Renal neuroendocrine tumors: clinical and molecular pathology with an emphasis on frequent association with ectopic Cushing syndrome

Abstract

Renal neuroendocrine tumors (RenNETs) are rare malignancies with largely unknown biology, hormone expression, and genetic abnormalities. This study aims to improve our understanding of the RenNETs with emphasis of functional, hormonal, and genetic features. Surgically resected RenNETs (N = 13) were retrieved, and immunohistochemistry and next-generation sequencing (NGS) were performed in all cases. In addition, all published RenNETs were systematically reviewed. Our cohort (4 men and 9 women, mean age 42, mean tumor size 7.6 cm) included 2 patients with Cushing syndrome (CS). WHO grade (23% G1, 54% G2, and 23% G3) and tumor progression did not correlate. CS-associated RenNETs (CS-RenNETs) showed a solid and eosinophilic histology and stained for ACTH, while the remaining non-functioning tumors had a trabecular pattern and expressed variably hormones somatostatin (91%), pancreatic polypeptide (63%), glucagon (54%), and serotonin (18%). The transcription factors ISL1 and SATB2 were expressed in all non-functioning, but not in CS-RenNETs. NGS revealed no pathogenic alterations or gene fusions. In the literature review (N = 194), 15 (8%) of the patients had hormonal syndromes, in which CS being the most frequent (7/15). Large tumor size and presence of metastasis were associated with shorter patients' survival (p < 0.01). RenNETs present as large tumors with metastases. CS-RenNETs differ through ACTH production and solid-eosinophilic histology from the non-functioning trabecular RenNETs that produce pancreas-related hormones and express ISL1 and SATB2. MEN1 or DAXX/ARTX abnormalities and fusion genes are not detected in RenNETs, indicating a distinct yet unknown molecular pathogenesis.

Keywords: Hormone; ISL1; Kidney; Neuroendocrine neoplasms; SATB2.

Fig. 1

Gross findings of two renal neuroendocrine tumors. A A nephrectomy specimen with a 7.5 cm large tumor extending from the middle part to upper pole of the kidney. The tumor is well demarcated and partly lobulated in shape, showing a red-brown to yellow–brown cut surface with partly septal fibrosis. B A partial nephrectomy specimen with a 6.2 cm large multilobulated tumor. A part of the tumor shows a cystic change. The cut surface is gray-whitish and focally yellowish in color

Fig. 2

Histological features of a non-functioning renal neuroendocrine tumor (A, B) and a Cushing syndrome-associated renal neuroendocrine tumor (C, D). A Cylinder-shaped tumor cells arrange in a single layer trabecula that branch and anastomose each other (hematoxylin and eosin staining) B and focally cytoplasmic PAS (periodic acid-Schiff) positivity in a non-functioning tumor. C Polygonal tumor cells with a wide eosinophilic cytoplasm grow in solid nests in a Cushing syndrome-associated tumor. D Tumor cells showing prominent nucleoli and occasionally intracytoplasmic eosinophilic inclusions (arrows)

Fig. 3

Immunohistochemical features of non-functioning (A, C, E) and Cushing syndrome-associated (B, D, F) renal neuroendocrine tumors. A Patchy expression of chromogranin A in a non-functioning renal NET and B diffuse and strong expression of chromogranin A in a Cushing-associated renal NET. C Diffuse somatostatin expression with heterogenous intensity in a non-functioning tumor. D Diffuse and strong ACTH expression in a Cushing syndrome-associated tumor. E Diffuse and strong nuclear expression of ISL1 in non-functioning tumor and F no expression of ISL1 in a Cushing syndrome-associated tumor