Gardner's syndrome

Gardner's syndrome (GS), a variant of FAP, is distinguished by the presence of prominent extracolonic lesions, such as desmoid tumors, osteomas, and cysts.

• In the member familial adenomatous polyposis (FAP) family, when these tumors arise, the family has traditionally been said to have Gardner's syndrome instead of FAP, since all the members of the family have the same mutation in the adenomatous polyposis coli (APC) gene.
  

In the early 1950s, Gardner described a kindred with intestinal characteristics of familial adenomatous polyposis (FAP), but also with a number of extra-colonic growths, including osteomas, epidermal cysts and fibromas.

The combination of these inherited colonic adenomatosis together with these extracolonic lesions has become known as Gardner's syndrome.

• FAP is characterized by 100’s to 1000’s of colonic adenomatous polyps that most often emerge in the second and third decades of life.
• The development of Colon cancer is inevitable if the colon is not removed.
• The polyposis is also usually observed in the stomach, duodenum, and small bowel, although the cancer risk in these locations is far less than in the colon.
• Shortly after discovery of the adenomatous polyposis coli (APC) gene, it became apparent that both FAP and Gardner’s syndrome arose from APC mutations.
• It is inherited as autosomal dominant, with near complete penetration of the gastrointestinal phenotype but with variable penetrance of the extraintestinal manifestations of the disease.
  
• Involvement of male and female is equal.
• New mutations have been represented by 20 to 30% of newly diagnosed cases.
• New cases may also arise from mosaic inheritance, which implies that a mutation occurred in parent's sperm or egg cells, but not in other cells of the body, so the parent did not have clinical disease.
• The number of the colonic polyp depends to some degree on where the mutation occurs in the APC gene.
• If the mutations occur in the center of the gene (often called the mutation cluster region), it give rise to dense polyposis, with 5000 or more colonic polyps when the disease is fully developed.
• If mutations occur proximal or distal to this central gene location, colonic polyps average approximately 1000 with full expression.
• Mutations in the extreme proximal or distal locations of the APC gene are associated with many fewer polyps (often less than 100). This clinical variation is referred to as attenuated FAP.
• Extraintestinal growths do not correlate with polyp density but have some correlation with mutation location.

The common extraintestinal manifestations associated with Gardner’s syndrome have been described in approximately 20 percent of patients with FAP.

• However, many more patients with FAP have these features if they undergo detailed physical and radiologic examinations.
• Thus, the difference between FAP and GS is somewhat semantic and GS is usually considered a subset of FAP.
• On the other hand, the term GS continues to be commonly applied, particularly in families that exhibit frequent and obvious extraintestinal lesions.

Extraintestinal benign lesions —

Gardner's syndrome is associated with several benign extraintestinal growths including:

• Osteomas
• Dental abnormalities
• Congenital hypertrophy of the retinal pigment epithelium
• Cutaneous lesions
• Desmoid tumors
• Adrenal adenomas
• Nasal angiofibromas

Osteomas

• Osteomas were originally described in the skull and mandible but more recently have been shown to involve other areas; they may be the only extracolonic manifestations.
• The bony tumors may be present for many years before the onset of intestinal symptoms they may appear denovo and continue to grow throughout the rest of life.
• Osteomas are found in about 20 percent of families with FAP and are the first described extracolonic lesions of GS.
• They are one to dozens in number and are of less than a millimeter to few centimeter in diameter.
• Radiologic examination of the mandible is a simple and noninvasive means to screen for young carriers of the FAP gene, but it is crucial to distinguish nonspecific sclerotic lesions in the mandible from true osteomas.
• Mandibular osteomas in FAP tend to be multiple, whereas nonspecific sclerotic bony lesions usually are single and located close to a diseased tooth.
• Because osteomas have no malignant potential, they are removed only for symptomatic or cosmetic reasons.

Dental abnormalities

• Dental abnormalities includ mandibular cysts, impacted teeth, and supernumerary teeths.
• They also appear before the development of colonic polyposis.
• Panoramic x-ray of jaw in FAP patients they are found in 90% of the cases but clinically their appearance is only 17% whereas 1 to 2 percent in general population.
• Again attention is needed only if there is a symptomatic or cosmetic problem.

Congenital hypertrophy of the retinal pigment epithelium

• Congenital hypertrophy of the retinal pigmented epithelium (CHRPE) has been reported in some families with FAP or Gardner's syndrome.
• More than 90% of patients with Gardner's syndrome have pigmented ocular fundus lesions (vs. 5% of controls), which are likely to be multiple (63% have four or more lesions) and are bilateral in 87% of those affected.
• The lesions are discrete, darkly pigmented, round, oval, or kidney shaped, ranging in size from 0.1 to 1.0 times the diameter of the disc.
• Pigmented ocular fundus lesions are found in approximately half of the unaffected but at-risk first-degree relatives and have been identified in infants as young as 3 months old, suggesting that they are probably congenital.
• The presence of multiple, bilateral lesions appears to be a reliable marker for gene carriage in FAP, and their absence predicts lack of carriage if carrier relatives show CHRPE.
• These marker lesions are asymptomatic curiosities that need not be sought in patients with an established diagnosis of FAP.
• Slit-lamp examination is usually required for detection.
• CHRPE is not known to cause clinical problems. CHRPE is observed with mutations between codons 311 and 1444, although this varies somewhat depending on the study.
• CHRPE perhaps reflects the most accurate genotype-phenotype correlation in FAP patients; these lesions occur in patients with APC gene mutations distal to exon 9 up through the proximal portion of exon 15.

Cutaneous lesions

Epidermal cysts:

• The association of epidermoid (sebaceous) cysts with FAP has been termed Oldfield's syndrome.
• As all other extraintestinal lesions they appear before puberty and also precedes polyposis.
• These cysts vary from few millimeters to many centimeters in size.
• They may appear any where on the surface of body but most frequently on the legs, face, scalp, and arms, in order of their occurrence.
• They are removed surgically if needed for cosmetic reasons.

Fibromas

• They appear on the cutaneous surfaces of the scalp, shoulders, arms, and back.
• They are few millimeter to few centimeter in size.

Lipomas

• There is an increase in the incidence of these lesions in Gardner’s Syndrome in compared to the general population.

Pilomatricomas
Desmoid tumors

• A particularly serious complication of the adenoma-tous polyposis syndromes is the development of diffuse mesenteric fibromatosis, also called desmoid tumors
• Desmoid tumors are usually benign fibromas that tend to infiltrate locally into adjacent tissue.
• They are rare in the general population (5 to 6 per million per year) but in FAP affect from 5 to 25 percent of patients.
• Studies have shown that the absolute risk of desmoids in patients with FAP is 2.56/1,000 person-years, with the comparative risk 852 times that of the general population.
• Usually, however, desmoid tumors become manifest from 1 to 3 years following surgery for polyposis.
• Desmoids can, however, occur in the absence of Gardner's syndrome.
• The peak incidence of desmoid occurrence in GS is between 28 and 31 years, although they may occur at any age.
• Independent predictors of their occurrence include APC gene mutations 3' of codon 1444, a family history of desmoids, female gender, and the presence of osteomas.
• Mutations between codons 1310 and 2011 are associated with a six-fold risk of desmoid tumors relative to the low-risk reference region (159 to 495).
• Although the lesion appears occasionally to emulate fibrosarcoma, metastasis does not occur.
• Local recurrence is the rule rather than the exception. The mass tends to develop in abdominal incisions, in the abdominal cavity (particularly the small bowel mesentery), and the retroperitoneum.
• Intra-abdominal desmoids may grow to massive sizes, sometimes occupying much of the abdominal cavity and encasing viscera.
• The condition may antedate the appearance of the polyposis by developing in an abdominal incision performed for another purpose (e.g., appendectomy).
• They may infiltrate adjacent structures, extend along facial planes, attach to and erode bones, and engulf and compress blood vessels, nerves, ureters, small bowel, and other hollow organs of the abdomen.
• Severe and sometimes fatal problems can arise especially if the mesenteric vessels or other hollow abdominal organs become obstructed.
• Clark and Phillips and others confirmed that intraabdominal desmoids behave unpredictably but are an important source of mortality in those with FAP.
• The authors also observed that signal intensity on magnetic resonance imaging reflects tumor cellularity, which may, in part, determine progression; this may aid in management of these individuals.
• Surgery (including colectomy) also appears to be an independent risk factor for desmoid disease in FAP, particularly with mutations in certain regions of the APC gene.
• Progression is often gradual and survival 10 years after the diagnosis is approximately 63 percent.
• Histologically, there may be some differences between fibroblastic growths in GS and sporadic desmoids.
• A distinctive fibroblastic growth, called Gardner associated fibroma, may be seen in young patients and appears to be the precursor lesion of desmoids in GS.
  o Desmoid tumors in GS are monoclonal growths, implying that they are true neoplasms.
  o Desmoids in FAP also arise from APC inactivation and subsequent accumulation of beta-catenin in cells.
  o In contrast, APC mutations are uncommon in sporadic desmoids.
  Adrenal adenomas
  o Adrenal adenomas in FAP harbor a somatic as well as germline APC mutation, indicating these tumors arise as part of FAP.
  o Most adrenal adenomas in Gardner’s Syndrome are found incidentally.
  o Their prevalence is 7 to 13 percent of patients with Gardner’s Syndrome whereas it is only 3 percent in the general population.
• Malignancy of the adrenal is rare in FAP.

Nasal angiofibromas

• They are described in some patients of Gardner’s Syndrome.

Extraintestinal malignant lesions
Patients with Gardener’s Syndrome have increased risk for the following malignancies:

• Upper Gastrointestinal Tumors (3 to 5 percent)
• Thyroid (2 percent)
• Pancreatic (2 percent)
• Gastric (0.6 percent)
• Central nervous system (<1>
• Hepatoblastoma (1.6 percent)
• Small bowel distal to the duodenum
• Possibly adrenal

Upper Gastrointestinal Tumors

• Periampullary carcinoma is a well-recognized disease that is associated with Gardner's syndrome.
• Twelve percent of patients in the St. Mark's Hospital series who survived for 5 years after colectomy developed carcinoma of the duodenum, ampulla of Vater, or pancreas.
• Sugihara and associates reviewed the literature and identified 29 such patients, with a mean age of 45 years.
• Eleven patients developed colorectal cancer, all of them having presented with symptoms before the periampullary malignancy.
• Gastrointestinal polyps and cancer have been frequently reported with this syndrome. Invasive upper gastrointestinal adenocarcinoma was found in 4.5% of patients with FAP as recorded in ten polyposis registries.
• Nederveen Cappel and associates calculated that the lifetime risk of developing duodenal cancer in FAP is 5%.
• The most frequent sites for upper gastrointestinal tumors are duodenum, followed by pancreatic ampulla and then stomach. J
• apanese studies reveal the incidence of gastric polyps to be as high as 70% with Gardner's syndrome, whereas the incidence of duodenal polyps approaches 100%.
• In Korea, where carcinoma of the stomach is the most common neoplasm, one survey identified 72 patients with FAP, three of whom (4.2%) were found to harbor gastric cancer.
• This is a much higher risk than would be anticipated from the general population in that country.
  

Periodic upper gastrointestinal radiologic investigation (optimally with double-contrast technique), or preferably endoscopy at intervals in all patients found to have FAP is recommended in order to diagnose and treat lesions at an earlier stage, before invasive carcinoma supervenes.

• This should be accomplished every 6 months to 4 years, depending on the polyp load.
• Their kindred should also be studied for the same.

Thyroid cancer

• Thyroid carcinoma has been reported to be associated with Gardner's syndrome.
• Unique about this observation is that the proliferative abnormalities of the syndrome as listed earlier are of mesenchymal origin, whereas thyroid tumors are not; this suggests a broader potential for the genetic defect.
• An association with thyroiditis has also been observed. Risk of thyroid cancer in Gardner’s syndrome is approximately 8 fold in comparison to normal population and occurs in about 12 percent on FAP patients.
• Average age of presentation is 33, presents as nodular growth, ultrasound is needed for screening, in addition to palpation.
• Histologically they are of papillary type and association of APC mutation in the 5’ end of exon 15 is documented.

Pancreatic cancer

• The risk of pancreatic cancer that is adenocarcinoma of pancreas in patients of FAP is 4 times to that of general population.
• It may present with any complication of ductal obstruction.

Hepatoblastoma

• This malignancy is 800 times more common in boys under age of 5 years in FAP children. But the risk of development remains up to 15 years.
• It has some association with mutation of APC at its 5’ end.

Miscellaneous Associations

Other conditions that are believed to represent manifestations of this syndrome include :

• carcinoid of the small bowel,
• adrenal cancer,
• adrenal adenoma,
• pheochromcytoma,
• skin pigmentation, and
• lymphoid polyposis.

There is, however, the possibility that the observations may merely be coincidental.

Peutz-Jeghers Syndrome

Introduction :

Peutz-Jeghers syndrome (PJS) is a rare entity characterized by hamartomatous polyps, usually less than 100 in number, found throughout the GI tract in association with hypermelanotic macules in the perioral region, buccal mucosa, digits (hands, feet), perianal and genital regions.

In 1921, Peutz reported a familial syndrome of polyps of the gastrointestinal tract with pigmentation of the mouth and other parts of the body. Later, Jeghers and his colleagues established the syndrome by describing a number of cases.

Hamartomas are growths of tissue that can be of endodermal, mesodermal, and/or ectodermal origin, but with an epithelial covering typical of the bowel location where the polyp is found.

• Peutz-Jeghers polyps are also hamartomas, arising from smooth muscle in the muscularis mucosa.
  
• These lesions are hemispheric or finger-like protrusions, ranging in size from 0.1 to 10 mm, but they may grow up to 4 cm in diameter.
• On microscopy, a core of smooth muscle penetrating into the overlying lamina propria is seen.

Genetic considration :
This familial syndrome appears to be inherited as a single pleiotropic autosomal dominant gene with variable and incomplete penetrance.

• Germline mutations of the STK11/LKB1, a serine threonine kinase gene on chromosome 19p, cause this syndrome, but not all families with PJS are linked to this gene locus, suggesting genetic heterogeneity.

• Although it has been assumed that these cancers arise from rare foci of adenomatous epithelium that may develop within the Peutz-Jeghers polyps, recent evidence for loss of STK11/LKB1STK11/LKB1 gene itself might be the gatekeeper to carcinogenesis in this syndrome, much like APC gene is the gatekeeper in FAP.

• This disorder exhibits autosomal dominant inheritance with variable penetrance.
• Significant progress has been made in the identification of a specific genetic defect.
  
• The PJS putative tumor suppressor gene maps to the telomeric region of chromosome 19p at 19p13.3and encodes the serine threonine kinase LKB1/STK11.
  
• Germline mutations in LKB1/STK11, probably in conjunction with acquired genetic defects of the second allele in somatic cells, result in the phenotypic manifestations of the syndrome.

Clinical features :

Polyposis develops early in life and commonly presents clinically by age 20.

• In addition, polyps in the upper respiratory tract, biliary tract, and urinary tract have been reported.
  
• GI bleeding (acute or chronic) and bowel obstruction secondary to intussusception are the most common presentations, but unusual symptoms and signs indicative of biliary obstruction or gastric outlet obstruction are possible.

The polyps are found most frequently in the small bowel, particularly the jejunum, but they also can occur in the stomach, colon, and rectum.

• Small intestine — 48 %
• Stomach — 24 %
• Colon — 24 %
• Pancreas — 5 %

Cutaneous pigmentation usually is noted at birth or in infancy, but the skin changes may actually disappear after puberty.

• They consist of clusters of black or dark brown spots resembling freckles, 1 to 2 mm in diameter, on and around the lips and buccal mucosa, fingers, and toes.

The most common symptom and the one most difficult to manage is abdominal pain, often caused by intestinal obstruction.

• The obstruction is usually the result of a polyp or of an intussusception.
  
• The other frequent complaint is rectal bleeding.
  
• Additional signs and symptoms include prolapse of the polyp, passage of the polyp, hematemesis, and anemia.

Diagnosis :
Diagnosis of the syndrome can usually be made on the basis of family history, skin pigmentation, and gastrointestinal symptoms. Contrast studies in addition to endoscopy confirm the extent of the polypoid disease.
In case of Histopathologically confirmed hemartoma, the diagnostic requirement of PJS is any two findings of the following three :

1. Family history with concomitant autosomal dominant inheritance
2. Mucocutaneous hyperpigmentation
3. Small-bowel polyposis

Complete upper and lower endoscopy in addition to small bowel contrast studies or enteroscopy, if available, are indicated to identify gastrointestinal polyposis.

• Modern endoscopic techniques make surveillance and removal of polyps up to 150 cm beyond the ligament of Treitz possible.

• Genetic testing is available. Not all mutations associated with PJS have been identified. So in such a case, a negative genetic test does not exclude the diagnosis.

Pathology :

Macroscopically, the polyps vary in size.

• They may be as large as several centimeters in diameter, and with increasing size, they tend to become pedunculated.
  
• In visual appearance, they look very much like adenomatous polyps (see Polypoid Adenoma, Adenomatous Polyp, and Tubular Adenoma).

Microscopically, the polyps seem to originate from intestinal glandular epithelium along with a muscular branching framework that arises from the muscularis mucosa.

• The tubules of epithelium rest on the branching bands of smooth muscle in a relationship similar to that of the glandular epithelium with the muscularis mucosa of the normal bowel.
• Because there is no evidence of hyperplasia, cytologic variation, or loss of differentiation, Morson suggested that the lesion represents a hamartomatous process or malformation, rather than a neoplasm.

Relationship with Cancer :
In a review by Konishi and colleagues, 117 neoplasms were found in 103 patients.There were 50 carcinomas of the gastrointestinal tract, the colon and rectum being the most common site.

It was established that some of these tumors arose within a Peutz-Jegher polyp, but many probably originated in otherwise normal mucosa.

• Giardiello and colleagues investigated 31 patients with this syndrome and found that 48% developed a malignancy; this rate was 18 times greater than would be expected.

The increased frequency was noted for cancers of both gastrointestinal and nongastrointestinal origin.

• Hizawa and co-workers investigated 75 gastrointestinal polyps resected surgically or endoscopically from seven patients with this syndrome. Nine were accompanied by an adenomatous component, two of which demonstrated malignant transformation with pedicle invasion.

According to one author, that neoplastic transformation was not a rare event and that their results suggested a hamartoma-adenoma-carcinoma sequence in Peutz-Jeghers polyposis.

Linos and colleagues, conversely, reported the considerable Mayo Clinic (Rochester, MN) experience (48 patients) and failed to document one definite instance of cancer; the median follow-up period was 33 years. The authors, furthermore, found that survival was similar to that of the population at large. They recommended that every effort should be made to conserve intestine in the management of this condition. Another reason to be concerned about an aggressive surgical approach is the possibility of misinterpretation of the histologic appearance. Dippolito and colleagues suggested that careful evaluation may reveal most of these lesions to be, in reality, enteritis cystica profunda.

• Patients with PJS typically have several potential complications from hamartomatous polyps.
  • Not only is malignant transformation a concern, but the polyps can also ulcerate, bleed, infarct, and intussuscept.
    
  • After the age of 30 years, malignant complications become the major concern; by the age of 65 years, over 90% of patients will have a malignancy.
    
  • The most common GI cancers include
    • colon, with a lifetime risk of 39%,
      
    • pancreatic, with a lifetime risk of 36%,
      
    • gastric, and SB (Giardiello et al, 2000).
      
    Non-GI malignancies include
    
  • breast (54% lifetime incidence),
    
  • ovarian (21% lifetime incidence),
    
  • Sertoli cell tumors (9% lifetime incidence with 10 to 20% becoming malignant), and
    
  • lung (15% lifetime incidence).

The high rate of extra-intestinal cancers also deserves attention with regular examination of potentially involved organs. Specific symptoms require special attention and should lead to an aggressive workup to exclude a malignant cause.

Proctalgia Fugax

Proctalgia fugax is a common cause of pain in the rectum. Symptoms consistent with proctalgia fugax occur in 13 to 19 percent of the general population.
Proctalgia fugax is underrepresented in the medical literature, and many physicians are unaware of its existence. Lack of familiarity on the part of the physician can result in unnecessary diagnostic evaluation. Contributing to the relative lack of familiarity is the fact that most patients with proctalgia fugax do not seek medical attention because the pain is usually brief and often infrequent. Patients may also be reluctant to disclose the symptoms because they fear potentially painful diagnostic procedures or the possibility of a serious condition

• Anorectal pain is a relatively common symptom first described by the Romans.
• Patients will often delay consulting a healthcare practitioner about this problem due to embarrassment and fear of a sinister diagnosis, tolerating disturbing symptoms for long periods.
• There are two functional anorectal pain syndromes:
• Proctalgia fugax (PF) (fugax=fugitive/fleeting in Greek) and
• Levator ani syndrome (LAS)
• They are both characteristic, benign anorectal-pain syndromes of uncertain aetiology.
• Despite their benign nature, they can cause severe distress to the sufferer. There is even an account of marital disharmony caused by proctalgia fugax.

Aetiology

• They are thought to occur due to spasm of the anal sphincter (PF) or pelvic floor muscles (LAS) but are something of an enigma.
• They may be associated with irritable bowel syndrome. The two affected muscles are anatomically contiguous so the two conditions may co-exist, or be different manifestations of the same underlying dysfunction.
• The diagnosis of these conditions can usually be made on the basis of the symptoms.
• However, more serious diagnoses can present similarly. Thus, it is essential to conduct a thorough clinical assessment to exclude other pathology before offering reassurance.
• May be associated with low-fibre diet and irritable bowel syndrome. More than half of affected patients are aged 30–60 years and prevalence declines after age 45.⁶
• It has been associated with a variety of other pathologies which may have aetiological significance, for example pudendal nerve neuralgia.

Epidemiology

• PF is estimated to affect 8–18% of the population in the developed world, and LAS around 6%.
• LAS seems to affect women more than men.
• It is thought that only 20–30% of sufferers of these conditions consult a healthcare practitioner.

Differential diagnosis

• Irritable bowel syndrome
• Haemorrhoids ± thrombosis
• Anal fissure (usually causes intense localised pain associated with and following defecation) – should be visible on proctoscopy.
• Solitary chronic rectal ulcer
• Rectal carcinoma
• Perirectal abscess or fistula; hydradentis suppuritiva
• Proctitis (especially gonococcal/chlamydial infection)
• Crohn's/Ulcerative colitis.
• Rectal foreign body
• Pruritus ani.
• Diverticular disease
• Rectal prolapse
• Coccygodynia (neuralgic pain around the region of the coccyx)
• Retrorectal cysts
• Condylomata acuminata (anogenital warts)
• Testicular carcinoma
• Prostatitis
• Cystitis
• Psychological cause (some hypothesise that these conditions are psychological rather than physical in origin)
• Alcock's canal syndrome (pudendal neuralgia due to entrapment, may present similarly to PF/be aetiologically relevant)
• Hereditary anal sphincter myopathy
• Bilateral internal iliac artery occlusion

Proctalgia fugax

Presentation

• Symptoms:
• Recurrent episodes of sudden, severe cramping pain localised to the anus or lower rectum.
• Last from seconds to minutes and resolves completely.
• The patient is entirely pain free between the episodes.
• Symptoms often occur at night and may wake the sufferer. Attacks are infrequent (<5>
• Attacks may come in clusters (occurring daily) then abate for long periods.
• Signs:
• PF has no signs and the diagnosis is made on the basis of characteristic symptoms and the absence of signs of other pathology.
• Abdominal and digital rectal examination should constitute the minimum assessment of anal pain.
• Ideally, anoscopy/proctoscopy should be carried out.
• Consider gynae/scrotal examination if relevant.
• Further examination with a sigmoidoscope or colonoscope may be necessary in selected patients where there is suspicion of pathology higher in the colon.
• It is worth checking for signs of anaemia if GI bleeding is suspected.

Management

• Once the diagnosis is made, reassurance is usually sufficient.
• The symptoms are so transient that drug therapy is rarely needed.
• In patients who suffer frequent, severe, prolonged attacks, inhaled salbutamol has been shown to reduce their duration.
• Clonidine and amylnitrate have also been used but no evidence exists for their efficacy.

Treatment of Cholangiocarcinoma

Preoperative preparation
Jaundiced patients require vitamin K.
Resective procedures for cholangiocarcinomas are major procedures and, therefore, patients should have good functional status especially if they are elderly.

Preoperative biliary decompression
In general, it is preferable to avoid stents, if possible. Many surgeons find the presence of any biliary stent a hindrance to determining the proximal tumor extent intraoperatively. On the other hand, cholestasis, liver dysfunction, and biliary cirrhosis develop rapidly with unrelieved obstruction. The extent of liver dysfunction is one of the main factors that increase postoperative morbidity and mortality following surgical resection.

• The chance of postoperative liver failure may be lessened by preoperative decompression, especially decompression of the side to be retained.

• Decompression has the dual purpose of allowing that side to recover function and actually to hypertrophy.
  
• On the other hand, stents may introduce bacteria and cause cholangitis.

• Selective percutaneous decompression is an accepted strategy in Japan and multiple stents are often inserted.

A reasonable strategy is to proceed to surgery in younger patients (age less than 70 years) without serious comorbidities who have been jaundiced for less than 4 weeks, whose serum bilirubin is less than 10 mg/dL and whose future remnant liver will be > 40% of total liver mass.

• Also, such patients should not have had biliary instrumentation, which always contaminates the obstructed biliary tract.
  

• For the remainder, we routinely decompress the side of the liver to be retained and wait until the serum bilirubin falls to 3 mg/dL.

Preoperative portal vein embolization —

• Because the achievement of histologically negative resection margins is so critical to outcome, preoperative portal vein embolization (PVE) has been used in an attempt to increase the limits of safe resection.
  
• The intent of PVE is to induce lobar hypertrophy in patients who have a predicted postoperative liver remnant volume of <25>
• By allowing a larger resection volume to be carried out safely, PVE may permit a margin-negative resection in patients who otherwise would be considered unresectable because of concerns about insufficient postoperative residual liver volume.

Treatment
Hilar cholangiocarcinoma

Criteria for resectability — The traditional guidelines for resectability of cholangiocarcinoma in the United States include :

• Absence of retropancreatic and paraceliac nodal metastases or distant liver metastases

• Absence of invasion of the portal vein or main hepatic artery (although some centers support en bloc resection with vascular reconstruction)

• Absence of extrahepatic adjacent organ invasion

• Absence of disseminated disease

The goals of surgical resection are to remove the tumour with negative resection margins and to perform a portal and coeliac node dissection.

• In order to achieve this, hemihepatectomy with resection of the caudate lobe as well as the suprapancreatic extrahepatic bile duct and the portal and coeliac lymph nodes is required.
  
• Resection of the caudate lobe is needed because, when the tumour is Bismuth 2 or greater, the orifices of the caudate ducts may be involved with tumour.
  
• Hemihepatectomy is required when the tumour involves the sectional ducts (Bismuth 3) on one side of the liver or the artery or portal vein to one side of the liver.
  
• Theoretically, resection of a Bismuth 2 tumour could be accomplished by resection of bile ducts with the caudate lobe but, in practice, negative margins are much more likely to be accomplished by a hemihepatectomy with resection of the caudate lobe.
  
• Therefore, surgical practice has evolved in the past 20 years to the point at which there is a consensus that virtually all hilar cholangiocarcinomas should be resected by hemihepatectomy and caudate resection.
  
• Low-lying Bismuth 1 tumours, in which a negative upper margin can be obtained on the common hepatic duct, i.e. below the level of the orifices of the caudate ducts, may be resected without removing liver tissue, but these instances are uncommon.
  

Unfortunately, cholangiocarcinomas have a well-known propensity to spread microscopically for long distances along the bile duct.

• A positive resection margin occurs in 20–40% of cases even when liver resection has been done.
  
• The resection margin may be extended by dividing through the termination of the sectional ducts, but there is a limit to how far this can be carried.
  
• Mobilizing the portal vein in the umbilical fissure aids this manoeuvre on the left as the bile ducts to the left lateral section pass behind this vein.
  
• The operation can also be extended by taking the left medial section with the right liver (right trisectionectomy) or the right anterior section with the left liver (left trisectionectomy).
  

• The operation may also be extended by vascular resections.
  • Involvement of the portal vein may require replacement of the anterior wall of this structure or circumferential resection with anastomosis of the main portal vein to the left portal vein or, less commonly, the right portal vein with or without an interposition graft.
• It has been proposed to remove the anterior wall of the portal vein as a routine in order to obtain a higher rate of negative margins.
  
• This recommendation lacks supporting randomized data and is not routinely followed.
  
• Arterial reconstruction of the proper hepatic artery is less commonly performed.
  
• Pancreatoduodenectomy is performed in up to 15% of cases in some series in order to obtain negative lower margins or to remove potentially malignant nodes.
  
• Reconstruction of the biliary tract is by a Roux-en-Y hepaticojejunostomy.
  
• The Roux limb is made at least 60 cm in length to avoid reflux of intestinal contents into the biliary tree.
  

Results
The important trends are as follows.

• Portal vein embolization is becoming more common as a preoperative preparation.
  
• Some 15–50% of patients are found to be unresectable at surgery but, in recent years, the figure has been decreasing towards the lower limit of this range.
  
• More procedures include a major hepatic resection because the chance of achieving an R0 resection is substantially higher when a major resection is performed.
  
• Mortality rates are falling.
  
  

Morbidity rates are still high, reflecting the magnitude of the procedure.
R0 resection is necessary for cure; almost no patients who have had R1 resection survive 5 years without recurrence.
Even with R0 resection, the overall 5-year survival is only 20–35%.
Factors affecting survival include

• R0 resection,
  
• en bloc hepatectomy,
  
• absence of tumour in lymph nodes,
  
• tumour grade and tumour type with IG type (papillary) having better survival than other types.
  

The need to perform a vascular resection is associated with a poorer outcome in some series. The value of pancreatoduodenectomy is unclear at this time. Most patients requiring this addition to the procedure have had a relatively short survival.

Lower duct tumours
The rationale and extent of the procedure is the same as that used for pancreatic carcinoma.
Distal lesions are usually treated with pancreaticoduodenectomy (Whipple procedure).

• Often, the tissue of origin of the tumour, i.e. whether pancreatic, ampullary or bile duct in origin, is uncertain until after the specimen is examined pathologically and, even then, doubt can remain.
  
• The main complication of this procedure is a fistula from the pancreatic–jejunal anastomosis, which occurs in 5–10% of patients.
  
• Biliary fistulas occur in about 2% of patients.
  
• Patients rarely die from these complications today because of improvements in diagnostic and interventional radiology, intensive care and treatment of infection.

Resection of part of the stomach is no longer required for lower duct cholangiocarcinoma, although there is little or no difference in short-term outcome or quality of life between the pyloruspreserving and standard types of pancreaticoduodenectomy.

• Many patients require pancreatic enzyme replacement after this procedure, but few become diabetic.
  

Five-year overall survival in recent case series varies from 16% to 37%, and results have not improved in the last decade. Overall, the results of pancreatoduodenectomy for lower bile duct cancer are much the same as those for adenocarcinoma of the pancreas and unlike those for ampullary and duodenal cancers, which have a much better prognosis.

Intrahepatic cholangiocarcinomas
The principles of treatment are as for other malignant intrahepatic hepatic lesions.

• The tumour must be resected with a margin of normal tissue to obtain microscopically free resection margins (a 1-cm tumour-free resection margin is the goal), yet leave enough normally functioning liver tissue behind for the patient to have adequate liver function in the postoperative period.
  
• The size of the resection may vary from a single segment or less to resection of three of the four hepatic sections.
  
• The role of resection of extrahepatic lymph nodes is unclear, but it is being done with increasing frequency. Lymph node positivity is common in tumours over 4.5 cm in size, but rare in patients with smaller tumours, and lymphadenectomy might reasonably be limited to large tumours.
  

Four recent series of patients with MF intrahepatic cholangiocarcinoma treated by surgical resection in 60, 35, 52 and 104 patients reported 5-year survival rates of 29%, 33%, 34%
and 10% respectively.
Multivariate analyses of prognostic risk factors identified -

• symptomatic patient,
• positive surgical margin,
  
• multiple tumours,
  
• vascular invasion,
  
• lymph node metastases
• high microvessel counts indicative of angiogenesis as predictors of poor outcome.
  
• Mucin (MUC)4 expression in carcinoma tissues is also associated with poor outcome in MF intrahepatic cholangiocarcinoma.
  

Fewer data are available for the less common IG and PI types of intrahepatic cholangiocarcinoma.

• The IG type has the best prognosis.

Liver transplantation
Liver transplantation has been performed for intrahepatic and upper duct cholangiocarcinoma, but the results have been disappointing until recently.

• In one series published in 1993,only 3 of 14 patients (21%) lived more than 28 months after the procedure.
  
• Even in a more recent series, in which transplantation was performed in patients with cholangiocarcinoma in the setting of PSC, the 5-year survival was only 35%.
  
• While these are not poor results for a visceral cancer, they must be evaluated with the knowledge that many patients with endstage chronic liver disease are dying while on a waiting list for liver transplantation, and the comparative survival rate in this group of patients would be expected to be about 90%.
  
• However, two American centres have reported better results for hilar cholangiocarcinoma.
  

The Mayo Clinic group reported on 56 patients who entered a trial of liver transplantation for unresectable cholangiocarcinoma or cholangiocarcinoma in the setting of PSC.

• The patients were staged by EUS and also by staging laparotomy.
  
• All patients received neoadjuvant chemoradiation.
• Approximately half the patients were transplanted, with a 5-year actuarial survival of 82% in transplanted patients.
  
• The other group using a similar approach achieved a 5-year survival rate of 50%.
  

Adjuvant chemotherapy or radiotherapy
One randomized controlled trial of adjuvant therapy using mitomycin C and 5-fluorouracil vs. surgery alone enrolled 139 patients with cholangiocarcinoma at various levels. There was no survival benefit, although there was benefit in a group of patients with gallbladder cancer treated with the same regimen. External beam radiotherapy was associated with improved postoperative survival in patients with hilar cholangiocarcinoma in one non-randomized trial. However, patients in the control group were treated at an earlier time period or tended to be in poor general condition. In an earlier study in which groups of patients with hilar cholangiocarcinoma were more comparable, external beam radiation did not result in
improved survival. Intraluminal brachytherapy does not extend survival and is associated with an increased incidence of complications.

Recurrence of cholangiocarcinoma is often local, suggesting that adjuvant chemotherapy and/or radiation would be beneficial but, currently, there is no evidence to support its use outside clinical trials.

Palliation
The purpose of palliation is to relieve jaundice and pruritus and to extend life.

• Jaundice and pruritus are treated by stenting, usually by endoscopic or percutaneous means or, less commonly, by surgery.
  
• Several randomized trials of surgical bypass vs. endoscopic intubation for lower duct tumours have been published.
  
• The three earlier trials favoured endoscopic stenting.
  
• Two of these trials were quite small and, in the third, the surgical procedures were performed by registrars; surgical complication rates were unusually high by current standards.
• The reintervention rate was high in the stent group.
• There was no difference in survival.
  
• In a more recent trial of patients found to be unresectable by staging laparoscopy, surgical bypass was favoured over stenting with the surgical group achieving a longer survival.
  

The current surgical consensus is that a surgical bypass should be performed by an experienced HPB surgeon in younger patients without distant metastases or obvious peritoneal disease.

• When unresectability is determined at laparotomy, a double bypass is performed to decompress the biliary tree and bypass the duodenum, which may become obstructed.
  
• Surgical decompression of hilar tumours may also be accomplished by bypass to the segment 3 duct, the so-called Bismuth–Corlette procedure.
  
• This provides decompression of the left liver.
  
• It is usually only done when a patient is found to be unresectable at the time of exploration.
  

Decompression with stents may be achieved by endoscopic or percutaneous means, with the former favoured because it is less invasive.

• Metal stents are generally used because of improved stent patency rates.
  
• In the hilum, plastic stents also have the theoretical disadvantage that their solid walls may block smaller side-branches.
  
• For lesions below the bifurcation, a single stent will decompress the entire liver.
  
• Bilateral stents or forked stents have been used to decompress tumours obstructing the confluence.
  
• However, it seems that a unilateral stent is often just as effective provided that it is placed selectively, based upon a preprocedure MRCP, on the side of the liver that will result in decompression of the most functional liver.
  
• It is essential that the side of the liver not to be stented is not cannulated as that often results in cholangitis on that side, and this is associated with much poorer results.
  
• Should inadvertent cannulation of the side of the liver occur on the side that was not intended to be decompressed, then it is best to employ bilateral stents in order to avoid cholangitis.
  

Intraluminal brachytherapy has not improved results and, as reported in the adjuvant setting, is associated with more complications.

Photodynamic therapy — Photodynamic therapy (PDT) involves the injection of an intravenous porphyrin photosensitizer followed by the endoscopic application of light (of a specific wavelength) to the tumor bed. The interaction between light and the photoagent causes tumor cell death, presumably by the generation of oxygen free radicals.

• Initial uncontrolled series suggested that in addition to facilitating biliary decompression in patients with locally advanced disease, that survival might be improved in patients who underwent PDT.
• It is thought that the survival benefit is related to prolonged relief of obstruction rather than to any reduction in tumor mass.

• PDT is now being studied preoperatively as a means of improving the likelihood of achieving a margin-negative resection. Unfortunately, treatment is not widely available.

Intrahepatic and Lower duct Cholangiocarcinoma

Lower duct cholangiocarcinomas
Rationale for diagnosis and surgical staging

• These tumours are located in the part of the bile duct that lies in the head of the pancreas or at the level of the first part of the duodenum.
  
• They are one of the members of the tetrad of ‘periampullary tumours’, which commonly present with obstructive jaundice.
  
• The group also includes cancers of the ampulla of Vater, duodenum and pancreas, the last being by far the commonest of the four.
  
• Presumably all three subtypes of cholangiocarcinoma can occur in this region but, as the MF (mass-forming) type would be very difficult to differentiate from pancreas cancer and as the IG (Intraductal-growing) type is very uncommon, it is the cicatrizing PI (Periductal-infiltrating) type that is usually recognized.
  

Diagnosis
In the patient presenting with jaundice, axial imaging may or may not demonstrate a pancreatic mass.

• If mass is present, the diagnosis is taken to be other than cholangiocarcinoma, either a malignancy of the head of the pancreas or focal pancreatitis, although, as already stated, some of these may actually be MF cholangiocarcinoma.
  
• When no mass is present, then cholangiocarcinoma is a possibility.
  

Surgical staging
When the tumours are at the upper border of their range at the level of the duodenum, involvement of the portal vein and hepatic artery is possible.

• The extent of the tumour in the bile duct is rarely a staging question as the treatment is a Whipple procedure in which the entire common bile duct is removed along with the gallbladder and cystic duct.
  

Diagnostic and staging tests
If the initial diagnostic test for painless jaundice is a CT scan, as we recommend, then the findings will be those of obstruction of the bile duct in the intrapancreatic portion with no mass.

• Dilation of the bile ducts may terminate anywhere from the upper border of the pancreas to the duodenum depending on the extent of the tumour.
  
• MRI or ERCP are currently both good choices as the second test under these conditions, and there are no evidence-based data to select between them.
  
• The former test is less invasive but also less informative.
  
• ERCP provides an endoscopic view of the duodenum that allows identification and biopsy of ampullary and duodenal tumours, which may block the bile duct and produce jaundice without being seen as a mass on CT scan, and MRI is less informative in this regard.
  
• ERCP may provide a tissue diagnosis and decompress the bile duct when that is desirable. On the other hand, ERCP requires the placement of a stent into the obstructed duct, and complications such as pancreatitis and haemorrhage have occurred.
  
• Both tests will confirm the presence of a bile duct stricture and display its form, although direct cholangiography is still somewhat superior.
  

The MRI characteristics are those for a PI as described under hilar cholangiocarcinoma.
Focal strictures, especially those with shoulders, suggest malignancy.

• Long tapering strictures limited to the intrapancreatic portion of the bile duct suggest chronic pancreatitis.
• Concomitant narrowing of the pancreatic duct in the head of the pancreas (double duct sign) suggests the presence of a small pancreatic cancer, not visible on CT scan.
  
• Longer or multiple pancreatic strictures suggest chronic pancreatitis.
  
• A single focal bile duct stricture in the absence of pancreatic duct abnormalities is the hallmark of cancer of the lower bile duct.
  
• Infiltrating cancers of the bile duct may cause more than one stricture along the bile duct but, when more than one stricture is present, other diagnoses such as PSC should be considered.
  
• Patients with the classical double duct sign or single focal shouldered bile duct strictures are likely to have small pancreatic or bile duct tumours.
  

Further diagnostic support is usually not needed prior to laparotomy, although it is reassuring when the CA19-9 is over 100 U.
When doubt persists after ERCP or MRI, EUS is often quite useful.

• EUS may identify a small mass not seen on CT scan and biopsies may be obtained.
  
• Occasionally, enlarged lymph nodes are seen by EUS, and these may also be biopsied. However, negative EUS biopsies in patients who present with painless jaundice do not exclude malignancy and, for such a patient with an identifiable mass on EUS, pancreatoduodenectomy is recommended, even in the presence of negative EUS-guided biopsy.
  

If a non-operative approach is followed, short-term follow-up at 4–6 weeks with repeat imaging and biopsy is mandatory.

• If findings persist, then laparotomy is advisable.
• At laparotomy, detection of a mass by palpation or intraoperative ultrasound is reasonable evidence of malignancy, and a pancreatoduodenectomy should be performed.
  
• In the absence of a mass and where clinical or imaging results suggest a benign aetiology for the stricture, ultrasound-guided core biopsies of the bile duct stricture may be helpful in avoiding pancreatoduodenectomy.

Intrahepatic cholangiocarcinoma

Diagnosis
Clinical diagnosis of the common MF type is dependent on the presence of a liver mass that resembles a metastasis on axial imaging, such as MRI or CT scan, in a patient without a history
of liver disease or evidence of an extrahepatic primary.

• The presence of an elevated serum CA19-9 level is helpful.
  
• To rule out primary tumours in the intestine, upper and lower endoscopy is usually performed.
  
• FDG-PET scan and mammography are other imaging tests that have been used to search for an extrahepatic primary.
  
• The pathological diagnosis may be made by needle biopsy, but this is required only when diagnostic doubt exists.
  

Surgical staging
The aim again is subservient to the surgical goals of removal of gross and microscopic tumour, while preserving adequate liver function. The questions to be answered are similar to those
for cholangiocarcinoma, although the vessels in question are the intrahepatic arteries and veins including the hepatic veins.

• Atrophy is less of an issue as it is almost always on the side to be resected, as is the case for the extent of bile duct involvement in the PI and IG types.
  

Diagnostic and staging tests

MRI

• The MF type usually appears as an unencapsulated tumour, hypointense on T1-weighted images and hyperintense on T2- weighted images, although the pattern varies depending on the presence of fibrosis, necrosis and mucin in the tumour.
  
• Hypointensity on T2-weighted images may be seen especially in larger tumours.
  
• In these cases, differentiation from the central scar of focal nodular hyperplesia (FNH) is usually possible by the use of gadobenate dimeglumine (Gd BOPTA).
  
• With dynamic imaging, peripheral enhancement with progressive filling towards the centre of the lesion is common.
  

• Satellite lesions are frequent as is capsular retraction.
  
• The PI type appears as a thickened branching spiculated duct with dilation of the ducts peripheral to the tumour, i.e., much like the PI type of hilar tumour but displaced beyond the sectional ducts.
  
• In later stages, the surrounding liver may appear to be invaded.
  
• The IG type is seen as an intraductal enhancing mass with dilation of ducts peripheral to the mass.
  
• The intrahepatic variant otherwise has the characteristics of the hilar type and, indeed, this tumour may exist at any and all levels of the biliary tree.

Computerized tomography
The typical appearance of the MF lesion is of a large hypoattenuating irregular mass, minimally enhancing at the periphery, sometimes with calcifications and often with capsular retraction,
satellite lesions and enlarged malignant-appearing periportal nodes.

Sonography
MF tumours are usually hypoechoic, but may be isoechoic or hypoechoic and homogeneous or heterogeneous. There are no features that differentiate them from metastatic disease, although peripheral ductal dilation is more common in cholangiocarcinoma.

ERCP
ERCP may be helpful in the PI and IG types when the diagnosis is unclear or after MRI when the extent of the tumour in the ducts is incompletely elucidated.

Differential diagnosis
Hilar and lower duct cholangiocarcinomas

1. Primary sclerosing cholangitis
2. Eosinophilic cholangitis and lymphoplasmocytic
   cholangitis
3. Benign inflammatory tumours
4. Cholelithiasis and choledocholithiasis
5. Adenoma of the bile duct
6. Carcinoma of the gallbladder
7. Neuroendocrine cancer of the bile duct
8. Granular cell tumours
9. Sarcoma of the bile duct
10. Lymph nodes

Intrahepatic cholangiocarcinoma

1. Hepatocellular carcinoma
2. Secondary tumours
3. Angiosarcoma
4. Epithelioid haemangioendothelioma (EHE)
5. Primary hepatic lymphoma
   

Cholangiocarcinoma; clinical features and diagnosis.

Clinical presentation

Cholangiocarcinomas usually become symptomatic when the tumor obstructs the biliary drainage system, causing painless jaundice.

Common symptoms include:

• pruritus (66 percent)

• abdominal pain (30 to 50 percent)

The pain is generally described as a constant dull ache in the right upper quadrant.

• weight loss (30 to 50 percent), and

In later stages of the disease, weight loss and inanition may appear.

• fever (up to 20 percent)

• fatigue

• anorexia and nausea

Rarely, the first manifestation of disease is pancreatitis, which is initiated by pancreatic duct obstruction by tumour emboli that have travelled down the bile duct.

• Cholangitis is an unusual presentation.

Patients with primary sclerosing cholangitis and cholangiocarcinoma tend to present with a declining performances status and increasing cholestasis.

Extrahepatic cholangiocarcinomas, whether in the lower duct or in the hilum, present with painless jaundice or jaundice with mild pain in more than 90% of cases.

Intrahepatic cholangiocarcinomas usually present consequent to detection of a mass or abdominal fullness by the patient or as upper abdominal discomfort or pain.

• Sometimes, the initial presentation is that of weight loss and inanition.

• Jaundice may occur as a result of compression of hilar structures by centrally placed tumours, secondary to tumour embolizing into major bile ducts or due to compromise of overall liver function in endstage disease.

• Occasionally, the tumour is detected by imaging done for investigation of an unrelated problem.

Sometimes, the first sign of disease is an abnormality in blood chemistry or an unexpected finding on imaging for another indication in an otherwise healthy individual.

• It is not uncommon for newly diagnosed patients to have recently had a cholecystectomy, presumably because it was believed that gallstones were the source of symptoms, or mild abnormalities in liver function tests.

A palpable gallbladder, caused by obstruction distal to the takeoff of the cystic duct (Courvoisier's sign), occurs rarely.

Diagnosis and surgical staging

Surgical staging questions for cholangiocarcinoma.

1. What is the macroscopic extent of the tumour along the bile ducts?
2. What is the relationship of the tumour to blood vessels?
3. What is the extent of hepatic atrophy?
4. What is the extent of local hepatic invasion by the tumour?
5. What is the extent of lymph node involvement?
6. Are there distant intrahepatic metastases?
7. Are there peritoneal metastases?
8. Are there extra-abdominal metastases?
   

Hilar cholangiocarcinoma

Surgical staging of a hilar cholangiocarcinoma is subservient to the goals of surgical resection.

• These are to remove all gross and microscopic tumour, while preserving adequate liver function.
  
• To achieve these goals, there must be no evidence of tumour spread outside the confines of the resection, such as lymph node metastases outside the resection zone, peritoneal metastases or extra-abdominal metastases.
  
• The upper extent of the tumour must be limited to the extent that a clear resection margin on the bile ducts can be obtained without the need to remove so much liver tissue that the risk of postoperative liver failure becomes prohibitive.
  
• This will be discussed further under surgical planning and preparation.
  
• If vascular invasion is present, it must be located on the side of a planned resection.
  
• Invasion of the main portal or proper hepatic arteries is a relative contraindication.
  
• If atrophy has affected one hemiliver, it must be on the side chosen for resection.
  
• If there is local invasion of the tumour into the liver, it must be limited to the extent that clear resection margins can be obtained during the planned resection.
  
• Tumour nodules within the liver distant from the hilum are considered to be a contraindication.
  
• These criteria are modified when the resection is part of an orthotopic liver transplant.

Serum and bile markers

The remarks in this section on serum and bile markers pertain to cholangiocarcinoma at all levels of the biliary tree.

• When the obstruction is complete, as it usually is at the time of presentation of hilar and lower duct tumours, the bilirubin rises over several weeks to a level of about 30 mg/dL.
  • The direct reacting fraction accounts for more than 50% of the total bilirubin.

• Marked elevation of serum alkaline phosphatase and γ- glutamyltransferase levels and mild elevation of transaminase levels are also usual.
  
• In intrahepatic cholangiocarcinoma, bile drainage from the unaffected side is usually unimpaired, and bilirubin levels are usually normal, but alkaline phosphatase levels are often elevated.

CA19-9 is the most commonly used tumour marker for diagnosis of cholangiocarcinoma.

• In a large study of 322 patients with biliary cancer, the sensitivity and specificity of CA19-9 were 78% and 83%, respectively, at the cutoff value of 37 U/mL in patients without cholangitis or cholestasis.
  
• In patients with cholangitis or cholestasis, the sensitivity and specificity of CA19-9 were 74% and 42%, respectively, whereas the specificity reached 87% at 300 U/mL.
  
• As many patients with cholangiocarcinoma have cholestasis or cholangitis, CA19-9 is most useful when the levels are quite elevated.
  

• In cholangitis, the level may be extremely high; therefore, it is advisable to obtain blood for measurement of CA19-9 in the jaundiced patient prior to instrumentation of the ducts.
  
• CA19-9 is not specific for cholangiocarcinoma and may be elevated in pancreatic cancer and in intestinal and gynaecological malignancies.
  
• In patients with PSC, the specificity of CA19-9 is low if the cutoff value of 37 U/mL is used. A cutoff value of 100 U/mL seems to provide the most satisfactory balance between sensitivity and specificity in PSC.

Serum carcinoembryonic antigen (CEA) levels may also be mildly elevated in cholangiocarcinoma and have been used by Ramage et al. to increase diagnostic accuracy for cholangiocarcinoma in PSC by combining CEA with CA19-9 levels to form an index, although others have found the index to be less useful. CA125 has a low sensitivity for detection of cholangiocarcinoma, but a high specificity as it is rarely elevated in inflammatory conditions.

CA19-9 and CEA in bile Attempts have been made to improve diagnostic sensitivity and specificity for the detection of cholangiocarcinoma by measurement of these markers in bile, but the results have been disappointing.

Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangioscopy (PTC)

ERCP and PTC are considered together as they both involve direct intubation of the bile ducts and the injection of contrast into potentially obstructed ducts.

• With both tests, ducts that have been injected with contrast must remain intubated because of the risk of infection.
  
• Often, ERCP is chosen as the first investigation when a patient presents with obstructive jaundice.
  
• In the case of hilar cholangiocarcinoma, the unfortunate result may be insertion of bilateral stents, including a stent into the hemiliver to be resected.
  • This is undesirable because the goal in the preoperative period is to encourage hypertrophy of the hemiliver to be retained and atrophy of the hemiliver to be resected.
    
  • Insertion of bilateral stents works against this purpose.
    
  • Also, if the malignant stricture is tight, ERCP may only show the lower limit of the stricture.
    
  • In the past, this problem has been approached by supplementing the ERCP findings with PTC, although PTC is uncommonly used for this particular purpose today.
    

Beginning the investigation of the jaundiced patient with axial imaging such as computerized tomography (CT) or magnetic resonance imaging (MRI) rather than ERCP has distinct advantages.

• If a hilar cholangiocarcinoma is present, it will be suspected by the presence of intrahepatic bile duct dilation in the absence of extrahepatic ductal dilation.
  
• Atrophy of a hemiliver or section may also be seen.
  
• Whether to use stents or not in hilar cholangiocarcinoma is debatable but, if a stent is inserted, only the side to be retained should be intubated.
  
• The side to be surgically removed should be intubated only if there is evidence of cholangitis on that side or if that side is inadvertently injected with contrast.
  
• Another disadvantage of early intubation of the biliary tree is that it interferes with staging by MRI.
  
• Even if the patient is not a surgical candidate, intubation of both sides of the liver by ERCP is disadvantageous because it commits the patient to bilateral rather than unilateral stenting.

One advantage of endoluminal techniques is that biopsies may be obtained by brushings, fine-needle aspiration or forceps biopsy.

• However, the individual sensitivity of these test is less than 50% and only 65% when combined.
  
• Attempts to improve the results of routine cytology include digital image analysis (DIA), which uses aneuploidy as a marker for malignancy, and fluorescence in situ hybridization (FISH).
  
• DIA was found to increase sensitivity from 18% to 40% but lower specificity from 98% to 77% in 100 patients.
  
• The FISH assay uses a mixture of fluorescently labelled probes to centromeres of chromosomes to identify cells with chromosomal abnormalities.
  
• In 100 patients, the sensitivity for the detection of malignancy in bile duct brushing specimens was 15% and 34% for routine cytology and FISH, respectively, and the specificity was 91% and 98%.
  

Percutaneous intubation of the bile ducts has been used to obtain biopsy material and to determine the upper extent of the lesion in the bile ducts.

Cholangioscopy may be useful in determining whether a focal biliary stricture is benign or malignant.

• Of particular interest is whether cholangioscopy might be able to determine reliably whether a focal stricture is benign and thus avoid unnecessary surgery or reduce the extent of surgical resection.
  
• However, as benign focal hilar strictures are uncommon and the case series are small, good data on this point are lacking.
  
• MRI and cholangioscopic findings were found to be highly correlated with respect to determining the upper extent of the lesion, a finding which indicates that cholangioscopy may no longer be required for this purpose.
  
• Cholangioscopy may be of most value when the upper limit of the lesion is indefinite on MRI and the tumour is mucin producing.
  
• In this case, percutaneous cholangiography is hampered by the thick mucin.
  
• With cholangioscopy, the mucin may be aspirated and the upper limit of the tumour defined.

Magnetic resonance imaging

MRI has been increasingly favoured for the diagnosis and staging of hilar tumours as this one study can provide a clinical diagnosis.

• In terms of bile duct involvement, MRI cholangiography has the same sensitivity (80%) and specificity (100%) as ERCP for the detection of malignancy.
  
• Furthermore, MRI is far superior to ERCP in detecting the upper extent of the lesion, for the reasons noted above.
• On MRI, an MF hilar lesion appears as a nodule 1–2 cm in diameter.
  • The tumour is usually hypointense on T1-weighted images but hyperintense on T2-weighted images.
    
• In the PI type, the tumour appears as a concentric, sometimes irregular, thickening with gradual or abrupt transition to normal duct.
  • The periductal tissue may appear to be invaded, and lymph node metastases are frequently seen.
    
• The IG type is seen as an intraductal enhancing mass confined to the lumen of the bile duct.
  • It may have a rounded or bullet shape or appear as a cast of the duct.
    
  • Usually, the bile duct wall can be visualized where it passes around the mass, i.e. as the tumour does not penetrate the duct, the outer bile duct margin is intact.
    
  • Portions of the tumour may break off and be seen in the lower ducts.
    
  • There may be multiple tumours along different segments of the bile ducts.
    
• In all three morphological types, obstruction of the bile duct is usually present so that the bile ducts peripheral to the tumour are dilated, although they usually display normal wall thickness.
  
• When atrophy has been induced in a hemiliver or hepatic section, the dilated bile ducts will make up much of the residual volume of the affected part, giving the appearance of ‘crowding’ of the ducts.
  
• Sometimes, MRI cholangiography may not give the fine detail required for surgical staging.
  • This is especially true when the tumour appears to encroach on sectional ducts on the side to be retained.
    
• Direct cholangiography by PTC remains superior to MRI when this level of detail is needed.
  
• MRI also accurately depicts the extent of liver invasion and secondary tumours in the liver.

Computerized tomography

• The typical PI cholangiocarcinoma is seen on the portal or delayed phases as an enhancing thickened bile duct and the MF type as a hypoattenuating mass.
  
• While usual spiral CT images have not been able to stage hilar cholangiocarcinomas with the detail provided by MRI, the newer multidetector row CT scanners provide high-quality images of the biliary tree and blood vessels after administration of intravenous contrast agents.
  
• These images provide the same information as MRI images.
  
• A disadvantage of the agents used in CT is that they are nephrotoxic, unlike MRI contrast agents, a feature that may be of importance, particularly in elderly patients.
  
• Thin section CT accurately predicted the upper extent of PG-type hilar tumours in 65% of cases in one study.
  

Ultrasonography

• Sonography may detect all three types of hilar cholangiocarcinoma and is generally more sensitive in the hilum than at lower levels of the biliary tree, where intestinal gas is more likely to interfere with visibility.
  
• It can often display the extent of the tumour in the biliary tree.
  
• Flow Doppler sonography is particularly useful for defining vascular invasion.
  
• The disadvantages of sonography is that it is more operator dependent than axial imaging techniques and its images are somewhat more difficult for the surgeon to use as a guide in the operating room.
  

Positron emission tomography (PET)
The role of 2-[18F]fluoro-2-deoxy-d-glucose (FDG)-PET in the diagnosis and staging of cholangiocarcinoma is incompletely investigated. At present, it is not a standard part of preoperative investigation.

Endoscopic ultrasound —

• For distal bile duct lesions, endoscopic ultrasound (EUS) can visualize the local extent of the primary tumor, and the status of regional lymph nodes.
  
• EUS-guided fine needle biopsy of tumors and enlarged nodes can also be performed. EUS with fine needle aspiration biopsy has a greater sensitivity for detecting malignancy in distal tumors than does ERCP with brushings.
  
• This technique also avoids contamination of the biliary tree, which can occur with ERCP.

Angiography

Angiography can accurately document vascular encasement or thrombosis of the portal vein and hepatic artery. However, with the advent of multiphasic CT and MRCP, it is rarely necessary before surgery.

Establishing a preoperative tissue diagnosis

The necessity of establishing a tissue diagnosis prior to surgery depends upon the clinical situation.

• It is not critical for planning surgery in patients with characteristic findings of malignant hilar biliary obstruction, and may not be necessary for planning palliative therapy, such as biliary drainage, in unresectable cases.

Tissue diagnosis is most important in the following circumstances :

• Strictures of clinically indeterminate origin (eg, in patients with a history of biliary tract surgery, bile duct stones, or PSC).

• A situation where the physician or patient would be reluctant to proceed with surgery without a tissue diagnosis, or if the patient's or family's acceptance and adjustment to the diagnosis would be facilitated by having a definitive diagnosis.

• Prior to chemotherapy or radiation therapy, particularly if the patient will be enrolling on a therapeutic clinical trial.

Staging laparoscopy

Despite the enhanced diagnostic capability of newer radiologic studies such as MRCP and dynamic CT, unless there is clear evidence of metastatic disease, true resectability can be determined only by operative evaluation.

• Laparoscopy can identify the majority of patients with unresectable hilar and distal cholangiocarcinoma, thereby reducing the number of unnecessary laparotomies.
  
• However, true resectability can often be determined only after a complete abdominal exploration.

Cholangiocarcinoma; pathogenesis and classification.

In 1965, the surgeon Gerald Klatskin reported the first series of patients with cholangiocarcinoma of the hepatic hilum, and introduced the concept of radical resection of the diseased bile duct.However, at this time surgery was associated with high morbidity and mortality rates.

• Cholangiocarcinoma is an uncommon epithelial malignancy of the biliary tract.
  
• Cholangiocarcinomas may arise at any level of the biliary tree.
  
• They are highly lethal because most are locally advanced at presentation.
  
• More recently, the term cholangiocarcinoma has been used to refer to bile duct cancers arising in the intrahepatic, perihilar, or distal (extrahepatic) biliary tree, exclusive of the gallbladder or ampulla of Vater.
  
• Intrahepatic cholangiocarcinomas usually present as liver masses, and extrahepatic cholangiocarcinomas tend to obstruct bile ducts and present with jaundice.
  
• Sporadic cholangiocarcinomas are relatively uncommon, but the incidence increases significantly in certain inflammatory and infectious conditions.
  
• Surgical resection is the most effective treatment and is currently the only option that provides a chance for cure, but the majority of patients are not eligible for surgical resection.
  

Incidence and natural history

• Cholangiocarcinomas account for approximately 3 percent of all gastrointestinal malignancies, with a prevalence in autopsy studies of 0.01 to 0.46 percent.
  
• As a general rule, the incidence of biliary tract cancers increases with age; the typical patient with cholangiocarcinoma is between 50 and 70 years of age.
  
• However, patients with primary sclerosing cholangitis (PSC) and those with choledochal cysts present nearly two decades earlier.
  
• In contrast to gallbladder cancer, where female gender predominates, the incidence of cholangiocarcinoma is slightly higher in men.
  • This probably reflects the higher incidence of PSC in men.
    
• Asians are affected twice as often as whites or black.
• Patients with intrahepatic cholangiocarcinoma, the 1-year relative survival increased from 16.4% in the period from 1975 to 1979 to 27.6% in the period from 1995 to 1999, but the 5-year survival rate remains unchanged and below 5%.
  
• Death is often related to infectious complications secondary to biliary obstruction and is rarely a result of tumour burden.
  

In fact, a number of authors have found that bile duct tumours are relatively slow growing, especially compared with tumours of the gallbladder or pancreas.

• Although nodal, peritoneal and haematogenous metastases have been described, local disease is the most common finding at presentation.
  
• Haematogenous metastases are uncommon, and nodal disease is present in about one-third of cases in series of resected patients.
  
• Extended survival depends almost entirely on complete surgical resection.
  
• Survival has traditionally been considered to be worse for lesions at the confluence and better for lesions at the ampulla, but this probably reflects relatively later presentation and more complex operative management as opposed to a difference in biology.
  
• Location within the biliary tree may have little impact on survival provided that complete resection can be achieved.
  

PATHOGENESIS

• Conversion from normal to malignant bile epithelium probably requires a stepwise accumulation of successive genetic abnormalities, similar to the sequence of events that underlies colorectal carcinogenesis.
  

However, the level of understanding of the molecular pathogenesis of cholangiocarcinoma is significantly less than that of other gastrointestinal cancers.

• A variety of molecular defects involving both oncogenes (K-ras, c-myc, c-neu, c-erbB-2, and c-met) and tumor suppressor genes (eg, p53, SMAD4) have been described in specimens of biliary tract tumors.
  
• As an example, between 37 and 80 percent of tumors overexpress p53 (implying the presence of mutations in this tumor suppressor gene), while abnormal expression of K-ras is found in 21 to 100 percent of cases.
  
• These genetic alterations are associated with a more aggressive tumor phenotype.
  
• The detection of these mutations in bile specimens may improve the sensitivity of cytopathology for diagnosing cholangiocarcinoma, although this technique is not widely used.

Some data suggest that p16INK4a promoter point mutations contribute to initiation and progression of cholangiocarcinoma in the setting of PSC. Others propose that intrahepatic cholangiocarcinomas share some common carcinogenic steps with hepatocellular carcinoma such as loss of heterozygosity (LOH) of chromosomes 4q and 6q, and/or inactivation of tumor suppressor genes on chromosome 1p.

RISK FACTORS

Endemic infections

• Liver fluke infestations with Opisthorchis species (Thailand) and Clonorchis species (China) are common in countries where raw fish is consumed with frequency.
  • In these countries, raw fish is more frequently consumed by men, partially explaining the higher incidence of cholangiocarcinoma in men.
    
  • The larval stage of flukes, as consumed in raw fish, establishes a chronic infection and inflammation in the biliary tree.
    
  • The risk of cancer has been associated with the degree of infestation as measured by the stool egg count.
    
  • In areas where these parasites are endemic, the incidence of cholangiocarcinoma is as high as 87 per 100 000.
    

Autoimmune diseases

• PSC is an autoimmune disease characterized by periductal inflammation, as seen on histological sections, and multifocal strictures of both intrahepatic and extrahepatic bile ducts, as demonstrated by cholangiography.
  • The majority of PSC patients (70–80%) have associated ulcerative colitis, but the converse is not true.
    
  • Approximately 10% of patients with ulcerative colitis have PSC.
    
  • The incidence of cholangiocarcinoma remains elevated in patients with PSC even when medical or surgical management appears to control the inflammatory process.
    
  • In other words, treatment of ulcerative colitis by colectomy does not offer protection from development of cholangiocarcinoma in patients with PSC.
    
  • Nearly 30 percent of cholangiocarcinomas are diagnosed in patients with PSC with or without UC.
    
  • The annual incidence of cholangiocarcinoma in patients with PSC has been estimated to be between 0.6 and 1.5 percent per year, with a lifetime risk of 10 to 15 percent.
    
  • However, the incidence is much higher (30 percent or more) in autopsy series.
    
  • Cholangiocarcinoma develops at a significantly younger age (between the ages of 30 and 50) in patients with PSC than in patients without this condition.
    
  • It is also more difficult to diagnose because of the diffusely abnormal biliary tree.
    
  • Over one-third of these cases are diagnosed within two years of the initial diagnosis of PSC, and the risk appears unrelated to the duration of the inflammatory disease.

• However, the number of patients who smoked or were former smokers was significantly higher in the cancer group.

• Alcohol consumption has been suggested to be a risk factor for the development of cholangiocarcinoma in patients with PSC.

• Certain genetic polymorphisms have been implicated as risk factors for cholangiocarcinoma in PSC.

Choledochal cysts and anatomical anomalies
The risk of development of cholangiocarcinoma in congenital biliary cysts may also be related to inflammation.

• Many patients with choledochal cysts have an anomalous pancreatobiliary junction (APBJ).
  
• In such patients, the confluence of the pancreatic duct and bile duct occurs at a greater distance from the ampulla than usual, thereby lengthening the common channel.
  
• This predisposes to reflux of pancreatic secretions into the biliary ducts.
  
• Presumably, the pancreatic enzymes become activated by bile and an inflammatory response follows.
  

Stasis in the ducts might also lead to bacterial contamination and additional inflammation.

• In patients who have early surgical intervention for choledochal cysts, the risk of cholangiocarcinoma is greatly reduced.
  
• There is some evidence that the incidence of cholangiocarcinoma increases dramatically in patients not treated until after the age of 20 years or in patients treated with cyst drainage as opposed to cyst resection.
  

Additional evidence that anatomical anomalies that result in reflux and inflammation may play a role in cholangiocarcinoma is seen in patients who undergo operative sphincteroplasty.

• Seven per cent of patients developed a cholangiocarcinoma in a series of 119 patients who had previously received a transduodenal sphincteroplasty for benign disease and who were followed for up to 22 years.
  
• Presumably, bacterial contamination and inflammation may result from surgical sphincteroplasty.
  
• There is currently no evidence to suggest that endoscopic sphincterotomy carries the same degree of risk.
  

Cholelithiasis and hepatolithiasis
While cholelithiasis is a well-described strong risk factor for gallbladder cancer, the association between gallstones and cholangiocarcinoma is less well established.

Toxic exposures
A clear association exists between exposure to the radiologic contrast agent Thorotrast (a radiologic contrast agent banned in the 1960s for its carcinogenic properties) and subsequent cholangiocarcinoma; malignancy usually develops 30 to 35 years after exposure.

Lynch syndrome and biliary papillomatosis

• At least two genetic disorders are associated with an increased risk of cholangiocarcinoma: the inherited "cancer family" syndrome termed Lynch syndrome II, and a rare inherited disorder called multiple biliary papillomatosis.
  
• The latter condition is characterized by multiple adenomatous polyps in the bile ducts, and repeated episodes of abdominal pain, jaundice, and acute cholangitis.
  
• Biliary papillomatosis should be considered a premalignant condition since a high proportion of these lesions (83 percent in one study) undergo malignant transformation.

Chronic liver disease

Hepatitis B virus (HBV) and hepatitis C virus (HCV) as well as liver cirrhosis regardless of etiology, have been examined as risk factors for intrahepatic cholangiocarcinoma.

Viral hepatitis
An association between hepatitis C viral infection (HCV) and cholangiocarcinoma was initially suggested in 1991. Since then, several reports have noted a higher than expected rate of HCV-associated cirrhosis in patients with cholangiocarcinoma, although the risk is much lower than for hepatocellular cancer.

Nonviral chronic liver disease
As with hepatocellular carcinoma, chronic liver disease of nonviral etiology also appears to be associated with intrahepatic cholangiocarcinoma.

Diabetes
An association between diabetes mellitus and cancer of the biliary tract has been suggested in several studies. The risk was increased by approximately two-fold in the population-based case-control study described above.

Obesity and HIV infection are also considered to be the risk factors for cholangiocarcinoma.

Classification

Pathology and classification

• The most widely used classifications are that of Weinbren and Mutum, who described the histological features of three subtypes of cholangiocarcinomas,
  • nodular,
  • sclerosing and
    
  • papillary,
    
• and that of Klatskin, who described three major macroscopic subtypes of hilar cholangiocarcinomas:
  • a small hard nodule,
    
  • a segmental stenosis and
    
  • a papillary growth.
    

The radiological appearance of these lesions has been variably described.
Recently, the Liver Cancer Study Group of Japan has proposed a new macroscopic classification for intrahepatic cholangiocarcinomas pairing the radiographical description with the gross appearance in three subtypes:

• mass-forming,
  
• periductal-infiltrating and
• intraductalgrowing
  

Thus, any tumour may have a component that infiltrates along the duct(periductal infiltrating(PI))or a component that projects into( intraductal growth (IG))or away from the lumen of the bile duct( mass-forming (MF)).

Mass-forming (MF) cholangiocarcinoma

MF tumours are less common than the PI type and more common than the IG type.

• MF tumours are the most common intrahepatic variant and have frequently been classified as nodular grossly and histologically.
  
• They are characterized by a nodular mass that projects into the lumen of the duct and out into the surrounding tissues.
  
• The tumour is firm and whitish grey on account of the large amount of fibrous stroma.
  
• The margin is often well circumscribed but may be lobulated.
  
• Multicentricity is more common for this subtype and may be the result of the propensity of the tumour to invade adjacent branches of the portal vein.
  
• Multicentricity may also be due to the fact that the MF growth pattern results in late onset of symptoms and thus provides more time for tumour growth compared with the IG or PI subtypes.
  
• Central necrosis is a common feature when the tumours are large.
  
• Bile ducts peripheral to the mass may or may not be dilated.
  
• Regional lymph node metastases are more common with large tumour masses and are therefore more common with this subtype.
  
• Enlarged metastatic lymph nodes are most commonly located in the porta hepatis.

Periductal-infiltrating (PI) cholangiocarcinoma

• In contrast to MF tumours, PI cholangiocarcinomas grow along the bile duct and are commonly described as elongated, branchlike or spiculated.
  
• They penetrate the bile duct wall, growing both in the wall and along the exterior of it for extended distances.
  
• Irregular narrowing or obliteration of the involved bile duct commonly occurs, and the proximal biliary tree is almost universally dilated.
  
• PI tumours are the most common variant and are the predominant subtype found at the biliary confluence.
  
• PI lesions are frequently described as sclerosing and fibrotic on histological examination.

• The overlying epithelium may appear atypical or may be absent.
  
• PI tumours are characterized by annular thickening with diffuse infiltration and fibrosis of the periductal tissues.
  
• PI lesions may be poorly differentiated and may show signet ring cells.
  
• In pure PI tumours, there is no mass, and differentiation from benign disease is occasionally difficult.

Intraductal-growing (IG) cholangiocarcinoma

• IG tumours account for approximately 10% of all cholangiocarcinomas.
  
• IG tumours grow into the lumen.
  
• Although they originate in the wall, they do not usually penetrate it, and the outer margin of the bile duct remains intact.
  
• IG tumours may be polypoid, sessile or can be elongated sheets of tumour spreading along the bile duct lumen, or skip lesions.

• These tumours can grow to several centimetres in size and may expand rather than constrict the bile duct, in sharp contrast to the sclerotic process seen in PI tumours.
  
• The majority of IG tumours are of the papillary subtype comprised of numerous frond-like infoldings of proliferated columnar epithelial cells.
  
• Atypical epithelium is easily identified in this variant and may be classified as well differentiated, meaning that much of the normal epithelial architecture is preserved.
  
• These may arise from a stalk or may be broader based, spreading superficially along the surface.
  
• Biliary obstruction may result from a large tumour blocking the duct, from an excessive amount of mucin or pieces of tumour that have broken off and embolized lower levels of the biliary tree.
  
• In some instances, these tumour emboli have even obstructed the common channel, leading to pancreatitis.
  
• There is a variant of this subtype that is very similar to intraductal papillary mucinous tumour (IPMT) of the pancreas, in which mucinous secretions are the predominant feature.
  
• Patients with IG tumours usually have a better outcome than those with other subtypes, in part because they tend to present at an earlier stage.
  
• Patients with the papillary subtype fare better than patients with the nodular sclerosing subtypes (MF, PI) even when compared stage for stage.
  
• This suggests that at least some of the observed difference in patient outcome is derived from the more favourable biological behaviour of the well-differentiated papillary subtype.
  

Adenocarcinomas account for more than 90% of all cholangiocarcinomas.

• Variants of adenocarcinoma of the bile duct include pleomorphic, giant cell, adenosquamous, oat cell and colloid carcinoma.
  
• The microscopic extent of these cancers frequently extends for long distances beyond the palpable tumour.
  
• In a series of 29 cases, the mean distance of microscopic invasion beyond the gross margin was 16.8 mm towards the liver and 6.5 mm towards the duodenum.
  

Cancers of the upper duct are more frequently well differentiated, whereas tumours of the lower duct are more frequently poorly differentiated.

• Well-differentiated cancers with little invasion are difficult to differentiate from inflammatory pseudotumour.
  
• Often, perineural invasion, a prominent feature of cholangiocarcinoma that is not present in PSC or other benign lesions, is the single most useful feature in sorting out the true nature of the disease.
  

• In series of upper duct lesions, benign inflammation accounted for 13–15% of resections. Poorly differentiated tumours of the lower duct may be difficult to distinguish from pancreatic or duodenal cancers.
  
• Biliary tumours of the lower duct, although often poorly differentiated, tend to present early.
  • Therefore, lower duct biliary tumours are less likely to have spread to surrounding lymph nodes or to have metastasized distantly than pancreatic cancers, portending a more favourable prognosis following a pancreaticoduodenectomy.

Anatomical classification

Most authorities in this area now classify cholangiocarcinoma into three types depending upon anatomical location.

These are

• intrahepatic cholangiocarcinomas,
  
• hilar cholangiocarcinomas and
  
• lower duct cholangiocarcinomas.
  

These are treated as distinct clinical entities linked by the cell of origin and aetiological factors.

• Synonyms for hilar cholangiocarcinoma are upper duct extrahepatic cholangiocarcinomas and Klatskin tumours.
  
• Synonyms for lower duct cholangiocarcinomas are intrapancreatic bile duct tumours (or cholangiocarcinomas)
  
• and distal bile duct tumours (or cholangiocarcinomas).

Hilar cholangiocarcinomas have been estimated to account for between 40% and 60% of all cholangiocarcinomas.

• Intrahepatic cholangiocarcinomas account for approximately 10% of cases with distal tumours making up the difference.
  
• Approximately 10% of patients with cholangiocarcinoma have multifocal disease.

Bismuth-Corlette classification

Cancers arising in the perihilar region have been further classified according to their patterns of involvement of the hepatic ducts (the Bismuth-Corlette classification):

• Tumors below the confluence of the left and right hepatic ducts (Type I)

• Tumors reaching the confluence (Type II)

• Tumors occluding the common hepatic duct and either the right or left hepatic duct (Types IIIA and IIIb, respectively)

• Tumors that are multicentric, or that involve the confluence and both the right or left hepatic duct (Type IV)

Bile duct tumors that involve the common hepatic duct bifurcation are referred to as Klatskin tumors regardless of whether they arise from the intrahepatic or extrahepatic portion of the biliary tree.

TNM staging classification

Cholangiocarcinomas involving the intrahepatic bile ducts are staged similarly to hepatocellular carcinoma.

TNM staging for hepatocellular cancer and intrahepatic bile duct cancer

Primary tumor (T)
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Solitary tumor without vascular invasion
T2	Solitary tumor with vascular invasion, or multiple tumors none more than 5 cm
T3	Multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic vein(s)
T4	Tumors with direct invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum
Regional lymph nodes (N)
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Regional lymph node metastasis
Distant metastasis (M)
MX	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis
Fibrosis score (F)
F0	Fibrosis score 0-4 (none to moderate fibrosis)
F1	Fibrosis score 5-6 (severe fibrosis or cirrhosis)
Stage grouping
Stage I	T1	N0	M0
Stage II	T2	N0	M0
Stage IIIA	T3	N0	M0
Stage IIIB	T4	N0	M0
Stage IIIC	Any T	N1	M0
Stage IV	Any T	Any N	M1

In contrast, the TNM staging system for hilar and distal tumors differs in the definition of T stage and stage grouping.

TNM classification for extrahepatic bile duct tumors

Primary tumor (T)
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ
T1	Tumor confined to the bile duct histologically
T2	Tumor invades beyond the wall of the bile duct
T3	Tumor invades the liver, gallbladder, pancreas, and/or unilateral branches of the portal vein (right or left) or hepatic artery (right or left)
T4	Tumor invades any of the following: main portal vein or its branches bilaterally, common hepatic artery, or other adjacent structures such as the colon, stomach, duodenum, or abdominal wall.
Regional lymph nodes (N)
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Regional lymph node metastasis*
Distant metastasis (M)
MX	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis
Stage Grouping
Stage 0	Tis	N0	M0
Stage IA	T1	N0	M0
Stage IB	T2	N0	M0
Stage IIA	T3	N0	M0
Stage IIB	T1-3	N1	M0
Stage III	T4	Any N	M0
Stage IV	Any T	Any N	M1

It should be emphasized that the current staging classification for cholangiocarcinoma does not predict overall survival or resectability.