Leiomyosarcoma of the gallbladder—A case report and a review of literature

Highlights • A leiomyosarcoma may appear in the gallbladder.• Leiomoysarcomas (LMS) are considered as a major subgroup of sarcomas.• In a non-metastatic stage, the cholecystectomy with wedge resection as well as lymphadenectomy of the hepatoduodenal ligament may be sufficient surgical approach.


Introduction
Primary sarcomas of the gallbladder (GB) are a rare disease that were first described by Griffon and Segall in 1897 [1]. Women are more often affected than men. In the majority of published cases, primary sarcomas of the GB appear between the 6th and 7th decade of life [2,3]. Leiomyosarcomas (LMS), as described in the case report at hand, are considered a major subgroup [2][3][4].
The work has been reported in accordance with the SCARE criteria [5].

Presentation of case
A 62-year-old female was referred to our hospital due to intermittent right upper quadrant and epigastric pain for 7 days in 2015. Her medical history consisted of hypothyroidism and pyelonephritis. Her surgical history included an appendectomy. During the clinical examination a positive murphy sign was found. The laboratory tests demonstrated an elevated bilirubin, y-glutamyl transferase, alkaline phosphatase, and lipase. Additionally, the inflammatory markers were elevated. The patient underwent an abdominal ultrasound. An inflamed GB with multiple gallstones was detected. Moreover, a 45 mm mass arising from the neck of GB was found (Fig. 1). Therefore, we conducted an upper endoscopy. No choledocholithiasis was detected. The 45 mm sized tumours had a space-occupying effect on the stomach. The endosonography, MRI and abdominal CT scan did not show distant metastases (Figs. 1 and 2). The mass of unknown dignity showed a contrast agent uptake, but no signs of an infiltrative growth pattern. After a multidisciplinary discussion within our tumor board, the decision was made to remove the mass, with the suspicion of finding a malignant entity. Intraoperatively, neither liver metastases nor the infiltration of the omental fat were revealed. We resected the inflamed gallbladder, as well as the fossa. Additionally, we performed a lymphadenectomy of the hepatoduodenal ligament. The frozen section analysis of the excision margins of the cystic duct did not show any malignant cells.

Pathological findings
The histopathological examination diagnosed an R0 resected 40 mm smooth bounded spindle-shaped epithelioid tumor in a chronic inflamed GB. The liver tissue and lymph nodes did not contain malignant cells (Fig. 3, Picture I).

Immunohistochemical findings
The immunohistochemical examination revealed the expression of DOG1, Calponin and Caldesmon (Fig. 3, Picture II-III).
The postoperative course was uneventful. We discharged our patient 12 days after surgery.
As a follow-up approach, we decided to perform a CT scan every 6 months. No tumor recurrence or metastases were detected up to this day. Our patient remains alive and in good health.

Discussion
Primary sarcomas of the GB are a rare malignancy. The majority of these sarcomas are leiomyosarcomas. An incidence is estimated as 1.4 per 1000 malignancies of the GB [6,7].
To reveal further knowledge on epidemiology, therapy and outcome of patients with LMS of the GB, we reviewed the literature using the search terms "Sarcoma," "Leiomyosarcoma," and "Gallbladder", with Google Scholar and PubMed. The search yielded 30 relevant publications [1,2,4,. We excluded publications without available abstracts or insufficient information regarding the patient's medical history. 10 publications were excluded ( Table 1). The articles' publication dates range from 1982 to 2018. Among the 20 publications, the medical history of 24 patients who suffered from a LMS of the GB was reported. In 23 cases, the LMS occurred primarily in the GB. 18 patients were female, and 6 patients were male with an average age of 65.95 years. The diameter of the mass ranged between 2 and 8 cm. Egorov et al. published a case of a large LMS that weighed 1500 g [22]. In 4 cases, the LMS infiltrated the surrounding organs.
The diagnosis of a LMS is established in accordance with the World Health Organization classification for soft tissue tumors [3]. This tumor entity consists of cells showing distinct smooth muscle features. Macroscopically, the LMS forms a white and grey coloured fleshy mass. The microscopic pattern typically consists of intersecting, sharply marginated groups of spindle cells. Usually, the LMS is immunohistochemically positive for desmin, h-caldesmon, and SMA. Immunostainings may be focally positive for CD34, epithelial membrane antigen (EMA), keratin, and S100 [3,10].
Patients who suffered from a LMS of the GB often present with abdominal pain, fever, jaundice, and weight loss [6]. In certain cases, as the one presented here, an acute or chronic cholecystitis, accompanied by cholelithiasis led to the diagnosis of a GB tumor. Predisposing factors regarding the pathogenesis of the LMS may be gallstones and chronic inflammation of the GB [6]. Our review revealed that the majority [13,24] of patients were referred to the hospital suffering from gallstones with an acute or chronic inflammation of the GB [1,2,7,11,12,14,15,17,19,20,23].
As a diagnostic approach, an ultrasound examination, a CT scan, as well as a PET-CT scan are recommended. The LMS may occur as a polypoid mass protruding into the lumen with an irregularly thickened wall. Nevertheless, the lack of specific radiological features makes the differentiation from an adenocarcinoma challenging [6].
Similar radiological, histological and immunohistochemical features make the adenocarcinoma, the rhabdomyosarcoma, the liposarcoma, the Kaposi sarcoma, and the angiosarcoma an important differential diagnosis to consider [12,13].
The therapy depends on the tumor extension. In a nonmetastatic stage, the cholecystectomy combined with a wedge resection of the surrounding liver tissue, as well as a lymphadenectomy of the hepatoduodenal ligament seems to be a sufficient surgical approach [6,9,10,15,19,25]. Contrarily, Guo et al. and Perez-Montiel et al. treated a LMS of the GB by performing a solely cholecystectomy. Their patients survival rate was about 2 years [8,14]. Our review revealed that an extensive surgery was per-formed in cases of a local tumor invasion [1,10,13]. There is not sufficient evidence in the literature regarding the effectiveness of adjuvant chemo-or radiation therapy. However, some authors reported that chemotherapy with doxorubicin, mitomycin C may improve the long term survival following surgery [1,17,26].
The LMS of the GB has a very poor prognosis, particularly in a metastatic stage [1,17]. By removing the LMS in an early tumor stage, a long term survival for several years, as shown in our case report, has been described [8,14].

Conclusion
Particularly when diagnosing a tumor of the GB in elderly women, a leiomyosarcoma should be taken under consideration.
In a non-metastatic stage, the cholecystectomy with a wedge resection of the surrounding liver tissue, as well as a lymphadenectomy of the hepatoduodenal ligament is described as a sufficient surgical approach.