To date, the presence of a gNEN in a patient with VHL has, to the best of our knowledge, only been described in a recent report by Kawaguchi et al., where a 45-year-old VHL patient presented with multiple gastric polyps, histologically diagnosed as NENs grade 2. Histologically, tumor cells were described with a circular nucleus and abundant foamy or granular cytoplasm. However, in this case, no atrophy of the gastric mucosa was observed, APCA antibodies were negative, while gastrin levels were slightly elevated, it not being clear whether this increase was due to PPI treatment. Interestingly, in the above publication, the discontinuation of PPI treatment resulted in a pronounced regression of these gNENs. Thus, the authors attributed the gNEN development to the chronic ECL stimulation from increased gastrin levels due to the PPI administration [11].

To further elucidate the presence of clear cells in NENs in VHL patients, a literature search with the keywords “von hippel lindau,” “neuroendocrine tumor,” and “clear cell” (von hippel[Author] AND ("lindau"[All Fields] OR "lindau s"[All Fields]) AND ("neuroendocrine tumor"[All Fields] OR "neuroendocrine tumors"[MeSH Terms] OR ("neuroendocrine"[All Fields] AND "tumors"[All Fields]) OR "neuroendocrine tumors"[All Fields] OR ("neuroendocrine"[All Fields] AND "tumor"[All Fields]) OR "neuroendocrine tumor"[All Fields]) AND ("clear"[All Fields] OR "cleared"[All Fields] OR "clearing"[All Fields] OR "clearings"[All Fields] OR "clears"[All Fields]) AND ("cells"[MeSH Terms] OR "cells"[All Fields] OR "cell"[All Fields]) was performed. Only four articles could be retrieved following the search, out of which two had to be excluded due to irrelevant content. From the citations of one publication, two further articles could be included in the analysis.

Specifically, Woo et al. described the case of a 47-year-old VHL patient presenting with a pancreatic lesion and two concomitant renal lesions. While the renal lesions were diagnosed as a clear cell and a cystic renal cell carcinoma, respectively, the pancreatic lesion was a well-circumscribed yellow solid mass, entirely consisting of clear cells. Although the initial assumption was that this lesion was a metastasis from the renal carcinoma, immunohistochemical analysis positive for the neuroendocrine markers and vimentin, classified the pancreatic lesion as a clear cell pancreatic neuroendocrine tumor [12]. Hoang et al. reported on five cases of clear cell panNENs in VHL patients, all of which presented histologically with a component of clear cells arranged in nests. Here again, two of the tumors were initially confused with metastatic renal cell carcinoma [13]. Similarly, Sinkre et al. described the case of a 38-year-old man with VHL disease, presenting with a carcinoid tumor of the gallbladder with lipid-containing clear cells, also initially interpreted as renal cell carcinoma, although it was positive for CgA, synaptophysin, cytoceratins, and inhibin [14]. Finally, Gucer et al. reported on a 60-year-old woman with known VHL and pancreatic lesions, positive on somatostatin receptor scintigraphy (OctreoScan), who underwent Whipple resection. Histologically, the resected pancreatic lesions were identified as multiple grade 2 NENs with variable clear cell change. In parallel, an incidental tubular adenoma with low-grade dysplasia was found in the ampulla and, adjacent to this lesion, an epithelial neoplasm in the duodenal ampullary mucosa was identified. This lesion consisted of epithelial cells resembling lipoblasts or signet ring cells, positive for inhibin [15].

In line with the previously reported cases, the gNENs identified in our patient were also composed of neoplastic cells with clear cytoplasm (clear cells), usually seen in tumors related to VHL disease [16]. The clear cell genotype–phenotype correlation has been observed in VHL disease and in VHL-associated tumors. The clear cell phenotype has been attributed to the activation of HIF1a resulting in a status of pseudohypoxia and, consequently, in lipid and glycogen accumulation within the tumor cells.

Interplay of neoplastic and autoimmune processes has recently been reported [17]. Despite the fact that these processes were initially thought to have opposite immunological properties, it has been proposed that cancer progresses from a proinflammatory state to an anti-inflammatory one, whereas an autoimmune disease can ab initio be characterized a proinflammatory state [17]. The mechanism that leads to their combined presence is based on a temporal change of immune response during the course of cancer development. Consequently, the present case illustrates that the histological finding of the change of clear cells may be dependent on the genetic background of VHL, while the real oncogenic stimulus can be more closely related to CAG than to the VHL disease. Therefore, it appears important to perform further clinical, biochemical, and imaging screening in patients presenting with clear cell NENs before excluding VHL disease [16].

The coexistence of autoimmune diseases in the context of neoplasmatic disease has been described as paraneoplastic syndrome; inversely, neoplasmatic disease has also been described in the context of immunosuppressive treatment. Moreover, it has been suggested that the proinflammatory environment of autoimmune traits may support both initiation and growth of early malignancy; hence, the low-grade inflammation of the autoimmune disease may prolong survival in a neoplasm with a low-malignant potential as opposed to more aggressive neoplasms that are early on characterized by increased immunological evasion [17]. Although a similar interplay between neoplastic and autoimmune processes can be hypothesized in this case report, a clear link between clear cell NENs and autoimmunity against a VHL background cannot easily be substantiated, as such cases are quite rare. A previous study of a case of VHL disease and another autoimmune disease, myasthenia gravis, investigated the role of the HIF-1α pathway and hypoxia in inflammatory response, underlining the need for further insight into the clinical, genetic, and molecular overlap of neoplasia and autoimmunity [18]. Thus, the establishment of an international multicenter registry for such patients would enable further observations and clinical, genetic, molecular, and histological correlations to corroborate this initial finding.

In conclusion, the current case illustrates that histopathological features should be considered and investigated separately, since more than one pathogenetic mechanism may crisscross within the same patient, also affecting the patient’s prognosis.