Gallbladder Sarcoma: A Clinicopathological Study of Seven Cases from the UK and Austria with Emphasis on Morphological Subtypes
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- Husain, E.A., Prescott, R.J., Haider, S.A. et al. Dig Dis Sci (2009) 54: 395. doi:10.1007/s10620-008-0358-z
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Background Primary sarcoma of the gallbladder (PGBS) is rare, with only 40 cases reported in the literature. Most of these have been diagnosed as leiomyosarcoma. We aimed to evaluate the histological features of a case series of this rare tumor and correlate these with clinical features. Design Cases recorded as “gallbladder sarcoma” from different institutes were reviewed and the clinicopathological features of these cases were recorded. Only primary gallbladder wall mesenchymal tumors were included. Epithelial tumors, mixed tumors (carcinosarcoma or sarcomatoid carcinoma), and tumors extending into the gallbladder from the abdomen or sarcoma with other known primaries were specifically excluded. Result PGBS occurred in one male and six females with a median age of 70 (range 64–82) years. Patients presented with acute or chronic cholecystitis, abdominal pain, weight loss, and pruritis. They were generally found to have elevated alkaline phosphatase and bilirubin, and leukocytosis. Tumors ranged from 1.1 to 4 cm with a median size of 3 cm. Most PGBS arose in the body but one arose in the fundus. All tumors were associated with ulcerated mucosa. Based on morphological and immunohistochemical features of the PGBS, there were three myxofibrosarcomas (malignant fibrous histiocytoma, MFH, storiform pleomorphic), one leiomyosarcoma (LMS), one angiosarcoma (AS), and two liposarcomas (LS). All patients received cholecystectomy and three received adjuvant chemotherapy. Follow-up revealed that six patients died of the disease 6 weeks to 2 years after diagnosis and one died of unrelated causes. Conclusion PGBS are rare and mainly occur in the gallbladder body in middle-aged females. They generally present with acute cholecystitis and have a very poor prognosis. A variety of sarcoma types are found with MFH being the predominant variant.
KeywordsPrimaryGallbladder sarcomaMorphological patternsHistopathologyClinical management
Benign mesenchymal proliferation is encountered commonly in the gallbladder with adenomyomotous hyperplasia accounting for more than 40% of tumor-like lesions of this organ [1, 2]. Malignant mesenchymal neoplasms of the gallbladder, however, are extremely rare and, for the most part, have been the subject of isolated case reports. Only 40 cases of primary gallbladder sarcoma (PGBS) have been reported in the world literature to date. In most cases, the patient has presented with right upper quadrant pain with or without jaundice. A variety of tumor types have been described including leiomyosarcoma (LMS) [3–6], rhabdomyosarcoma (RMS) [7, 8], angiosarcoma [9, 10], Kaposi’s sarcoma , malignant fibrous histiyocytoma [12, 13], and synovial sarcoma . Of these, LMS is the most common type of PGBS reported in the literature. In order to learn more about this rare neoplasm, we evaluated a series of PGBS for histopathological features and clinicopathological correlates.
Materials and Methods
Cases recorded as “gallbladder sarcoma” were retrieved from a number of different institutes and the clinicopathological features were tabulated. Only primary gallbladder wall mesenchymal tumors were included. Epithelial tumors, mixed tumors (carcinosarcoma or sarcomatoid carcinoma), and tumors extending into the gallbladder from the abdomen or sarcomas with known primaries were excluded. The diagnoses were reviewed by the authors and were established in accordance with the new World Health Organization classifications for soft tissue tumors and the most recent published soft tissue criteria. Slides and clinical information on 12 cases were available for review. Five tumors were excluded from the current study. Two were gastrointestinal tumors (GISTs), one with benign features and another which extended into the gall bladder from the abdomen. The other three were excluded because they were either mixed epithelial tumors (carcinosarcoma or sarcomatoid carcinoma) or the primary sites were not the gallbladder.
In each case, initial review was of the hematoxylin and eosin-stained sections and, in most cases, the immunohistochemical studies that had been performed. In selected cases where additional unstained slides or paraffin blocks were obtained further immunostaining was undertaken.
The antibodies used
AE1/AE3a and LP34b
3 min protease
Boehringer Mannheima (Indianapolis, IN, USA); Dakob (Cambridge, CA, USA)
Smooth muscle actin (SMA)
Biogenex Laboratories, San Roman
Clinical details of primary gallbladder sarcoma (PGBS)
Progressive painless jaundice and itching of one week duration
Chronic cholecystitis and malignant tumor
The average size of the tumors was 2.45 cm (range 1.1–4 cm). Grossly, tumors were solid, tan-grey in color with some showing focal hemorrhage or necrosis. Most appeared poorly circumscribed and most tumors involved the whole wall. Multi-nodularity and necrosis were also described. In addition, most tumors had an ulcerated mucosa of the body (n = 6); one was of fundus.
Four sarcomas were of intermediate grade, two were of high grade, and one was of mixed intermediate and high grade (Table 2).
Follow-up on and clinical information on the seven PGBS is presented in Table 2. Follow-up information was obtained on all patients. Six patients died of disease, 6 weeks to 2 years after diagnosis, and one died of unrelated causes (myocardial infarction, bronchopneumonia, and cardiac insufficiency not otherwise specified).
PGBS is exceedingly rare and only 40 cases have been reported in the World literature. The morphological patterns and the follow-up on PGBS in the literature are either largely unknown or incomplete.
This study represents the second largest series of PGBS (n = 7). None of the cases has been reported previously (the largest series is in press, personal communication with Dr. J. C. Fanburg-Smith, AFIP, Washington DC, USA). We wanted to study the clinicopathological features of PGBS as it is an extremely rare tumor. We also studied the different histological subtypes and their correlation with clinical outcome. In addition, the management proposals are discussed, in the view of the available literature.
Our series differs from the summated data of isolated case reports. In the latter, LMS was the most common type of PGBS whereas in our series the common type was actually MFH. In addition, we found one angiosarcoma and two liposarcomas of the gallbladder.
Histogenesis of PGBS is not clear. PGBS may arise from an aberrant tissue component such as striated muscle. Histological subtypes may include sarcoma of any type. These include primary LMS, RMS, AS, synovial sarcoma, and undifferentiated sarcomas .
The pathogenesis of PGBS is poorly understood. It has been speculated that PGBS or sarcomatoid carcinoma (which was excluded from this study) of the gallbladder arise from totipotential stem cells [1, 2], rest cells of mesoblasts that retain the capability of transformation, primitive undifferentiated mullerian stroma [2, 16, 17], or paramesonephric tissue , although cholelithiasis with accompanying cholecystitis (n = 12, in the current series) has been suggested as a promoting factor [1, 2, 16, 17, 19–21]. Abnormal bile composition that causes stones, and subsequent chronic inflammatory changes and irritation, have been suggested as promoting factors in the pathogenesis. However, a “cause and effect” relationship remains circumstantial and unclear, and further studies are, indeed, needed. An aetiological role for sarcomas has also been suggested for alterations in regulatory genes p53 and RB . Anomalies of the junction of the cystic duct and common bile duct have been observed frequently in patients with gallbladder carcinoma or even carcinosarcoma. Ethnicity may be a predisposing factor because gallbladder cancer is more common in Latin Americans and less in blacks [1, 2, 16, 17, 19, 22, 23].
Interestingly, the average age of patients with PGBS is usually the seventh to eighth decade of life at diagnosis, as in this study. This differs slightly from gallbladder carcinoma, which usually occurs in the seventh decade. In addition, PGBS is more common in women than in men by a ratio of six to one in our study. In contrast, although gallbladder carcinoma has female predominance, the female to male ratio is 3:1.
The clinical presentation of PGBS is non-specific and is similar to cholelithiasis and cholecystitis. The symptoms can include right upper quadrant pain, nausea, vomiting, jaundice, and fever. In addition, symptoms related to the malignant nature of the disease, for example weight loss, may also be present.
The diagnosis of PGBS is usually impossible to make before operation or post-mortem examination. In the current study, pre-operative suspicion of malignancy was found in two cases only based on the radiological findings. CT and ultrasound may show enlarged gallbladder with thickening of the wall and a mass within the lumen. Although these tests are diagnostic adjuncts, histological confirmation is required.
The differential diagnosis essentially includes primary or metastatic undifferentiated carcinoma, LMS, RMS, epithelioid AS, and metastatic melanoma. Before the advent of immunohistochemistry, reported primary sarcomas of the gallbladder were likely to be undifferentiated carcinoma or sarcomatoid squamous cell carcinoma. An important differential diagnosis is with sarcomatoid (spindle cell) carcinoma or carcinosarcoma of the gallbladder. Such tumors are often biphasic in appearance, with a neoplastic glandular component intimately associated with a sarcoma-like spindle cell component. In such circumstances, both the glandular and the sarcoma-like spindle cell proliferation show epithelial differentiation by immunohistochemistry and/or electron microscopy [24, 25]. Areas of high-grade dysplasia or in-situ carcinoma have been reported in 79–85% of cases and are also an important clue for diagnosis of these tumors [1, 2]. In our study, such tumors have been excluded on the basis of histological and, when available, negativity for all the epithelial markers. A LMS would express smooth muscle actin and desmin; likewise a RMS would express desmin and myoglobulin. Metastatic malignant melanoma can express CD117 (C-KIT) [26–30]; however, reactions for S100, Melan A, and HMB45 would be positive.
A lesion worth mentioning is a relatively recently described tumor of the gallbladder with a phenotype of gastrointestinal stromal tumor (GIST) with a benign or malignant histology derived from the cells of Cajal [26–30]. This tumor is characterized by a spindle cell proliferation that is positive for CD117. This might account for the reports documented previously as primary LMS of the gallbladder. There are only three reports of well documented primary gallbladder GIST, two of which are benign GIST [31, 32] and one malignant GIST . In the current study, a fourth case of GIST of the gallbladder was identified but was excluded as it had a benign morphology.
The biological behaviour of PGBS is, in general, very similar to that of aggressive sarcomas. Most cases of PGBS presented at an advanced stage and showed rapid growth, with a large mass. The outlook is grim for most patients. Follow-up on and clinical information on the seven PGBS is presented in Table 2.
Because of limited experience with the disease, there is no consensus about management. Long-term survival after surgical resection for PGBS might be possible if the tumor is confined to the submucosa. However, most patients with PGBS do not fit this category. It does not appear that simple cholecystectomy provides adequate treatment for tumors confined to the gallbladder wall. Because most patients present with advanced disease, extensive resection and adjuvant chemo-radiotherapy is often required. Very similar to gallbladder carcinoma, it seems that curative resection for PGBS is not usually possible. Given the absence of clinically involved lymph nodes or obvious metastatic disease in the current series, a curative resection (including hepatic bed resection) should always be attempted.
Reports of involvement of the liver in up to 75% of patients have been described. This is not the case in our experience. Accurate diagnosis, and equally important relief of symptoms remains the priority in the treatment of PGBS, and this is usually best achieved surgically.
PGBS are rare. These mainly occur in the gallbladder body in aged females with acute cholecystitis, with overall poor prognosis. A variety of sarcoma types are found, yet MFH is the predominant variant. GIST can exceptionally occur in this location. Awareness of this rare malignancy may also prevent false diagnosis of cholelithiasis and cholecystitis. Frozen section biopsy can aid in the event of a suspicious finding at the time of routine cholecystectomy. This can guide intra-operative decision of wider excision.