New Pathological Insights into Biomarkers for Multimodal Therapeutic Approach in Hepatic Neuroendocrine Tumors: A Detailed Case Report

Discussion

NET is a rare form of cancer, occurring in approximately 8 out of every 100,000 individuals (2). Originating from enterochromaffin cells, these tumors can manifest throughout the body (16). NETs can be categorized as functional or nonfunctional based on the presence of clinical symptoms. Known as carcinoid syndrome, these symptoms often present nonspecifically, such as cough, flushing, and chronic diarrhea, leading to occasional misdiagnoses (1-3, 7, 17). The symptoms are attributed to the tumor’s secreted enzymes, resulting in diverse nomenclature such as insulinoma, glucagonoma, somatostatinoma, vasoactive intestinal peptide-secreting tumor, and other names (1, 3, 4, 11, 17, 18).

Diagnosis of NETs is frequently delayed, with an estimated time to diagnosis of around 5 years since the primary tumor’s development (4). Over the years, the World Health Organization (WHO) has evolved its classification system based on biological behavior, Ki-67 index, and tumor size. In 1980, carcinoid was used for all related tumors. In 2000, WHO classified these into three groups, while in 2010, they became classified into grades 1, 2 and 3 (10).

For tumor detection and evaluation, the metabolite of serotonin, 5-hydroxyindole acetic acid, can be identified through 24-h urine collection. Chromogranin A stands out as the most reliable biomarker for diagnosing NETs (4, 12, 18, 19).

Our patient underwent octreotide treatment for over a year before surgery. Octreotide, a somatostatin analog, targets somatostatin receptor subtypes 2 and 5 (17). Apart from its direct tumor effect, octreotide effectively controls symptoms and also contributes to a significant increase in median overall survival compared to no use (112 vs. 53 months) (19).

Tetra-azacyclododecane-1,4,7,10-tetraacetic acid (DOTATOC), a gallium-68-labeled somatostatin analog, is used in positron-emission tomography–computed tomography. Tumors with prominent DOTATOC scan images, indicative of dominant somatostatin receptor expression, generally exhibit lower pathological grading and may be suitable for treatment with somatostatin analog (16, 20, 21).

Peptide receptor radionuclide therapy is a highly targeted and effective form of radiopharmaceutical therapy, with a reported hazard ratio of 0.18 for progression-free survival compared to 60 mg octreotide (16, 21). Despite the potential benefits, our patient did not undergo DOTATOC scan or peptide receptor radionuclide therapy treatment due to associated high costs and limited accessibility in Taiwan.

In terms of surgical intervention, adhering to updated guidelines, treatment for liver tumors encompasses hepatic resection, ablation, and hepatic artery embolization (1, 3, 11). In our case, through a combination of various surgical procedures, multiple tumors were effectively removed.

According to our pathological report, immunohistochemical staining of the major liver specimen from the left lobe (S2 and S3) revealed low expression of CDK5 and p35 (the activator of CDK5), along with weak staining for chromogranin A but strong staining for synaptophysin. In addition, the major tumor exhibited significant necrosis (Figure 3A). On the other hand, the small liver specimen from the right lobe (S7) showed low CDK5 expression, high p35 expression, and strong synaptophysin staining (Figure 3B, Table I).

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Figure 3.

Immunohistochemical staining of liver tumors for cyclin-dependent kinase 5 (CDK5) and its activator p35. A: Main tumor of the left lobe S2, S3. B: Small tumor of the right lobe, S7. The tumors in A (main tumor) showed weaker staining of CDK5 and its activator p35 than that shown in B but staining for chromogranin A and synaptophysin was similar.

For NETs with positive staining of chromogranin A immunohistochemically, the expression of chromogranin A correlated not only with tumor progression but also with treatment effect (1). CDKs, a family of proteins regulated by cyclins and phosphorylation, participate in cell-cycle regulation. CDK5, activated by p35 protein, has been demonstrated to have a role in neurodegeneration, as well as endocrine and cancer biology (7-9, 14, 15). CDK5 and p35 are known to influence nerve and muscle development; however, accumulating evidence suggests their role in tumor growth (7-9, 14, 15). To our knowledge, primary NETs in the liver have been reported (12), as have intrahepatic metastases (5, 6, 11-13).

We hypothesized that the lesion originated in the left lobe and subsequently metastasized to the right lobe of the liver. The lesions in the right lobe appeared to be newer, possibly resistant to treatment. The reduced CDK5 expression in the left lobe might be attributed to tumor necrosis from previous octreotide treatments, while the lower expression in the right lobe might be due to these being newly developed lesions. Conversely, the higher expression of p35 in the right lobe compared to the left suggests new lesion development in the right lobe but necrosis in the major tumor in the left lobe.

Activation of CDK5 requires its activator, p35, for tumor development. In our unpublished data, we observed an increase in cell count in NET cell lines transfected with CDK5 and p35 proteins. In the case presented here, our findings suggest that CDK5 and p35 may be crucial for the development of NETs and might potentially serve as therapeutic targets.

Our presented case continues to take mechanistic target of rapamycin kinase inhibitor everolimus (10 mg daily) plus somatostatin analog octreotide (30 mg every 28 days) for disease control, maintaining a stable disease condition. Our final diagnosis for the patient is primary hepatic NET with intrahepatic metastases, and to our knowledge we are the first to report such an extremely rare case, adding to the knowledge already provided by others (6, 12, 13, 19). We will monitor his clinical presentation with functional and non-functional imaging studies (5, 11, 17, 20, 21).