Cholecystocutaneous Fistula Associated with Edwardsiella tarda as a Result of Aggressive Lymphoma Development

Abstract

A cholecystocutaneous fistula is a type of external biliary fistula that occurs when there is an abnormal connection between the gallbladder and skin. We report the first case of a cholecystocutaneous fistula that occurred in association with the development of lymphoma in the gallbladder. A 76-year-old woman who was under observation for follicular lymphoma with a low tumor burden presented with fatigue and abdominal pain. Imaging studies revealed cholecystitis associated with an abdominal subcutaneous abscess, and lymphoma transformation was confirmed by a lymph node biopsy. Edwardsiella tarda was cultured from both the abdominal subcutaneous abscess and percutaneous transhepatic gallbladder drainage, demonstrating cholecystocutaneous fistula, and open cholecystectomy revealed lymphoma cell infiltration into the gallbladder. Our case showed unique complications, and its successful management was associated with aggressive lymphoma development.

Introduction

A cholecystocutaneous fistula is a type of external biliary fistula that allows pathological connections between the gallbladder and skin (1). Gallstones are primarily associated with fistula formation, since gallstones obstructing the cystic duct increase intra-gallbladder pressure, leading to gallbladder necrosis and perforation. Gallbladder fistulas are usually caused by bacterial infections, although there have been a few reports of fistulas associated with malignancy, such as adenocarcinoma of the gallbladder (2,3).

We report the case of a 76-year-old woman who presented with diffuse large B-cell lymphoma (DLBCL) that transformed from follicular lymphoma (FL). The patient simultaneously developed a cholecystocutaneous fistula. A culture of the cholecystocutaneous fistula was positive for Edwardsiella tarda (E. tarda). This case report describes a previously undescribed complication of aggressive lymphoma.

Case Report

The patient was a 76-year-old woman who had been diagnosed with FL, which involved tumors in the intra-pelvic space and lymph nodes at the chestwall, axillary, submandibular, and inguinal regions, four years previously. No lymphoma was detected in the gallbladder or adjacent lymph nodes. Although follicular lymphoma international prognostic Index (FLIPI) (4) and FLIPI2 (5) were high, she was under watchful observation on an outpatient basis due to a low tumor burden according to the Groupe d'Etude des Lymphomes Folliculaires criteria (6). About a month before admission, she began experiencing generalized fatigue and anorexia, which led to her becoming bedridden. She also experienced gradual abdominal pain and noticed a reddish mass in the right upper abdomen, which worsened over two weeks. The patient was hospitalized for emergency evaluation and treatment. The cervical and inguinal lymph nodes were bilaterally palpable, suggesting lymphoma involvement. A reddish warm mass of approximately 7 cm in diameter was noted in the right upper abdomen (Fig. 1a). Laboratory evaluation demonstrated increased C-reactive protein (5.52 mg/dL), acute kidney injury (blood urea nitrogen, 42.8 mg/dL; creatinine 3.16 mg/dL), and coagulopathy (prothrombin time-international normalized ratio, 1.15; D-dimer 22.8 μg/mL), while liver function tests were within normal ranges (aspartate aminotransferase, 20 U/L; alanine aminotransferase, 8 U/L; total bilirubin, 0.6 mg/dL). Serum markers for lymphoma were elevated, with a lactate dehydrogenase level of 456 U/L and a soluble interleukin-2 receptor level of 10,900 U/mL. Computed tomography (CT) on admission revealed multiple intra-abdominal tumors involving the subdiaphragmatic space, para-aorta, intrapelvic space, adrenal glands, and inguinal areas. An abdominal subcutaneous mass was noted; however, fluid accumulation inside the mass and enhancement of the surrounding fat tissue were associated with an abscess rather than lymphoma (Fig. 1b). CT also revealed bilateral hydronephrosis, which suggested the ureteral involvement of the tumor, and acalculous cholecystitis, manifested by gallbladder distention, wall thickening, and enhancement of the surrounding fat tissue (Fig. 1c). Abdominal ultrasound revealed a subcutaneous mass that contained fluid and blood flow signals in the septum and a dilated gallbladder filled with sludge (Fig. 1d, e). ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) confirmed lymphoma involvement with the accumulation of ¹⁸F-FDG in the lymph nodes at the cervix, hepatic hilum, para-aorta, and inguina, left lung, adrenal glands, skull bones, scapula, ribs, vertebrae, and pelvic bones. There was no accumulation of FDG in the gallbladder. At its center, the abdominal subcutaneous mass was devoid of ¹⁸F-FDG accumulation, which further supported the involvement of the abscess rather than lymphoma (Fig. 1f). A biopsy of the bilateral inguinal lymph nodes was performed. On histological examination, atypical lymphocytes with centroblastic morphology were noted. These were immunopositive for CD10, CD20, BCL2, BCL6, and MUM1, and immunonegative for CD3 and CD5. Therefore, the patient was diagnosed with DLBCL transformed from FL. The cells of origin were considered to be germinal center B-cells according to Hans' criteria (7). The Ki67 proliferation index was approximately 80%. Fluorescence in situ hybridization was positive for IGH::BCL2 translocation and negative for IGH::MYC translocation.

Figure 1.

Imaging studies of the abdominal subcutaneous abscess and gallbladder. (a) Macroscopic findings of the abdominal subcutaneous abscess. One graduation on the ruler represents 1 cm. (b, c) CT imaging of the abdominal subcutaneous abscess (b) and gallbladder (c). (d, e) Ultrasound imaging of the abdominal subcutaneous abscess (d) and gallbladder (e). Fluid accumulation inside the mass and enhancement of the fat tissue surrounding the abdominal abscess are observed (b and d). Gallbladder distention associated with wall thickening (c and e). (f) On positron emission tomography/computed tomography imaging, there is no accumulation of ¹⁸F-fluorodeoxyglucose at the center of the abdominal subcutaneous abscess. Gb: gallbladder, Lv: liver, Sp: spleen, St: stomach

To investigate the etiology and source of inflammation/infection in the subcutaneous mass and gallbladder, percutaneous abdominal abscess puncture and percutaneous transhepatic gallbladder drainage (PTGBD) were performed along with antibiotic (ampicillin/sulbactam) treatment. The subcutaneous abscess was characterized by inflammatory cells, mostly neutrophils, and bile pigment (Fig. 2a). An abscess culture was positive for E. tarda. On PTGBD, white infected bile was drained and the culture was positive for E. tarda. Both E. tarda samples were sensitive to ampicillin, amikacin, aztreonam, ceftazidime, cefazoline, cefmetazole, ceftriaxone, meropenem, flomoxef, gentamicin, latamoxef, minocycline, cefditoren pivoxil, cefepime, sulfatrimethoprim, levofloxacin, ampicillin/sulbactam, and piperacillin/tazobactam. These results strongly indicated that cholecystitis had spread to the subcutaneous abscess. Blood culture results were negative. It was deemed necessary to eliminate the source of infection before initiating chemotherapy for DLBCL. Therefore, open cholecystectomy was performed on day 25 after admission. Histologically, diffuse infiltration of lymphoma cells, which were morphologically and immunohistochemically similar to those observed at the inguinal lymph nodes, was observed at the walls of the gallbladder (Fig. 2b-d). Three cycles of rituximab, cyclophosphamide, doxorubicin, and prednisolone combination regimens were administered with tumor shrinkage on follow-up CT. However, chemotherapy was terminated due to the exacerbation of delirium and breathing problems. The patient died four months after admission.

Figure 2.

Pathological findings of the abdominal subcutaneous abscess and gallbladder. (a) Hematoxylin and Eosin staining (×200) of the subcutaneous abscess. Bile pigment is observed in the abscess. (b-c) The infiltration of lymphoma cells is observed throughout the gallbladder (b, ×40). Diffuse proliferation of medium to large lymphoid cells (c, ×600). Lymphoma cells are strongly positive for CD20 (d, ×600).

Discussion

To the best of our knowledge, this is the first case of cholecystocutaneous fistula associated with lymphoma development. Although the disease was first described in the seventeenth century, it has only been reported anecdotally and infrequently (1,8). The fistula is most commonly associated with gallstones. Gallstones obstructing the cystic duct increase intra-gallbladder pressure and reduce perfusion with necrosis, leading to gallbladder perforation and abscess formation in the adjacent tissue (9). Other reported etiologies include cholecystitis (10-12), adenocarcinoma of the gallbladder (3), trauma (13), and IgG4-related disease (14). Elderly women are the most affected patients, possibly due to a weak abdominal wall. The condition can be managed conservatively or surgically (1). In the present case, cholecystitis was evident on CT and PTGBD drainage, although liver function test results were within the normal range on admission. Fistula formation from the gallbladder and abdominal skin was considered reasonable given the observation that the same bacteria, E. tarda, were identified from the abdominal subcutaneous abscess and PTGBD drainage, and that bile pigment was noted in the subcutaneous abscess. The etiology of cholecystitis, and subsequent fistula formation, was determined to be lymphoma. This was due to the presence of lymphoma cells in the resected gallbladder and the absence of gallstones on CT and during surgery. Lymphoma at the hepatic hilum, as suggested by ¹⁸F-FDG accumulation, may also contribute to bile duct obstruction and cholecystitis. Rare cases of lymphoma involving the gallbladder and extrahepatic bile ducts can present with symptoms that mimic cholecystitis (15).

Another unique observation in the present case was that E. tarda was cultured from a subcutaneous abscess and PTGBD drainage. A review of the relevant literature revealed that Escherichia coli was the most common microorganism found in cholecystocutaneous fistulas (1). Other microorganisms include coliforms and Klebsiella pneumoniae, however, E. tarda has not been associated with cholecystocutaneous fistula (1). E. tarda is a gram-negative rod-shaped bacterium that is commonly found in fresh and brackish water environments, as well as some animals, including catfish, flounder, and eels (16-19). Microorganisms are usually cultured from fecal samples in most cases of E. tarda infection. However, extraintestinal infections, including bacteremia, wound infection, meningitis, cholecystitis, liver abscess, peritonitis, endocarditis, urinary tract infection, tubo-ovarian abscess, and brain abscess, can occur in rare instances (17,20-27). Our case highlights that E. tarda can cause a cholecystocutaneous fistula as an extraintestinal complication.

Our case demonstrates that E. tarda can be associated with cholecystocutaneous infection, which occurred as a result of aggressive lymphoma development in the present case. The patient was successfully treated with PTGBD, cholecystectomy, and chemotherapy. Cancer treatment with myelosuppressive chemotherapeutics causes neutropenia and carries the risk of life-threatening infection (28). Oncologists should be vigilant about any source of infection and make appropriate treatment choices to control the infection.

Written consent was obtained from all patients.

The authors state that they have no Conflict of Interest (COI).