Primary GB carcinoids are extremely rare. The first case of a carcinoid tumor of the GB was reported in 1929, and 43 cases of carcinoid tumors have been reported to date. Approximately half of the reported cases of GB carcinoid tumors appear to be endocrine cell carcinomas [3
]. At present, 278 cases of GB NETs are reported in the Surveillance, Epidemiology, and End Results (SEER) database. Only five well-differentiated NETs are registered in SEER, indicating that the entity of "benign" NETs is very rare in the GB [1
]. Neuroendocrine cells derive from local multipotent gastrointestinal stem cells rather than, as initially guessed, by migration by the neural crest. GB NETs may develop from endocrine cells induced by intestinal metaplasia of the body and fundus as well as from pre-existing endocrine cells in the neck of the GB [1
]. The age at presentation of GB NETs ranges from 38 to 81 years, and there is a markedly higher incidence in women [10
]. Carcinoid syndrome is very rare (<1%), and most GB carcinoids are diagnosed incidentally during a histological examination of GB specimens at autopsy, after cholecystectomy for acute or chronic cholecystitis, or after surgery for another suspected biliary pathology [6
The case reported here was initially diagnosed as a polyp after an ultrasound examination. PLGs are readily detected by US [18
] with high specificity (95.8%) [19
]. The lifetime prevalence of GB polyps ranges from 1% to 4%. PLGs are "incidentally detected" in approximately 4% to 7% of patients undergoing US of the GB [20
], and PLG is one of the most common diseases in biliary surgery.
The majority of GB polyps are non-neoplastic and most commonly include cholesterol polyps (60%) or inflammatory ones (10%). Adenomyomas represent the second most common type of GB polyps (25%). This type of lesion is associated with an increased incidence of GB cancer, and the GB should be removed surgically. Adenonomatous polyps represent a minority. They can progress to cancer, and this risk is related to their size: polyps larger than 1 cm are considered high-risk lesions. The fifth class of GB polyps consists of rare lesions that include heterotopic gastric glands, neurofibromas, carcinoid tumors, leiomyomas, and fibromas.
The specificity of abdominal US in PLG detection is high [19
], but the sensitivity of US was reported to be low [21
]. Endoscopic US (EUS) may become the standard to define PLGs. Studies have shown a correlation between EUS characteristics and the actual histology of PLGs. EUS is considered to be superior to all types of imaging for GB lesions, particularly for early GB cancer because of the higher operating frequency (7.5 to 12 MHz) that can provide high-resolution images of small lesions and a diagnostic sensitivity for GB malignancy of 90% [21
]. High-resolution US (HRUS) has demonstrated a diagnostic sensitivity of as high as 90% and an accuracy of 62.9% for staging the depth of cancer invasion [22
]. Both EUS and HRUS minimize the changes of not identifying pre-malignant lesion. If the polyps are severe or appear malignant or if large or irregular lesions are found, a CT scan should be performed in order to avoid missing a GB carcinoma. Pre-operative suspicion and a differential diagnosis of GB cancer are very important for selecting the optimal treatment. CT could be used not only to distinguish an early GB carcinoma from a PLG but also to assess the tissue around the malignant PLG and regional lymph node metastases [19
]. Although imaging such as US, EUS, or CT has been widely used, it is still difficult to differentiate cancer from non-neoplastic lesions before an operation. Hence, differentiating a pre-cancerous lesion from early GB cancer is essential. The risk of malignancy is between 45% and 67% in polyps from 1 to 1.5 cm in size [21
Operative indications for PLGs included a maximal diameter of 1 cm, a wide-base lesion, lesions tending to become enlarged in a short period, patient age of more than 50 years, a single polypoid lesion, coexisting GB stones, and a PLG associated with irregular thickening of the local GB wall.
Our patient's histological results after cholecystectomy were suggestive of an NET tumor. The determination of the histological type of the tumor and differential diagnosis from GB adenocarcinoma are often difficult. The identification of neuroendocrine cells and the immunohistochemical expression of marker proteins as well as other cell type-specific amines and peptides are necessary to define a GB NET. Our patient's immunohistochemistry test results were negative for cytokeratin, vimentin, and CD-31 and CD-34, allowing us to exclude a likely diagnosis of adenocarcinoma, sarcoma, or vascular tumor, respectively. The combination of the high histological differentiation, the tumor size, the absence of angioinvasion and infiltrative growth, and the immunohistochemical staining supported the final diagnosis of a "typical" rather than of an "atypical" NET tumor.
When feasible, surgical treatment, with the goal of complete resection, is the gold standard for typical carcinoids of the GB. For pre-invasive and early-detected cancer (T1s and T1), simple cholecystectomy is probably an adequate therapy. For advanced lesions, a more aggressive radical surgery, including radical cholecystectomy and regional lymphadenectomy combined with a hepatic resection in order to obtain adequate free margins, is needed [1
]. Additional therapies in an adjuvant setting are not required for typical carcinoids according to the low metastatic potential of the neoplasia as well as to the general insensitivity to traditional radiotherapy and chemotherapy in low-grade cancer disease.
For many years, sieric CgA and urinary 5-HIAA, each of which has a specificity of nearly 100% but a low sensitivity, have been the gold standard for detecting carcinoids and conducting follow-up [23
In-pentetreotide has a high affinity for somatostatin subtype 2 and 5 receptors, which are present on the cell membranes of carcinoid tumor cells, making 111
In-pentetreotide scintigraphy a good technique for imaging carcinoid tumors [24
]. Standard bone scintigraphy has a higher sensitivity for the detection of bone metastases in patients with carcinoid tumors [25
]. Post-operative specific tumor markers, total body CT, 111
In-pentetreotide scintigraphy, and bone scintigraphy tests in our patient were all normal, indicating the lack of metastases and the successful surgical treatment of a "typical" carcinoid of the GB. Indeed, in one study, 82.4% of GB carcinoids remained localized and only 11.8% of patients demonstrated distant metastases [3
]. The same source reported a five-year survival of 60.8% ± 14.8%. Modlin and colleagues [1
] reported a median survival of 9.8 months among 278 cases of GB NETs reported in SEER. The five-year survival rates for tumors classified as carcinoids-neuroendocrine carcinoma or small-cell cancer were 36.9% and 0%, respectively [1