Cholangiocarcinoma

*the history is already altered and permission was gained from the patient to share her history only for educational purpose*

History and findings

A patient was referred from a hospital in other district for further investigation in Hospital Y. She presented with yellow discoloration of skin and sclera for 4 days duration prior to admission.

Daughter started to notice yellow discoloration of patient’s skin and eyes at afternoon under the sunlight. It was sudden in onset and progressively turn into deeper yellow. Her daughter then brought her to the hospital X. It was associated with tea-colored urine and her stool was pale. However she did not experience abdominal pain, nausea, vomiting and fever. In hospital X, chest X-ray and full blood count was done but she was unsure about the findings. She was then referred to hospital Y on the same day for further investigation.

On further questioning, she noticed loss of appetite over one month but was not sure if she had lost significant weight. She also complained of malaise and fatigue. There was no history of breathlessness.

She had history of bilateral hip pain for 2 months duration. The pain was mild, constant, radiated to bilateral lower limbs downwards and associated with progressive weakness of bilateral lower limbs. It is not preceded by trauma or fall. It started gradually, in which initially she could walk with help but became worse until she has to sit or lie down as she became unable to stand. Previously she was independent in doing her daily routine. During the first week of the symptoms, she went to Hospital X and was prescribed painkiller, however the pain did not subsided and she stopped going to hospital. The weakness is progressive, making her not ADL independent and stayed on bed.

No history of chronic cough or contact with tuberculosis or jaundiced patient. There was no changes in urinary or bowel habit.

She was diagnosed with diabetes mellitus and hypertension on the same occasion since a year ago in primary care clinic. Diabetes mellitus is well-controlled with metformin and the medication for her hypertension are amlodipine and captopril. She is compliant to the drugs consumption. There was no change of drug prescription for diabetes mellitus and hypertension and never had undesirable side effects from those medication.

            Apart from these, there is no significant past medical or surgical history. No history of previous admission. Both parents died of old age. All of her siblings are alive and healthy except for her first sibling, which is her older brother has passed away due to acute heart attack. Otherwise, there was no similar problem or history of malignancy in any family members.

 Otherwise, not significant. 

On examination, generally, she was jaundiced, ill-looking and cachexic. And of course muscle wasting of lower limbs should be expected lah sebab lama tak boleh jalan. Dont forget to the all the necessary examinations including musculoskeletal test. Otherwise, normal findings...and confidential.

PROVISIONAL DIAGNOSIS

Choledocholethiasis secondary to cholangiocarcinoma.

DIFFERENTIAL DIAGNOSIS

1.      Choledocholethiasis

2.      Periampullary carcinoma

3.      Carcinoma of the head of pancreas

4.      Ascending cholangitis

INVESTIGATIONS

1. Full Blood Count

Reason: To assess if there is reduced in haemoglobin level in which chronic disease can cause anaemia. It also serves as baseline investigation.

2. Renal Profile

Reason: To assess if there is any renal impairment secondary to chronic kidney disease or obstruction to the ureter that might lead to hydroureter and hydronephrosis.

3. Liver Profile

      Reason : To check the nutrition status of the patient. All bilirubin components increase several fold indicating obstructive jaundice or posthepatic jaundice. It is also done to check if there is obstruction in the billiary tract, in which the liver enzyme Alkaline Phosphatase will be increased.

4. Coagulation Profile

 Reason : To assess any abnormalities in coagulation cascade secondary to liver disease or blood disorders.

5. Random Blood Sugar

Monitor her diabetic state

6. Tumour Marker 

Reason: To rule out the pathology that the patient has which is either malignancy or not. Thus, determination of tumor marker level is important to support the diagnosis.

7. Thoracolumbar X-Ray

Abnormality of the vertebrae.

8. Pelvic X-Ray

            Suspicious area of round, glass opacities at left greater trochanter.

9. Knee X-Ray

            i. Right : Lytic lesion most likely benign

            ii. Left : No radiographic evidence of lytic sclerotic bony lesion

10. Ultrasonography Abdomen

i. Left paravertebral mass with possible involvement of the adjacent vertebra (about          

   L3/L4)

            ii. Choledocholithiasis with soft tissue density in the gall bladder, probably soft stone 

11. CT Scan of Thoracic, Abdomen and Pelvis

Extrahepatic intraductal mass highly suspicious of cholangiocarcinoma. Evidence metastasis to the L3 lumbar spine with extension of the metastasis soft tissue mass into the spinal canal stenosis and to the left paravertebral and left psoas muscle.

12. MRI Lumbar Spine with Contrast

Multifocal heterogeneously enhancing vertebral lesions, pathological fracture of L3 associated with large soft tissue mass causing spinal stenosis, suggestive of metastasis. Tuberculosis spine is differential.

13. MRI Thoracic Spine with Contrast

These could represent metastases and Tuberculosis spine is differential.

14. CT-Guided Biopsy of Paraspinal Mass

Trace for Histopathological Examination (HPE) was sent and currently waiting for the result.

15. Endoscopic Retrograde Cholangiopancreatography (ERCP)

To see any dilated intrahepatic ducts or presence of common bile duct stones. For therapeutic ERCP, commonly done for stenting of malignant strictures.

Final diagnosis : Choledocholithiasis secondary to cholangiocarcinoma.

Discussion

Cholangiocarcinoma are adenocarcinomas that arise from cholangiocyte lining the intrahepatic or extrahepatic ducts but are more common near the confluence of right and left hepatic ducts (Kaltskin tumour). It may present in the periphery of the liver, centrally within the liver, or involving the extrahepatic bile ducts. The location determines the nature of the symptoms experienced by the patient. Peripheral tumors may be asymptomatic while central or Klatskin tumour  may cause obstructive jaundice and a bile duct stricture on ERCP investigation.

It is not a common type of cancer but it occurs mostly in persons 50 to 70 years old, relatively RARE. Both inta- and extra-hepatic cholangiocarcinomas generally are asymptomatic until they reach an advance stage, hence contributing to its low survival rate. Risk factors include primary sclerosing cholangitis, fibropolycystic diseases of biliary tree, and infestation by Chlorchis Sinensis or Opisthorchis viverrini. All risk factors for cholangiocarcinome seems to cause chronic cholestasis and inflammation leading to consistent genetic changes at mole cular level.

Regarding to a case I have seen. the patient was 60 years old lady and the identified possible risk factor is only diabetes mellitus. However the diabetes mellitus in this patient is not the longstanding one which can be associated with most malignancy. Gallstone which is one of the risks could be asymptomatic. In this patient it is not know between gallstone and the cholangiocarcinoma, which one came first. The other risk factors are absent which includes

•   Infection by liver flukes or other parasite which is not endemic in Malaysia.
• Chronic liver diseases, be it in the form of viral hepatitis, alcoholic liver disease or cirrhoses.
•    Absence of inflammatory bowel diseases or primary sclerosing cholangitis
•    Carcinogenic chemical exposures
•   Congenital diseases of the biliary tree, including choledochal cyst and Caroli disease which are associated with cholangiocarcinoma.

            The general symptoms commonly associated with cancer such as malaise, loss of weight and cachexia which are seen in this patient. Symptoms include jaundice, pale-colored stools, tea-colored urine likely due to bilirubinuria, and the constitutional symptoms of malignancy (loss of weight and appetite). Pruritis is absent, if it is present, it may be relate to circulating bile acids. She denied abdominal pain, which could be common in advanced disease and often described as a dull ache in the right upper quadrant.

Symptoms of metastases are shown as the liver is already affected and there are pathological bone fracture and lesion.

            Assesment consists of clinical examination, imaging and biopsy. Imaging test such as ultrasound, MRI, X-ray, ERCP, CT scan were done for this patient. Biopsy in this patient consists of CT guided biopsy of paraspinal mass for confirm the origin of carcinoma.

            Once the diagnosis of cancer has been made, the disease should be staged to define the extent of tumour spread. The TNM system classifies according to depth of tumor penetration and regional spread :

Primary tumor (T)

Tx        Primary tumor cannot be assessed.                                                      

T0        No evidence of primary tumor.

Tis       Carcinoma in situ

T1a      Tumor invades mucosa

T1b      Tumor invades muscularis

T2        Tumor invades perimuscular connective tissue

T3        Tumor invades liver, gallbladder, duodenum, stomach, pancreas or colon

Regional lymph nodes (N)

Nx       The regional lymph nodes cannot be assessed.

N0       No regional lymph nodes metastases.

N1       Metastases in cystic duct or pericholedochal or hilar lymph nodes of hepatoduodenal ligament

N2       Metastases in peripancreatic (head only), periduodenal, posterior pancreaticoduodenal, periportal, celiac, or superior mesenteric regional lymph nodes

Distant metastases (M)

Mx       Cannot be assessed.

M0       No distant metastases.

M1       Distant metastases (includes lymph node metastases beyond N2)

The American Joint Committee on Cancer (AJCC) uses TNM grading to generate an overall stage for individual patients as shown below.

T status	N status	M status	AJCC stage
Tis	N0	M0	Stage 0
T1	N0	M0	Stage I
T2	N0	M0	Stage II
T1-T2	N1-N2	M0	Stage III
T3	N0-N2	M0	Stage IVa
T1-T3	N0-N2	M1	Stage IVb

The principle managements of the cholangiocarcinoma are to establish the diagnosis, control disease invasion and metastases, prevent and treat local and regional disease in early stage and to control advanced and disseminated disease.

The treatments available for cholangiocarcinoma are surgical tumor resection, chemotherapy  and palliative treatment. The treatment would be depending on the assessment whether the tumor is resectable. However to assess whether it is resectable, exploratory surgery need to be done unless the tumor is in very advanced stage wherein majority of cases are unresectable. However, 70 % of the cases of diagnosed cholangiocarcinoma were unsuited to surgery and of those went for surgery, 76% of the cancer recur. The surgical procedure comprises major hepatectomy together with extrahepatic bile duct excision and caudate lobe resection. The surgery makes 5 years survival about 30% . Surgery remains the only bastion for cure.

Palliative stenting and chemoradiation are reserved for advanced, non-resectable patients as well as those with recurrence or decline surgery.

REFERENCES

Burkitt, H.G, et. al, Essential Surgey: Problems, Diagnosis & Management(2007), Fourth Edition., 

N.L, et. al, Browse’s Introduction to the Symptoms and Signs of Surgical Disease(2005), Fourth Edition, Hodder Arnold, UK.

Longmore M, et. al, Oxford Handboook of Clinical Medicine, Ninth Edition.       

Yusoff A.R, et.al, Cholangiocarcinoma: A 10-year experience of a single tertiary centre in the multi-ethnicity-Malaysia. Med J Malaysia 2012; 67: 45-51

Kumar, V, et. Al, Robbins Basic Pathology (2013), Ninth Edition