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Case Report

Case Report: Metastatic breast cancer to the gallbladder

[version 1; peer review: 2 approved]
PUBLISHED 11 May 2020
Author details Author details
OPEN PEER REVIEW
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This article is included in the Oncology gateway.

Abstract

Cholecystitis is one of the leading causes of emergency surgical interventions; the occurrence of metastases to the gallbladder is rare and has only been reported in the literature exceptionally. Metastatic breast cancer to the gallbladder is even less frequent; in fact, breast cancer usually metastasizes to bone, lung, lymph nodes, liver and brain. We report the case of an 83-year-old female patient with a previous history of breast surgery with axillary dissection in 1997, followed by adjuvant chemotherapy due to invasive ductal carcinoma of the left breast. The patient was admitted at the emergency department for sepsis and an episode of acute kidney failure, anuria and fever. Right-upper quadrant abdominal pain triggered by food intake and abdominal tenderness was also present, placing the diagnostic suspicion of biliary sepsis due to acute cholecystitis. The histological examination of the surgical specimen highlighted the presence of metastasis from an infiltrating ductal breast carcinoma with positive hormone receptors. We also report here the results of a review of the literature looking at articles describing cases of gallbladder metastasis from breast cancer.

Keywords

Emergency surgery, Breast cancer, Cholecystitis

Introduction

Cholecystitis is one of the leading causes of emergency surgical interventions. The diagnosis of acute cholecystitis is usually based on physical examination, laboratory tests and abdominal ultrasound. The surgical options for cholecystitis are either open and laparoscopic cholecystectomy; the latter is nowadays considered the gold standard of treatment. Surgical specimens must be sent for histopathological examination to rule out cancer1.

The occurrence of metastases to the gallbladder is rare and has only been reported in the literature exceptionally2. Primary tumors can metastasize to the gallbladder either by proximity, such as hepatocellular carcinoma and pancreatic carcinoma, or by blood diffusion3.

Chan reported, in a series of 7910 cholecystectomy specimens, that 36 cases of metastatic carcinoma were found, more often secondary to the stomach, lower gastrointestinal tract, liver, kidney or skin (malignant melanoma) cancer4. Another more recent study shows that metastasis to the gallbladder accounted for 7/225 (3.1%) of the incidental gallbladder malignancies5. Metastasis from breast cancer to the gallbladder is even less common; in fact, breast cancer usually metastasizes to bone, lung, lymph nodes, liver and brain.

We describe here the case of a patient who underwent cholecystectomy for acute cholecystitis with gallbladder metastasis from breast cancer. Subsequently, we present the results of a literature search concerning this disease.

Case report

We report the case of an 83-year-old female patient with a previous history of breast surgery with axillary dissection in 1997, followed by adjuvant chemotherapy due to invasive ductal carcinoma of the left breast. The family history was negative for neoplastic diseases, both mammary and belonging to the gastrointestinal tract. Oncological follow-up was negative, and the patient considered disease-free for almost 15 years. During 2012, an X-ray of the spine, performed for the appearance of lumbar pain, revealed the presence of vertebral metastases. The patient was treated with radiotherapy and spinal stabilization. In addition to this, a deep venous thrombosis episode was reported in 2017, and treated with anticoagulant therapy. In the same year, multiple myeloma associated with mild chronic kidney disease was diagnosed. Neither myeloma nor kidney disease had requested specific treatments.

In July 2018, the patient was admitted to the emergency department for sepsis and an episode of acute kidney failure, anuria and fever. Right-upper quadrant abdominal pain triggered by food intake and abdominal tenderness was also present, placing the diagnostic suspicion of biliary sepsis due to acute cholecystitis.

This condition was conservatively treated with intravenous antibiotic therapy with renal adjusted dose of piperacillin-tazobactam and hemodialysis for two weeks. Subsequently, kidney function improved, diuresis had an increasing glomerular filtration rate and sepsis was cured. Abdominal CT-scan performed during this hospitalization had shown a diffuse thickening of the gallbladder’s wall associated with stones as well as pericholecystic fluid (Figure 1). The CT-scan didn’t highlight pathological findings on the liver, such as enlarged regional nodes. A dilated common bile duct with the presence, in its proximal portion, of tenuously hyperdense material was described.

5f011039-d1c2-4f37-82b8-2d574ae37a66_figure1.gif

Figure 1. CT-scan showing a diffuse thickening of the gallbladder and inflammatory pericholecystic fluid.

Endoscopic ultrasound was performed, and it confirmed the presence of both gallbladder and common duct stones, the largest was 7 millimetres, and biliary sludge with lack of dilatation of the intrahepatic biliary tract. Several stones were removed via endoscopic retrograde cholangiopancreatography, and a nasobiliary tube was left behind. Subsequent cholangiography demonstrated the regular calibre and morphology of the cystic duct, the principal biliary tract, and the intrahepatic biliary tree. However, the gallbladder appeared distended with several little stones inside.

The patient, after 6 days from the admission, finally underwent laparoscopic cholecystectomy. Intraoperative findings showed the gallbladder with thickened walls and densely fused with the liver but without other pathological findings. No intraoperative complications occurred. Histological examination of the surgical specimen highlighted the presence of metastasis from an infiltrating ductal breast carcinoma with positive hormone receptors: Estrogen Receptors (MoAb SP1) 98%, Progesterone Receptors (MoAb 1E2) 95%, Cytoprolferative Activity (MoAb MIB-1) 10%, c-erbB2 (MoAb 4B5) score: 0. The cystic lymph node showed no evidence of metastasis. The postoperative course was regular, and the patient was transferred to a rehabilitation ward five days after surgery.

After completion of the rehabilitation program, the patient was discharged, and hormone therapy (letrozole 2.5 mg once a day) was started. The patient died 15 months later due to peritoneal and bone progression of the disease.

Review of the literature

We conducted a systematic review in which all articles describing cases of gallbladder metastasis from breast cancer were considered eligible for inclusion. Abstracts, conference papers and studies concerning animals were excluded. No restrictions were applied to publication date or languages, if there was an English version of the article available.

A systematic search for articles published up to February 2020 using PubMed, Scopus, Google Scholar and Web of Science databases was performed, and references of articles that were retrieved in the full text were also searched. The search strategy utilized in all databases included the combination of the keywords: “gallbladder metastasis”, “breast cancer”, “acute cholecystitis”, “biliary colic”, “cholelithiasis”. A minimum number of two search keywords were utilized, one of which was always “breast cancer”.

A total of 848 potentially relevant articles were retrieved in Google Scholar, 427 in Scopus, 182 in Web Of Science and 123 in PubMed. Among these 22 studies were identified to be strictly matched with our research (Figure 2). Our case was also included in the review.

5f011039-d1c2-4f37-82b8-2d574ae37a66_figure2.gif

Figure 2. Flow diagram of articles included in the literature review.

Discussion

In consequence of advances in medical chemotherapy and endocrine therapy in the last years, the outcomes for breast cancer are improved. Disease recurrence is more common within five years of surgery while late recurrences after more than 10 years are very uncommon. The literature outlines risk factors for late recurrence as lymph node metastases, ER + status and HER-2 negative status6,7. Breast cancer metastases occur through contiguous, lymphatic and hematogenous spread. It usually metastasizes to bone, lung, lymph nodes, liver and brain. Less frequently invaded are the endocrine organs, pericardium, abdominal cavity and eyes. Metastasis in the extrahepatic digestive system are infrequent and characteristically appear after a long latent period, which takes from three to up to 20 years5.

Concerning gallbladder metastases by breast cancer, autopsy findings have shown that secondary hematogenous metastases (also from other primary organs) to the gallbladder initially generate small flat nodules below the mucosal layer. They grow as a pedunculated tumor, rarely reaching higher than several millimetres in size. The growth pattern clarifies why gallbladder metastases rarely result in clinical symptoms and that they are not diagnosed during patients’ lives. Metastatic gallbladder tumors rarely show signs; acute cholecystitis is the most frequent clinical presentation8. Obstructive jaundice, haemobilia, even bile peritonitis due to perforation, are seldom described. When a gallbladder metastasis is identified after surgery, the primary tumor can be not easily defined. Distinguishing between primitive gallbladder carcinoma and metastases from breast cancer is crucial for proper post-surgery therapy; in this way, immunohistochemical evaluation is necessary. The most reliable markers are gross cystic disease fluid protein such as 15 (GCDEP -15), plus cytokeratin 7, cytokeratin 20, and estrogen and progesterone receptors. Usually, their positivity is present in metastatic breast cancer, but not in all cases9.

At microscopic pathological examination, metastases are often represented by small clusters and chains of neoplastic cells, commonly of the signet-ring histotype. Pathological diagnosis of metastases from lobular breast cancer can be difficult because signet-ring cells could be present in tumors originating from different organs, such as the stomach10.

Our review of the literature conducted on secondary lesions of the gallbladder from breast cancer has confirmed the rarity of this disease (see Table 1 for a summary of the cases). Gallbladder metastasis is only described in 23 patients, including our case: 11 from infiltrating lobular, 7 ductal origins, 3 mixed ductal and lobular infiltration, and 3 not specified. This analysis reveals how, in most cases (12), the diagnosis of metastatic lesions was made after surgery was performed for acute cholecystitis. There was evidence of gallstones in 8 cases; 9 cases were patients who often suffer from abdominal pain and/or vomiting (symptoms of biliary colic), and so they underwent an elective cholecystectomy. Only in 2 cases, the main symptom was obstructive jaundice or bile peritonitis for necrotic gallbladder.

Table 1. Brief analysis of all cases of metastasis to the gallbladder we have found in the literature.

Author
(year)
Age of
patients
(years)
Symptoms and
signs
Timing of biliary
symptoms after
breast surgery
GallstonesType of breast
cancer
HistologyImmunophenotypeRecurrence
(months)
Exitus
Di Vita 20111148Abdominal pain in
the last 3 months.
3 weeks after
surgery diagnosis
of chronic
cholecystitis at the
ultrasound
NoMixed ductal-
lobular k (G3, pT2
N3 M0)
Isolated
neoplastic
epithelial cells
in the muscular
layer of the
gallbladder
CK 7+, EMA +,
ER+, PR+
12 SNC
mets
Died 14
months
after
surgery
Beaver 19861273Abdominal pain
and vomiting
(cholecystitis), also
10 months before
3 years after
surgery
YesNot specifiedSmall cell
tumour growing
in an indian file
pattern
N/AN/AN/A
Shah 20001378Bile peritonitis for
necrotic gallbladder
11 years afterYesNot specifiedFocus of poorly
differentiated
adenocarcinoma
characterized by
gland formation
and cells with
eccentric
cytoplasm
N/AN/ADied 5
days after
surgery
Rubin 19891455Biliary colic for 12
months
SynchronousYesLobular carcinomaCarcinoma cells
infiltrating singly
an in file, mostly
in the fibrous
tissue deep to
the muscular
layer focally
extended up to
the mucosa
N/AN/AN/A
Manouras
20089
46Cholecystitis2 years after
surgery
YesDuctalGlandular poorly
differentiated
metastases
invading the
muscular and
serosa layers;
scattered
signet-ring cells
infiltrating the
mucosa
Lactalbumin +; CKT
7+; CKT 20 -; ER -;
PR -
N/ADied 1
year after
surgery
Hashimoto
201615
59Abdominal pain
(Cholecystitis)
12 years after
surgery
NoDuctal (pT1c, pN0)Poorly
differentiated
carcinoma full-
thickness in the
cystic duct and
gallbladder neck
ER+; PR+; CKT 7+;
her 2 -; CKT 20-;
GCDEP 15 -
N/ADied 5
years after
surgery
Coletta 20141656Obstructive
jaundice
13 years after
surgery
NoDuctalSolid
honeycombs
of malignant
epithelial cells
localized only
in the external
side of the
biliary duct wall;
mucosa free
ER+; PR+; CK 7+;
her 2 -; CK 20 -
N/AAlive 1
year after
surgery
Nair 20121754Symptomatic
gallstones
5 years after
surgery
YesLobular (T3 pN1,
pMx)
The wall
infiltrated by
very small
regular cells
arranged in
Indian file
N/AN/ADied 2
years after
surgery
Al-Rawi
201218
61CholecystitisSynchronousYesLobularSerosa and
adjacent fat
showed focal
infiltrates of cells
with rounded
nuclei and small
cytoplasmic
vacuoles. The
cells
Cytokeratins +;
Epithelial Membrane
antigen +; CK 7 +;
ER +; CK 20 -
N/ADied 5
years after
surgery
Ebrahim
201519
65Asymptomatic
cholelithiasis at
the diagnosis of
the tumour; after 2
months of chemo
cholecystitis
After 2 months of
therapy
YesInflammatory
ductal breast
cancer
6–7 mm module
with a pale
yellow-white
solid cut
surface in the
gallbladder wall
ER +
PgR +
N/AN/A
Molina-Barea
201420
62Biliary colicAfter 5 years from
surgery
YesLobularInfiltratedCK 7 +; ER +N/ADied 12
months
after
surgery
Muszynska
20192
71Biliary colicFew months before
the diagnoses of k
Not
specified
Bilateral ductal
and lobular
N/AN/AN/AN/A
Murguia
20065
62Symptomatic
cholelithiasis
10 years after
surgery
YesDuctalFocal broad-
based lesion on
the mesenteric
face of the body
with poorly
differentiated
adenocarcinoma
infiltration,
without mucosa
involvement
CK 7 +; CK 20 –; ER
+0; PgR +
N/ADied 2
years after
surgery for
myocardial
infarction
(2 months
before she
had done
PET and
CA 15.3,
normal)
Mouchli
201921
52Acute cholecystitis1 year after
surgery
NoDuctalN/AN/AN/ADied
several
days after
the surgery
Riaz 20122242Asymptomatic
(finding of a focal
area of thickening
in gallbladder’s
body during the US
for staging)
SynchronousNoLobularCords and nests
of malignant
cells showing
moderate
amount of
eosinophilic
cytoplasm
containing
irregular
hyperchromatic
nuclei; indian
file pattern is
present
Cytoplasmic mucin
+; CK 7 +; CK 20 –;
E-cadherin –; ER +;
PgR+
N/AStable
disease
until her
last follow
up
Markelov
201123
67Nausea + weight
loss (gallbladder
dyskinesia)
6 years after
surgery
Not
specified
Lobular with some
foci of in situ
ductal
Foci of tumour
with a single file
arrangement
present outside
the muscularis
propria and
some tumour
cells within
the muscolaris
propria
ER +; PgR +; Ki67
+; HER 2 -
N/AN/A
Zagouri
200724
59Acute cholecystitis20th month after
surgery
YesBilateral
synchronous
lobular + ductal
The muscular
layer and
adventitia of
the body of
gallbladder was
infiltrated
ER +; PgR –; CK
AE1/AE3 +
N/AAlive 1
year after
surgery
Abdelilah
201425
45Acute cholecystitis3 months after
surgery
YesLobular (T3 N1
M0)
1.5 cm palpable
mass
ER +
PgR+
N/AN/A
Zamkowski
201726
64Acute cholecystitisSynchronousNoLobular bilateralNot describedER +; PgR – ; HER2
–; Ki67 +
N/AAlive at the
moment
of the
drafting of
the article
Fleres 20142783Biliary colic with
gallstones also in
VBP
SynchronousYesLobularParietal
infiltration
Ck AE1/AE3 +; CK
7 +; CK 8 +; ER +;
PgR -
N/AAlive 3
years after
surgery
Herrera
201028
46Acute cholecystitis10 years after
surgery
YesLobularNot specifiedN/AN/AN/A
Machida
200729
53Acute cholecystitis18 years after
surgery
NoLobularNecrotic change
was seen until
the muscular
layer; white
nodules were
detected in the
submucosal
layer of the neck
N/AN/AN/A
Our
experience
86Acute cholecystitis21 years after
surgery
YesDuctalParietal
infiltration
ER +; PgR +; Mib 1
10%; HER2 0
13 months
peritoneal
and bone
Died 15
months
after
surgery

Instrumental diagnostics are useless as they do not show significant data on gallbladder walls that are suspicious for malignancy; the identification of the neoplastic disease is possible only after surgery during histological examination of the specimen, as was shown in our case. From the analysis of the cases described in the literature, it follows that the most frequent tumor histology associated with gallbladder metastasis by breast cancer is infiltrating lobular carcinoma.

This review shows how the detection of gallbladder metastasis usually occurs any time after the surgery for the primary tumor. In essence, we would highlight that in 6 cases, it happened after more than 10 years from primary surgery, in 7 cases between 1 and 6 years, and 3 cases within the first year. Only in 6 cases was the detection of breast cancer and gallbladder metastasis synchronous.

Conclusions

This report emphasizes the importance of long-term follow up in patients with a history of breast cancer.

Our experience and data from the literature suggest carefully evaluating every anomaly observed during routine staging examinations, even when apparently due to benign, mild disease. Metastatic disease always should be included in the differential diagnosis of a patient with a history of invasive breast cancer and new onset of abdominal pain. Conventional methods of documenting gallbladder disease are nonspecific concerning the malignant disease. This may pose a diagnostic challenge in patients with abdominal symptoms after resection of malignancies, also because they need to be aggressively treated as it can improve the poor prognosis of these cases. From our case and literature review, we recommend the following:

  • 1. Consider the oncological story of the patients in the emergency setting;

  • 2. Metastatic disease should be included in the differential diagnosis in patients with a history of breast cancer.

Consent

Written informed consent for publication of clinical details and clinical images was obtained from the patient on admission to hospital prior to the patient’s death.

Data availability

No data is associated with this article.

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Missori G, Serra F, Prestigiacomo G et al. Case Report: Metastatic breast cancer to the gallbladder [version 1; peer review: 2 approved]. F1000Research 2020, 9:343 (https://doi.org/10.12688/f1000research.23469.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
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PUBLISHED 11 May 2020
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Reviewer Report 15 Oct 2020
Francesco Fleres, Department of Human Pathology, University of Messina, Messina, Italy;  ASST Valtellina e Alto Lario, Sondrio Hospital, Sondrio, Italy 
Approved
VIEWS 10
  • The authors have reported a very interesting and rare case. They have described very well the rarity of the case and oncologic history.
     
  • Moreover they have performed an interesting and very complete
... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Fleres F. Reviewer Report For: Case Report: Metastatic breast cancer to the gallbladder [version 1; peer review: 2 approved]. F1000Research 2020, 9:343 (https://doi.org/10.5256/f1000research.25900.r72530)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Reviewer Report 30 Jul 2020
Giorgio Ercolani, Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum - University of Bologna, Bologna, Italy 
Approved
VIEWS 10
I believe that the case-report is interesting, well reported and should be accepted.

However, I have a minor concern:
  • Did the authors perform a liver resection of the gallbladder bed? Is it reported in
... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Ercolani G. Reviewer Report For: Case Report: Metastatic breast cancer to the gallbladder [version 1; peer review: 2 approved]. F1000Research 2020, 9:343 (https://doi.org/10.5256/f1000research.25900.r64929)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

Comments on this article Comments (0)

Version 1
VERSION 1 PUBLISHED 11 May 2020
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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