Gallbladder Carcinoma Presenting As Right

Upper Quadrant Pain: A Case Report

In partial fulfillment of the requirements for

Post-graduate internship
Chong Hua Hospital, Cebu, Philippines
February 2019

Mary Mc Sherry Yongco

Post-Graduate Intern
Chong Hua Hospital

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 ABSTRACT

Gallbladder Carcinoma Presenting As Right Upper Quadrant Pain: A Case

Report

SYNOPSIS: Gallbladder carcinoma is a rare disease affecting only 1.2% of the

population but it is second most common primary biliary malignancy and the fifth

most common malignancy of the GI tract. The female to male ratio is 3:1.

Cholelithiasis is the major risk factor, but <1% of patients with cholelithiasis

develop this cancer.

CLINICAL PRESENTATION: This is a case of a 71-year-old female, a known

hypertensive and a diabetic for 2 years with complaints for right upper quadrant

pain, weight loss and anorexia. Other pertinent findings noted were absence of

murphy’s sign , right upper quadrant tenderness and jaundice. The patient was

treated as Acute Cholecystitis with Choledocholithiasis as seen on the CT-Scan.

ERCP and Laparoscopic Cholecystectomy was done, patient improved and was

discharged.

CONCLUSION: This is a report on a case of Gallbladder Carcinoma presenting

as right upper quadrant pain and was treated as Acute Cholecystitis with

Choledocholithiasis. Diagnosis was mainly based on CT scan and ERCP which

was suggestive of Acute Cholecystitis with Choledocholithiasis further work up

with biopsy of the Gallbladder results showed moderately differentiated

carcinoma, At present, a multidisciplinary approach is most prudent to allow

prompt treatment for better survival rates for Gallbladder adenocarcinoma.

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KEYWORDS: Gallbladder Carcinoma, Cholecytitis, Choledocholithiasis, Right

Upper quadrant pain.

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 OBJECTIVES

General Objectives:

To report a case of Gallbladder Carcinoma presenting as right upper

quadrant pain in a 71 year old female Filipino.

Specific Objectives:

1. To discuss the epidemiology of Gallbladder carcinoma worldwide.

2. To briefly discuss the etiology, clinical manifestation, diagnosis, staging

and treatment of Gallbladder Carcinoma based on published literature

and in comparison to the patient’s profile.

3. To discuss the dilemma encountered in the patients with Gallbladder

carcinoma.

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 INTRODUCTION

Gallbladder carcinoma is a rare disease affecting only 1.2% of the

population. [1] It is more common among American Indians, patients with large

gallstones and those with extensive gallbladder calcification due to chronic

cholecystitis. Manifestations of gallbladder carcinoma may range from

incidental findings at cholecystectomy done to relieve biliary pain to

cholelithiasis to advanced disease with constant pain, weight loss, and an

abdominal mass or obstructive jaundice.

Staging of gallbladder cancer follows the TNM classification. [2] The most

accurate technique to define staging and vascular and biliary tract invasion is the

magnetic resonance cholangiopancreatography. CT and PET scan can be also

useful for preoperative staging.

The mainstay of treatment is surgical, either simple or radical chole-

cystectomy for stage I or II disease, respectively. Only 20% of patients are candi-

dates for surgery with a curative intent. [4]Survival rates are near 80–90% at 5

years for stage I, and range from 60 to 90% at 5 years for stage II. Regional

nodal status and the depth of tumor invasion are the two most important

prognostic factors. Adjuvant therapy has not proven effective. Gallbladder

cancers at stage III and IV are considered unresectable.

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 THE CASE

This is a case of a 71-year-old female who presented with right upper

quadrant pain associated with weight loss and anorexia. The patient is a known

hypertensive and a known diabetic since 2017 with good control and good

compliance with maintenance medication. The patient has had no previous

surgeries but was admitted last 2017 at their district hospital in Surigao City due

to a mild stroke as claimed by the S.O., patient has no neurologic deficits.

Personal and Social history was unremarkable. Heredofamilial disease includes

hypertension on her maternal side.

4 weeks prior to admission, patient had sudden onset of right upper

quadrant pain after intake of regular meals associated with anorexia, no

medications were taken. Pain was relieved temporarily by flatus, no consult was

done, condition was tolerated. There was no history of fever, jaundice, weight

loss, loose stools or any other constitutional symptoms.

2 weeks prior to admission, right upper quadrant pain persisted now

associated with constipation and early satiety. Patient sought consult with AP

and work up was done, Chest X-ray, CT-scan of the whole abdomen with

Contrast, Blood chemistry and Colonoscopy was requested. Patient then

followed up with AP with results, Chest Xray results showed essentially clear

lung fields, Blood chemistry results showed Slightly elevated SGPT at 51ul/l,

normal alkaline phosphatase at117iu/l, Slightly elevated total Bilirubin at 1.1mg/dl

and indirect bilirubin of 0.4mg/dl, normal indirect bilirubin of 0.7mg/dl and serum

protein of 6.9g.dl, decreased albumin of 3.4g/dl, slightly increased globulin at

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3.5g/dl, decreased A/G ratio at 1.0 and increased GGT at 79u/L, normal FT4

15.7pmol/l and TSH levels of 2.443iU/ml, CEA levels showed 6.37ng/ml and

elevated CA19-9 at 98.91 U/ml. Colonoscopy results showed internal

hemorrhoids in the rectum, grade I-II, 0.8cm sessile polyp 5cm from the anal

verge and 1.2cm sessile polyp 10cm from the anal verge and at the sigmoid

there was a 0.5cm sessile polyp at 20 cm from the anal verge and was removed

by cold biopsy. Ultrasound of the Whole Abdomen showed That the gallbladder

is dilated due to hydrops. There is thickening of the gallbladder wall with an

enhancing mass along its ventral aspect, The later finding measures

approximately 1.4x1.5x1.1cm. The pericholecystic fat planes are ill defined.

There are calcified stones noted in the distal common bile duct forming a row

causing obstruction. The findings may represent a cholecysto-choledocholithiasis

with hydrops. The enhancing mass along the ventral wall of the gallbladder is

suspicious for malignancy. Presence of multiple slightly enlarged lymph nodes in

the periaortic and interaortic regions. Whether these are due to reactive

lymphadenopathies or neoplastic lymph nodes is not differentiated. Patient was

then Advised for Admission for ERCP and Laparocopic Cholecystectomy based

on the CT- scan results.

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 Figure 1. CT- Scan of the whole abdomen Showing cholecysto-choledocholithiasis with hydrops
and an enhancing mass along the ventral wall of the gallbladder

Upon admission patient was seen alert, awake, and not in respiratory distress with
blood pressure of 110/80mmHg, respiratory rate of 20 and pulse rate of 82. Pertinent
physical examination revealed patient was not jaundice, negative murphy’s sign and
negative right upper quadrant tenderness. Neurologic exam was also unremarkable.
The patient had ERCP done on hospital Day 1, Results showed
Choledocholithiasis, Dilated CBD, GB stone and Peri-ampullary diverticulitis, stone was
then retrieved using biliary balloon catheter.

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 Figure 2. ERCP results showing Choledocholithiasis, Dilated Common bile duct, Gallbladder stone and
Peri-ampullary diverticulitis

On Hospital Day 2 patient had Laparoscopic Cholecystectomy, Post operative

findings were 1.5 cm Gallbladder Nodule, Severe adhesions with distorted anatomy was
noted and Subtotal cholecystectomy was done, Gallbladder mass was then sent to the
laboratory for Biopsy. During Post-op patient had well controlled pain on post op site and
had unremarkable recovery. Patient was then discharged after 3 days. Biopsy results of
the Gallbladder showed Adenocarcinoma with Atypical glands which are lined with
pleomorphic cells with enlarged hyperchromatic nucleoli and scant cytoplasam.
2 weeks after, Patient had followed up with AP with biopsy results and was
advised to continue maintenance medications and have monthly follow up check up with
AP in their hometown in surigao. No further management was advised.

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 DISCUSSION

Gallbladder cancer is a rare biliary tract malignancy in most western

countries, but is much widespread in some other regions of the world. Moreover,

this carcinoma is infrequent in developed countries but more common in some

developing countries, characterized by its lack of symptoms at initial stage

leading to difficulties in treatment. The extensive variation in geography, ethnicity,

and cultural differences in the incidence of gallbladder cancer suggests the role

of key genetic and environmental factors associated with the development and

progression of the disease [3]. The lack of a serosal layer of gallbladder adjacent

to the liver thus enabling hepatic invasion and metastatic progression is one of

the major causes of its miserable prognosis [4].

There is a widely variable geographic pattern for gallbladder cancer, unlike

other tumors of the extrahepatic biliary tract and the ampulla of Vater. The

incidence rates are extraordinarily high in Latin America and Asia, relatively high

in some countries in eastern and central Europe (eg, Hungary, Germany, and

Poland), yet low in the United States and most western and Mediterranean

European countries (eg, UK, France, and Norway)[5]. Gallbladder cancer tends to

particularly afflict indigenous populations, according to a vast global cancer

registry on five continents (representing 704.4 million people or 11% of the world

population [6]. Mapuche Indians from Valdivia, Chile, South America exhibit the

highest rate of gallbladder cancer: 12.3/100,000 for males and 27.3/100,000 for

females. American Indians in New Mexico, USA, follow, with an average annual

rate of 8.9/100,000. For these native people, gallbladder cancer mortality rates

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exceed those for breast (8.7/100,000), cervical (8.0/100,000), pancreatic

(7.4/100,000), and ovarian cancers (7.3/100,000)[7].

Figure 3. Gallbladder cancer incidence rates are highest among certain ethnicities, particularly South American Indians
and East Indian (northern India) females. Statistics derived from Cancer Incidence in Five Continents [8].

The cause of gallbladder carcinoma is not well understood but is thought

to be multifactorial. Several risk factors for gallbladder carcinoma have been

described see figure 3. The primary risk factor for gallbladder carcinoma is

cholelithiasis, which is in the case of my patient. Gallstones are found in 65% to

90% of patients with gallbladder carcinoma. Populations with high rates of

cholelithiasis also have high rates of gallbladder carcinoma. Gallbladder

carcinoma actually develops in only 1% to 3% of patients with cholelithiasis, and

20% of patients with gallbladder carcinoma do not have evidence of

cholelithiasis. [9].

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 Figure 3. Risk Factors for Gallbladder Carcinoma

From 80% to 95% of gallbladder carcinomas are adenocarcinomas; the

majority of these are moderately to well differentiated Adenocarcinomas are

further divided into papillary, tubular, and nodular variants, with the papillary

adenocarcinomas being the least aggressive form. Less common types, in order

of frequency, include undifferentiated or anaplastic carcinoma, squamous cell

carcinoma, and adenosquamous carcinoma. Rare types include carcinoids, small

cell carcinomas, malignant melanomas, lymphomas, and sarcoma[9]. for my

patient she had moderately differentiated adenocarcimona.

Sixty percent of gallbladder carcinomas are located in the gallbladder

fundus, 30% in the body, and 10% in the gallbladder neck. Analogous to

cholangiocarcinoma, the papillary form of gallbladder carcinoma has a lower

potential for invasion and metastatic spread to lymph nodes. Gallbladder

carcinoma spreads via direct invasion, lymphatic or hematogenous metastasis,

perineural invasion, and intraperitoneal or intraductal invasion. Lymphatic tumor

cell spread is determined by the physiologic gallbladder lymphatic plexus,

including the first-level lymph nodes along the biliary tract (cystic duct, bile duct,

and hepatic duct), followed by pancreaticoduodenal lymph nodes, as well as

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lymph nodes along the common hepatic artery and celiac axis. Lymph node

metastases are described in 54% to 64% of patients and correlate with the depth

of invasion. Gallbladder carcinoma has a predisposition to involve the liver bed

because of venous drainage, predominantly into hepatic segments IVb and V

and the anatomic approximation that allows direct hepatic invasion. Perineural

spread is observed in 24% and intraductal spread in 19% of cases[9]. Patient

had Presence of multiple slightly enlarged lymph nodes in the periaortic and

interaortic regions which was suspicious of malignancy.

Gallbladder cancer arises in the setting of chronic inflammation. In the

vast majority of patients (>75%), the source of this chronic inflammation is

cholesterol gallstones. The presence of gallstones increases the risk of

gallbladder cancer 4- to 5-fold. [10] Other more unusual causes of chronic

inflammation are also associated with gallbladder cancer. These causes include

primary sclerosing cholangitis, ulcerative colitis, [11]Liver flukes,

chronic Salmonella typhiand paratyphi infections, [and Helicobacter infection[12].

An increased incidence of gallbladder cancer also occurs in hereditary

syndromes including the following [13]:

 Gardner syndrome

 Neurofibromatosis type I

 Hereditary nonpolyposis colon cancer

The role of various oncogenic mutations in gallbladder cancer is an area of

active research. For example, a small study of gallbladder cancer from Japan

reported an excess risk associated with polymorphism of the cytochrome P450

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1A1 gene (CYP1A1), which encodes a protein involved in catalyzing the

synthesis of cholesterol and other lipids. [14] In up to 60% of patients with

gallbladder carcinoma, mutations of the K-ras oncogene have been detected; the

frequency is highest in patients with AUPBD [9].

Figure 4. Gallbladder Carcinoma Cancer Progression

In 47% to 78% of patients, gallbladder carcinoma is found incidentally

during cholecystectomy for presumed benign disease, reflecting the initial

clinically silent nature of this malignancy. Common clinical presentations include

biliary or abdominal pain and jaundice secondary to direct invasion of the biliary

ducts or metastasis to the hepatoduodenal ligament. Weight loss, abdominal

distention, or other symptoms [9]. In the case of this patient, the patient

presented with vague right upper quadrant, anorexia and weight loss. CEA and

CA 19-9 are the most commonly used tumor markers for gallbladder carcinoma.

At a cutoff at 4.0 ng/mL, an elevated serum CEA level has a sensitivity and

specificity of 50% and 93%. The sensitivity and specificity of an elevated serum

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CA 19-9 level at a cutoff of 20 U/mL are 79% and 79% ,[9] As with my patient

CA19-9 leves were markedly increased at 98.91 and CEA levels were only

slightly elevated at 6.7.

Abdominal US is often one of the first imaging studies performed in a

patient who presents with the aforementioned symptoms. The sensitivity and

accuracy of US for gallbladder carcinoma are 85% and 80%, respectively.

Typical imaging presentations of gallbladder carcinoma include focal or diffuse

mural thickening of the gallbladder, an intraluminal mass greater than 2 cm in

size that originates in the gallbladder wall, and a subhepatic mass that replaces

or obscures the gallbladder and often invades adjacent organs Findings

indicative of the malignant nature of a gallbladder lesion include irregular,

asymmetrical mural thickening greater than 1 cm in depth and a nodular or

smooth intraluminal mass greater than 1 cm in size, with fixation to the

gallbladder wall, that is not displaced by the patient’s movements and has no

acoustic shadow[9]. My patient presented with a thickening of the gallbladder wall

with an enhancing mass along its ventral aspect measuring approximately

1.4x1.5x1.1cm with Presence of multiple slightly enlarged lymph nodes in the

periaortic and interaortic regions suspected as neoplastic lymphnodes.

Staging systems for gallbladder carcinoma include the Nevin-Moran

classification system and the Japanese Biliary Surgical Society staging system.

The most commonly used staging system is the TNM system described by the

AJCC and UICC. The TNM-based staging system correlates with survival.

Reported 5-year survival rates for patients with stages 0, I, II, III A, III B, IV A,

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and IV B gallbladder carcinoma are 80%, 50%, 28%, 8%, 7%, 4%, and 2%,

respectively [9]. As for my patient she had T2N1M0- stage IIIB.

Figure 5. TNM and American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC)Staging Systems for
Gallbladder Carcinoma

Surgery is the only potentially curative therapeutic option for gallbladder

carcinoma. Only 15% to 47% of patients are candidates for surgical resection at

the time of diagnosis because the stage of the disease is advanced in most

cases. Contraindications to resection include multiple hepatic or distant

metastases, gross vascular invasion or encasement of major vessels, malignant

ascites, and poor functional status. Direct invasion of the colon, duodenum, or

liver is not considered an absolute contraindication to surgical resection. The

goal of surgical treatment is an R0 resection, defined as negative margins and

nodal dissection one level past microscopically involved lymph nodes. R0

resection in gallbladder carcinoma has been shown to correlate with survival and

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with significantly increased 5-year survival rates. In retrospect during inta-op,

laparoscopic cholecystectomy should have been converted to open

cholecystectomy and an R0 resection should have been done instead of subtotal

cholecystectomy for better survival benefit of the patient.

Figure 6. Algorithm for the management of gallbladder carcinoma discovered

intra- or postoperatively at laparoscopic cholecystectomy

The standard of care for patients with unresectable gallbladder carcinoma

is chemotherapy with gemcitabine combined with cisplatin and gallbladder

carcinoma is considered radioresistant. In the case of my patient chemotherapy

was no longer offered as a treatment option considering her age.

The dilemma in treating elderly patients with gallbladder carcinoma is that

there are operative risk such infections, comorbidies and distorted anatomy as

presented in my patient and willingness to undergo additional surgery,

considering the very low survival rates of gallbladder carcinoma.

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