Three hundred sixty-one pancreatic neoplasms originally classified as PanNETs were reviewed. Of these, 24 were noted to have hyaline globules. Due to the known association between hyaline globules and SPNs, immunolabeling with synaptophysin and β-catenin was performed to confirm whether all 24 cases were truly PanNETs or in fact solid SPNs misclassified as PanNETs (, ). In 18 of the 24 cases, nuclear labeling for β-catenin was absent (not shown), and synaptophysin was positive (diffusely in 17 cases, focally in 1 case), confirming these neoplasms as true PanNETs (). In 6 of the 24 cases, there was nuclear labeling for β-catenin and cytoplasmic CD10 positivity (not shown), and these neoplasms were re-classified as SPNs (). Synaptophysin immunoreactivity was present in 5 of 6 SPNs and was typically focal (not shown). Therefore, a total of 18 (5%) of 355 histologically confirmed PanNETs in this series contained hyaline globules.
Figure 1 This pancreatic neuroendocrine tumor (PanNET) demonstrates abundant hyaline globules of varying size (A). The neoplastic cells are strongly immunoreactive with antibodies to synaptophysin (B). Solid-pseudopapillary neoplasm (SPN) displays characteristic (more ...)
The mean age in years (±SD) for the total number of cases with hyaline globules (n=24), as well as the confirmed PanNETs (n=18) and reclassified SPNs (n=6) was 54.1 (±13.4), 56 (±12.4), and 48.3 (±14.7), respectively (PanNETs vs. SPNs, P = 0.2312). There was no difference in patient gender (PanNETs: 55.6% male vs. SPNs: 50% male, P = 1.000). In 5 (27.8%) of the 18 confirmed PanNETs, the neoplasm was clinically functioning. Three of these were insulin secreting, while two were glucagon secreting. Two (11.1%) of the 18 confirmed PanNETs arose in patients with multiple endocrine neoplasia 1 (MEN 1).
The mean tumor size in cm (±SD) for confirmed PanNETs was 4.7 (±2.9). For the reclassified SPNs, it was 6.3 (±6.0) (PanNETs vs. SPNs, P = 0.3720). The body and tail were most frequently involved in confirmed PanNETs (72.1%), while the body and head were the most common sites of the reclassified SPNs (33.3% each). Tumors were predominantly unifocal (88.9% PanNETs vs. 100% SPNs, P =1.000). Both the confirmed PanNETs and reclassified SPNs were most frequently solid (72.2% and 50%, respectively), though they occasionally showed pure cystic or a combination of solid and cystic growth. A statistical comparison of the location distribution, focality, and type of growth in PanNETs vs. SPNs was precluded due to the small sample size.
The hyaline globules in the 24 cases ranged dramatically in size, and were both intracytoplasmic and extracellular (). They did not show any unique distribution within the tumor. In both PanNETs and SPNs, they were frequently focal, and therefore no significant differences in their prevalence in PanNETs vs. SPNs were readily recognized. In all tested cases, they were PAS-positive (, ), diastase resistant. Hyaline globules in 12 (80%) of the 15 tested confirmed PanNETs, as well as 6 (100%) of the 6 tested reclassified SPNs had globules immunoreactive with alpha-1-antitrypsin (, ). In one PanNET, the globules were positive for trypsin (not shown).
The hyaline globules of pancreatic neuroendocrine tumor (PanNET) are PAS-positive (A). In most cases, these hyaline globules immunolabel with alpha-1-antitrypsin (B).
The 24 cases with hyaline globules were histologically re-evaluated to assess whether any features aside from CD10 and nuclear β-catenin labeling could help distinguish PanNETs with hyaline globules from SPNs. All 24 cases were histologically examined for the pattern of invasion, and presence or absence of the following features: microcystic change, hemorrhage, cholesterol clefts, clear cells, foam cells, nuclear grooves, and foci of discohesion within the tumor (, ). Clear cells, characterized by clear cytoplasm and an eccentric nucleus, were one feature more commonly seen in SPNs (, 100% SPNs vs. 27.8% PanNETs, P = 0.0034). An additional feature frequently observed in SPNs was an insidious pattern of invasion (). In this pattern, the neoplastic cells subtly penetrate around and entrap normal pancreatic elements. Insidious invasion was noted in 83.3% of the SPNs and in only 11.1% of the PanNETs (P = 0.0027). Although rare and focal, longitudinal nuclear grooves were more often present in SPNs than PanNETs, while the nuclei of PanNETs more commonly were round with speckled chromatin and lacked grooves (, 50% SPNs vs. 0% PanNETs, P = 0.0099). Foci of discohesive, single cells were only rarely present in either neoplasm (), but surprisingly were not statistically more frequent in SPNs (33.3% SPNs vs. 5.6% PanNETs, P = 0.1433). Other features such as foam cells (), hyalinization (), cholesterol clefting (), microcystic change (not shown), and hemorrhage (not shown) were compared, but showed no statistically significant differences between SPNs and PanNETs (). Of the 6 SPNs, 4 were purely solid, with no pseudopapillary or pseudoglandular features, while 2 were predominantly solid with only a small focus of discohesion imparting a pseudopapillary appearance.
Figure 3 Comparison of the microscopic features of pancreatic neuroendocrine tumor (PanNET) and solid-pseudopapillary neoplasm (SPN) reveals similarities and differences between the two lesions. Three morphologic features can distinguish PanNET from SPN. Clear (more ...)
The PanNETs were assigned a WHO grade of 1, 2, or 3 on the basis of the Ki-67 immunolabeling index3,43
. The Ki-67 labeling indices of the SPNs were similarly grouped for the purposes of comparison. Fifty percent of confirmed PanNETs vs. 66.7% of reclassified SPNs were grade 1, 50% of PanNETs vs. 33.3 % of SPNs were grade 2, and 0% of either PanNETs or SPNs were grade 3. Using American Joint Committee on Cancer (AJCC) staging criteria6
, the primary tumor in cases of confirmed PanNETs was T1 in 22.2%, T2 in 33.3%, and T3 in 44.5% of cases. In cases of reclassified SPNs, the primary tumor was T2 in 100% of cases. Five (27.8%) of 18 PanNETs showed nodal metastases at the time of diagnosis, while 3 (16.7%) of 18 PanNETs had distant metastases. In contrast, none of the SPNs demonstrated nodal or distant metastases at the time of initial diagnosis. A statistical comparison of these parameters in PanNETs vs. SPNs could not be performed due to the small sample size.
The mean follow-up time in years (±SD) for the confirmed PanNETs was 5.7 (±5). For the re-classified SPNs, it was 10.2 (±3.3) (SPNs vs. PanNETs, P = 0.0532). Fifteen (83.3%) of 18 confirmed PanNETs and 5 (83.3%) of 6 reclassified SPNs were alive with disease over the duration of the follow-up period (SPNs vs. PanNETs, P = 1.000). Eight (44.4%) of the 18 PanNETs, and 0 (0%) of the 6 SPNs immunolabeled with CK19 (PanNETs vs. SPNs, P = 0.0664). Only patients in the PanNET group developed metastases subsequent to the time of initial diagnosis. One (5.6%) of the 18 PanNETs metastasized to lymph nodes, and 3 (16.7%) had a metastasis to the liver. The mean time (± SD) in years from the initial diagnosis to the metastasis was 3.2 (±2.4).