated 710 people died of anal cancer in 2009.

 

Symptoms

 

Symptoms of anal cancer include bloating and change in bowel habits, a lump near the anus, rectal bleeding, itching or discharge. Women may experience lower back pain due to pressure the tumor exerts on the vagina, and vaginal dryness.

 

Risk factors

• Human papillomavirus examination of squamous cell carcinoma tumor tissues from patients in Denmark and Sweden showed a high proportion of anal cancers to be positive for the types of HPV that are also associated with high risk of cervical cancer (90% of the tumors from women, 100% of the tumors from homosexual men, and 58% of tumors from heterosexual men).[3] In another study done, high-risk types of HPV, notably HPV-16, were detected in 84 percent of anal cancer specimens examined.

• Sexual activity: Having multiple sex partners or having anal sex, due to the increased risk of exposure to the HPV virus. Homosexual and bisexual men are 17 times more likely to develop anal cancer than heterosexual men.

• Smoking: Current smokers are several times more likely to develop anal cancer compared with nonsmokers.

• Immunosuppression, which is often associated with HIV infection.

• Benign anal lesions (inflammatory bowel disease (IBD), hemorrhoids, fistulae or cicatrices). Inflammation resulting from benign anal lesions, such as hemorrhoids and anal fistulas, has been considered to cause a predisposition to anal cancer.

 

Prevention

 

Since many, if not most, anal cancers derive from human papillomavirus infections, and since the HPV vaccine prevents infection by some strains of the virus and has been shown to reduce the incidence of potentially precancerous lesions,[10] scientists surmise that HPV vaccination may reduce the incidence of anal cancer.

 

Screening

• Anal Pap smears similar to those used in cervical cancer screening have been studied for early detection of anal cancer in high-risk individuals.

 

Treatment

 

Localised disease

 

Anal cancer is most effectively treated with surgery, and in early stage disease (i.e., localised cancer of the anus without metastasis to the inguinal lymph nodes), surgery is often curative. The difficulty with surgery has been the necessity of removing the anal sphincter, with concomitant fecal incontinence. For this reason, many patients with anal cancer have required permanent colostomies.

 

In more recent years, physicians have employed a combination strategy including chemotherapy and radiation treatments to reduce the necessity of debilitating surgery. This “combined modality” approach has led to the increased preservation of an intact anal sphincter, and therefore improved quality of life after definitive treatment. Survival and cure rates are excellent, and many patients are left with a functional sphincter. Some patients have fecal incontinence after combined chemotherapy and radiation. Biopsies to document disease regression after chemotherapy and radiation were commonly advised, but are not as frequent any longer. Current chemotherapy active in anal cancer includes cisplatin and 5-FU. Mitomycin has also been used, but is associated with increased toxicity.

 

Metastatic or recurrent disease

 

Up to 10% of patients treated for anal cancer will develop distant metastatic disease. Metastatic or recurrent anal cancer is difficult to treat, and usually requires chemotherapy. Radiation is also employed to palliate specific locations of disease that may be causing symptoms. Chemotherapy commonly used is similar to other squamous cell epithelial neoplasms, such as platinum analogues, anthracyclines such as doxorubicin, and antimetabolites such as 5-FU and capecitabine. J.D. Hainsworth developed a protocol that includes Taxol and Carboplatinum along with 5-FU.