So far 24 cases of ITPN arising in the pancreas and 13 cases arising in the bile duct have been reported [1, 4–12]. All these cases showed the characteristic ITPN morphology with tubulopapillary growth pattern, absence of acinar differentiation and no detectable secreted mucin. All these features were also detectable in the case presented here but unlike the other ITPN cases, this tumor here consisted of tumor cells with abundant clear cytoplasm that has to the best of our knowledge, not been reported in the literature so far. Intraductal papillary mucinous neoplasm (IPMN), pancreatic intraepithelial neoplasia (PanIN), mucinous cystic neoplasm of the pancreas (MCN), acinar cell carcinoma, solid-pseudopapillary neoplasm (SPN) and tumor metastasis of renal cell carcinoma (RCC) were considered as possible differential diagnosis. In our eyes the most difficult discrimination lies between ITPN and IPMN pancreatobiliary type (PB type) [1, 13, 14]. However, MUC5AC expression, which was not detectable in our case, is considered to be a hallmark for IPMN (Table 1) . Mutational analyses in IPMNs and intraductal carcinoma revealed also a very high frequency (up to 80%) of KRAS and GNAS (up to 60%) mutations [1, 2, 5]. Since in our tumor we detected wild-type sequences for KRAS, GNAS, β-catenin, BRAF this favors ITPN .
Acinar cell carcinoma, also a potential differential diagnosis, was not considered since neither did the tumor cells stain with PAS nor were immunohistochemical markers of pancreatic exocrine enzymes like trypsin and chymotrypsin observable. As well, PanIN was disregarded due to the size of the lesion and the lack of small epithelial papillae . In SPN a combination of solid and pseudopapillary growth pattern is frequently present but these tumors are usually immunoreactive for CD10, vimentin, chromogranin A and nuclear β-catenin [16, 17]. Although a clear cell variant and a chromogranin A negative SPN has already been reported, our case did not show nuclear β-catenin nor vimentin expression, therefore ruling out SPN [16, 18]. MCN is not connected to the pancreatic duct system and contains epithelium (in rare cases squamous epithelium), surrounded by an ovarian-like stroma that stains positive for progesterone receptor, inhibin, CEA, and chromogranin A . Moreover, the epithelial component of MCN is positive for MUC5AC and negative for MUC1 and MUC2, obviously in difference to our results [2, 20]. Metastasis of an extrapancreatic primary clear cell tumor, particularly renal RCC was seriously considered especially since CD10 expression was expressed focally and with faint intensity, however no invasiveness and the absence of vimentin positivity argues against pancreatic metastases of RCC. In addition, the profile of expressed mucins, several tumor free MRI scans of the kidneys and the uneventful clinical follow-up for now over two years rule out RCC metastases .
The molecular basis of clear cell morphology in the presented tumor is unknown and only a few studies discussed genesis of clear cell morphology. So far, the best studied tumor in this context is clear cell RCC and hypoxia regulatory factors have been identified as driving force for the clear cell phenotype . HIF-1α, carbonic anhydrase IX, and GLUT1 have been described as markers for the hypoxia-inducible factor pathway . In the current case we were able to detect a strong staining against carbonic anhydrase IX (FLT4 or GLUT1 were negative) arguing that the clear cell phenomenon in our case might also be associated with hypoxia. However, we cannot rule out that carbonic anhydrase IX, which can also been seen in normal stomach, liver and gallbladder may simply represent a differentiation towards the pyloropancreatic pathway of intraductal papillary neoplasms. Basturk and colleagues claimed that the tubular/tubulopapillary pathway of ITPN forms a subgroup within the pyloropancreatic pathway .
In conclusion, we consider this tumor as ITPN with very unusual clear cell morphology. Recognition of similar tumor cases and clinico-pathological correlations are needed to illuminate the clinical relevance of this obviously rare ITPN subgroup.
Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.