-guided fine-needle aspiration diagnosis of large cell neuroendocrine carcinoma of the gallbladder
and common bile duct
: Report of a case --- Cytopathologic findings on a 67-year-old woman who presented with progressive
abdominal pain and jaundice was reported. EUS-FNA of the mass involving the common bile duct
and of a porta hepatis lymph node showed abundant cellularity with tumor cells arranged singly and occasionally in tight and loose clusters and rosette-like structures in a background showing extensive necrotic debris. The tumor cells were predominantly plasmacytoid, showed a moderate amount of focally vacuolated cytoplasm and large round to oval hyperchromatic nuclei with prominent nucleoli, numerous mitoses, and apoptotic bodies. The differential diagnosis included poorly differentiated
adenocarcinoma, lymphoma, melanoma
, and poorly differentiated
neuroendocrine carcinoma (NEC
), large cell type. The tumor cells were strongly and diffusely positive for cytokeratin AE1/AE3, CD56
, and chromogranin and showed a very high proliferative fraction on Ki67 staining, supporting the diagnosis of a high-grade NEC
. Due to the large size of the neoplastic cells, moderate amounts of cytoplasm and prominent nucleoli, a diagnosis of LCNEC
was made on the EUS-FNA sample.
Anti-Leu 7 monoclonal antibody
, which allegedly detects mononuclear cells with natural killer or killer activity, recognized lymphoid cells among intestinal epithelial cells and in the germinal centres of solitary lymphoid follicles of small and large intestine, and a few in gallbladder
and the lamina propria of the intestine. In addition, peripheral nerve fibres, endocrine cells in the gut and pancreas and carcinoid and islet cell tumours were also positively stained. At the ultrastructural level, Leu 7 antigen was localized on the plasma membrane of granulated lymphoid cells in the gut mucosa and on the secretory granules of intestinal endocrine cells. In normal pancreas, Leu 7 immunoreactivity was demonstrated in most cells containing pancreatic
polypeptide and in many cells containing somatostatin or glicentin. Insulin-containing cells, however, lacked Leu 7 immunoreactant. These findings were obtained in both frozen sections and paraffin-embedded sections. The possible cross-reactivities of monoclonal antibodies are raised as an important caveat in immunohistochemical studies using these antibodies.
Eligible patients had the following substantial daily symptoms: for patients with carcinoid tumors, three or more stools and/or 1.5 or more flushing episodes; for patients with gastrinoma
, greater than 50% elevated basic acid output; and for patients with vasoactive intestinal peptide-secreting tumors (VIPomas), four or more stools and/or a stool volume of >/= 800 mL, a measurable tumor, and an elevated biochemical tumor marker (>/= two times the upper limit of the normal reference range). Lanreotide
PR was administered intramuscularly every 14 days at 30 mg for 6 months. We measured efficacy
by studying symptoms, tumor markers, tumor size
, and QOL
. Side effects were scored according to the National Cancer Institute's toxicity grading system and ultrasound
examination of the gallbladder
. Fifty-five patients were included in the study (48 patients with carcinoid tumors, six patients with gastrinoma
, and one patient with VIPoma). Symptomatic improvement (> 50% reduction) occurred in 38% of the assessable patients with carcinoid tumors, in 67% of the gastrinoma
patients, and in the VIPoma patient. Tumor markers normalized in two of 45 assessable patients, 19 patients exhibited a reduction (> 50%), 19 patients exhibited no change, and tumor markers rose by more than 50% in five patients. Tumor size
was reduced in two of 31 assessable patients and remained stable in 25 patients; four patients experienced progression
assessments after 1 month showed improvements in emotional and cognitive function, and diminished fatigue, sleeping disorders, and diarrhea. Eight of 30 assessable patients developed gallstones.
A 46-year-old woman was hospitalized with a preoperative diagnosis of gallbladder
carcinoma, The patient was referred for surgical opinion and laparotomy was subsequently performed. A 4 x 5 cm mass was found within the gallbladder
, located on the free surface of the body and fundus of the gallbladder
. Neither metastases nor direct invasion to the liver
was found. The entire mass and gallbladder
were excised and intact. Histologically, the tumor consisted of small oval cells with round-to-oval neclei and tumor cells formed small nodular, trabeculare and acinar structures. The tumor showed moderate pleomorphism with scattered mitotic figures, but no definite evidence of vascular permeation, perineural invasion or lymphatic permeation was seen. The tumor cells invaded the mucosa extensively, and some penetrated the muscular layer but not through the serosa of the gallbladder
into the liver
. Immunohistochemical studies revealed strong positive reaction for chromogranin A and NSE
. This lesion was proved to be a primary carcinoid tumor of the gallbladder
. A brief review of literature, clinical feature, pathology and treatment of this rare disease was discussed.
Background and Aims: Almost all gastrointestinal
neuroendocrine tumors (NETs) (pancreatic
endocrine tumor/carcinoids) over express somatostatin receptors and this is now widely used to localize these tumors using radiolabeled somatostatin analogues such as 111In-labeled pentetreotide combined with single photon emission computed tomographic (SPECT
) scanning (i.e. somatostatin receptor scintigraphy
Methods: Briefly review results of our prospective
studies and others assessing its benefits and shortcomings.
Setting: Almost all studies were in large referral centers.
Participants: Patients referred for treatment of neuroendocrine tumors to referral centers comprising from 15–450 patients in different reports.
Intervention: After intravenous injection of 111In pentetreotide (usually 6 mCi) both spot views and SPECT
images were taken.
Results: Advantages: In most studies SRS has a greater sensitivity than conventional imaging
, computed tomographic scans, angiography) for detection both the primary lesion and metastatic
lesions in patients with NETs. In prospective
studies on patients with gastrinomas, Octreoscan
localized 60% of all the primary tumors and had sensitivity equal to that seen with all the above conventional imaging
studies combined. For metastatic
identified 92% of the patients proven to have liver metastases
and had higher sensitivity than any conventional imaging
study. Studies with other pancreatic
endocrine tumors (except insulinomas) and carcinoids demonstrate SRS will localize more primary and metastatic
lesions than conventional imaging
studies for detecting bone metastases
or other distal metastases from NETs show that SRS is more sensitive that conventional imaging
studies (listed above, bone scanning). SRS has the added advantage of allowing in one session rapid scanning of the entire body. SRS allows the identification of patients with advanced metastatic
disease who might be candidates for either treatment with unlabeled somatostatin analogues to control symptoms due to ectopic hormone
/bioamine secretion or for peptide receptor
studies demonstrate that the inclusion of SRS in the workup of a patient with a neuroendocrine tumor will alter the management in 12–47% of patients. Limitations. To obtain adequate sensitivity SPECT imaging
must be performed and may not be available except at a referral center. SRS will miss small lesions (50% <0.5–1 cm) and thus may not identify small primaries or metastatic
deposits. SRS has limited ability to resolve closely adjacent lesions (such as a duodenal tumor and adjacent lymph node) and thus may show these as single lesions underestimating the true number which could affect the surgical or medical approach to treatments. SRS alone does not allow exact placement of the lesions with a given tissue only regional placement. This limitation may be overcome with the increased use of combined MRI
with SRS, however only a regional referral center may have such an instrument. SRS generally has a high specificity, however, it can give false positive results (infections, thyroid disease, gallbladder
uptake, ectopic spleen uptake, inflammatory diseases, other tumors such as central nervous system tumors, breast
disease, granulomatous diseases). In one prospective
study 12% of all Octreoscan
results demonstrated a false positive response, however by carefully evaluating the clinical context only 3% were possibly clinically misleading.
Conclusions: Because of its increased sensitivity, generally excellent specificity and ability to image the entire body at one session, the results of a large number of studies support the conclusion
that SRS is now the imaging
study of choice to initially assess NETs primary location and tumor extent. It is important to remember that false positives can occur and they must be evaluated within the disease context and that small lesions or insulinomas are frequently missed so there is a place for even more sensitive imaging
modalities in the future.
Found 2 matching records related to the same work.
Despite greater sensitivity than conventional imaging
modalities for localizing NET primaries or metastases, a few cautionary points should be made about the general use of SRS. First, to achieve excellent sensitivity with NETs with SRS, SPECT
(single photon emission computed tomography) is essential.(25, 39, 46) For example, in one recent study(39) of 145 patients with various NETs, SPECT imaging
identified malignant lesions in 60/65 (92%) of those with liver metastases
, whereas planar imaging
identified malignant lesions in only 38/65 (58%) of the patients with metastases. SPECT imaging
only, identified liver metastases
in 13 patients.(39) Second, SRS detection appears to be affected by the size of the NET and therefore frequently misses small (i.e., 2 cm were localized by SRS, but only 30% of those post operative sites >renal
parapelvic cysts >procedural aspects of the SRS (Table 2). Sixty-two percent of the false-positive localizations were extra-abdominal and included in relative frequency: thyroid disease >granulomatous disease of the lung
diseases >other causes (arthritis, abscess, heart disease, carotid tumor). This study(45) demonstrates that overall SRS has a false-positive rate for NETs of 12%, a high specificity of 86%, and that if the clinical context of the SRS is appropriately considered, only 2.7% (13/480) of all SRS’s resulted in a change in management because of the false-positive response. This study(45) therefore demonstrates SRS has a high specificity. Other studies(36, 39) report a specificity of 53–100% for SRS in various NETs. Despite its high specificity, the study by Gibril at al.(45) has important implications for the proposed use of SRS in diagnosis of NETs.(50) It was recently proposed50 that because PETs, in contrast to pancreatic
adenocarcinomas, have a high density of somatostatin receptors, SRS could be useful for the diagnosis of a PET
. The above study of specificity45 demonstrates false-positive localizations are not rare with SRS. Furthermore, up to 1.5% of normal individuals at autopsy have a small asymptomatic PET
detected. Therefore, SRS alone should not be used for diagnosis and any SRS result should be interpreted carefully only within the clinical context of other pertinent results.
In addition to the above prospective
study, occasional false-positive localizations have been reported with SRS and they are summarized in Table 2. An important point to remember is that many normal tissues as well as pathological changes not due to NETs can over express somatostatin receptors including activated lymphocytes, benign and malignant thyroid disease, other types of tumors and granulomatous diseases.(2,45) Therefore in most of these cases this non-NET uptake is not a true false positive, but false positive only from the perspective of not being an NET. In Figure 1 a number of examples of these false positive uptakes are shown in patients with an NET including uptake in the thyroid gland (Figure 1A), uptake in a dental abscess (Figure 1B), uptake by an accessory spleen (Figure 1C) and accumulation in the gallbladder
due to slow excretion (Figure 1D).(45) Each of these examples was determined to be a false positive by carefully evaluating the clinical context of the localization.45
The frequency of carcinoid tumors in unselected series of appendectomy specimens ranges from 0.2-0.9%;(4,5) but more recent data suggests that the overall trend is towards a decrease in prevalence. Inexplicably, the incidence is orders of magnitude higher than might be predicted given the small size of the organ. Although it is reported that appendiceal carcinoid occurs twice as often in women as in men, this observation may reflect the frequency of incidental appendectomy in gynecological and gallbladder
surgery. Nevertheless, the female to male ratio remains 2:1 even after a correction for this factor.(5) Appendiceal carcinoid tumor can occur at any age including in children, and the median age is in the fourth decade, younger than the reported median age for carcinoid tumors at other sites of the luminal gastrointestinal
The type of surgery depends on the localization, the size and the suspected malignancy of the tumor. Small, non-malignant, easily accessible tumors can be treated by local resection
(enucleation or “central” pancreatectomy). With a limited resection
of this type, pancreatic
parenchyma can be preserved, avoiding exocrine and endocrine pancreatic
insufficiency, while on the other hand the risk of a postoperative pancreatic
fistula is high. Localization of the tumor in the pancreatic
head or suspected malignancy may require larger, more typical resections, i.e. pancreaticoduodenectomy or left pancreatectomy.(63–65)
The possibility of effecting a surgical cure has to be weighed against the operative morbidity, mortality and potential long-term complications associated with pancreatic
surgery. In patients with NF-PETs as part of the MEN1
syndrome, especially with small lesions, surgical intervention remains controversial.(66,67)
Aggressive surgery with curative intent for locally advanced
NF-PETs may prolong survival (5-years survival up to 80%).(65, 68, 69) However, all available data are retrospective
analysis refer to a mixed functioning
tumor cohort. No data support debulking procedures in unresectable
, locally advanced
NF-PETs. Partial resection
of the primary is associated with a high risk of bleeding, tumors recur and there is no data supporting survival advantage in such circumstances.
Surgery in metastatic
NF-PETs should undertaken in patients with a low volume of liver metastases
, but life threatening or unbearable symptoms.(68,69) The 5-year survival of hepatic resection
in recent series ranges from 47% to 76%, which in comparison to a 30–40% 5-year survival in untreated patients.(70–72) However, the rate of tumor recurrence is high (up to 76%) and half occur within 2 years after resection
. Surgery should only be undertaken if at least 90% of the tumor mass can be removed successfully and this may be possible in only up to 10% of the patients.(70) The type of surgery depends on the location of the metastases and may range from enucleation of one or more metastases to segmental resections, hemi-hepatectomy or extended hemi-hepatectomy. Intraoperative US must be performed for detection of all liver metastases
. If feasible, the surgical procedure should include cholecystectomy to obviate later adverse events related to the use of somatostatin analogue or hepatic embolization therapy
(cholelithiasis or ischemic gallbladder
Somatostatin Analogues --
Although natural somatostatin-14 reduces symptoms in patients with the carcinoid syndrome
, its use is limited by its short half-life (~2.5 minutes). During the last two decades, synthetic somatostatin analogues (octapeptides) have been developed for clinical use. Octreotide
is the most commonly available drug; other analogues are lanreotide
The somatostatin analogues used in clinical practice (octreotide
) both bind to receptors sst-1 and sst-5 and, with lower affinity, to sst-3. They exert their cellular action through interaction with specific cell and transmembrane receptors belonging to the superfamily of G protein–coupled membrane receptors. They inhibit adenylate cyclase
activity, activate phosphotyrosine phosphatases (PTPs), and modulate mitogen-activated protein kinases (MAPKs).58 Receptor
subtypes 2 and 5 modulate K+ and Ca2+ fluxes in the cell. Activation of all these pathways results in inhibition of known growth factor
production and release as well as antiproliferative effects.(58) It is now known that different subtypes of somatostatin receptors form heterodimers (sst-1 and sst-5) and heterodimers with dopamine receptor
D2R. This cross-talk modulates the intracellular signal and gives a “fine tuning” of the mediated effects.(59) All five subtypes of somatostatin receptors are expressed in carcinoid tumors; they are expressed in various combinations, although some tumors express all five subtypes. The receptors are expressed not only on tumor cells but also in peritumoral veins.(60) Antiangiogenesis might be another antitumor mechanism of somatostatin analogues. Tachyphylaxis (reduced sensitivity) to somatostatin analogues may develop during long-term therapy
.58 Long-acting, slow-release formulations of octreotide
have been developed, and doses of 20 to 30 mg (Octreotide
or 90–120 mg Lanreotide
) given once a month (octreotide
) or every 2 weeks, control clinical symptoms and hormone
levels in 50% to 60% of patients with the carcinoid syndrome
.(61) The long-acting formulations of somatostatin analogues have clearly improved the quality of life of patients by reducing the number of injections and provide more stable control of clinical symptoms.(61) High-dose therapy
(12 mg/day) and octreotide
(3 mg/day) has generated an increased number of significant tumor reductions (12% versus 5% for the standard dose). Induction of apoptosis
has been reported during high-dose therapy
,(62) possibly mediated through activation of receptor
subtype 3. For patients at risk for carcinoid crisis
, somatostatin analogue therapy
is the treatment of choice. Patients usually experience severe flushing, diarrhea, abdominal pain, and hypotension. Continuous infusion with somatostatin analogues, 50 to 100 µg/hour, is recommended and usually alters the life-threatening condition. It is also recommended that patients be given subcutaneous somatostatin analogues before surgery or before other stressful situations. Side effects of somatostatin analogue therapy
have been of a low-grade variety, occurring in 20% to 40% of patients. These include pain at the injection site, gas formation, diarrhea, and abdominal cramping. Significant long-term side effects include gallstone formation, “sludge” in the gallbladder
, steatorrhea, deterioration of glucose tolerance, and hypocalcemia.61 The incidence of gallstones in patients treated over the long-term has varied from 5% to 70%, and the incidence of symptomatic gallstones requiring surgical treatment is less than 10%.
Found 2 matching records related to the same work.
Another means of tumor reduction is hepatic artery embolization, which not only improves the carcinoid syndrome
in about 50% of the patients but also reduces the tumor size
in as many. The therapeutic effect may last from 9 to 12 months, and the procedure can be repeated. Chemoembolization, simultaneous embolization with surgical gel (Gelfoam), and chemotherapy
(doxorubicin, mitomycin C, cisplatin, 5-fluorouracil
), or interferon has resulted in symptomatic improvement in a significant number of patients with the carcinoid syndrome
.(72) However, hepatic artery occlusion or embolization may result in serious side effects (nausea, vomiting, liver
pain, fever) and major complications (hepatorenal syndrome, sepsis, gallbladder
perforation, and intestinal necrosis). Complications are seen in 5% to 7% of patients.(73) Other cytoreductive treatments may include cryotherapy and radiofrequency ablation. However, this procedure is limited to patients with smaller tumor burden, tumors less than 3–5 cm in diameter, and a limited number of metastases.
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