Endocrine Tumors-Part 2

Abstract

The second of the 2 issues devoted to the new World Health Organization (WHO) Classification of Tumors of Endocrine Organs includes review articles discussing the WHO 2017 positions on the following topics: (1) tumors of the neuroendocrine tumors (NETs) of the pancreas, (2) tumors of the adrenal medulla and extra-adrenal paraganglia, and (3) inherited endocrine tumor syndromes. Two case reports, one on metastatic NETs to the breast and the second on an unusual metabolically active NET of the rectum, are also included. NEUROENDOCRINE TUMORS OF THE PANCREAS The review, written by Dr Kloppel, discusses the modifications included in the new 2017 WHO Classification. The pancreatic neuroendocrine neoplasms include well-differentiated nonneuroendocrine neoplasm, which are further divided into NET grades 1 through 3 (G1, G2, and G3). Well-differentiated NET G3 is the new category, composed of well-differentiated NETs with Ki67 index higher than 20%. Poorly differentiated neuroendocrine carcinoma (NEC) category remains unchanged. The term mixed neuroendocrine-nonneuroendocrine neoplasms is recommended instead of mixed adenoneuroendocrine carcinoma, because sometimes the neuroendocrine component is well differentiated—NET G1 or G2. In addition, recent advances in our knowledge of genetic alterations and genetic susceptibility for this category of tumors have been included in this edition and are summarized in Dr Kloppel’s review. These advances include the molecular genetics of pancreatic NETs (PanNETs). MEN1 gene is somatically inactivated in 45% of cases. DAXX and ATRX are also frequently altered in PanNETs, with 45% of cases having a mutation in 1 of these 2 genes. The genetic alterations in pancreatic NECs differ considerably from those in PanNETs; they include TP53, RB1, CDKN2A, which are somatically targeted in pancreatic NECs, whereas MEN1, ATRX, and DAXX are not. TUMORS OF THE ADRENAL MEDULLA AND EXTRA-ADRENAL PARAGANGLIA These tumors include pheochromocytoma, head and neck paraganglioma, sympathetic paraganglioma, neuroblastic tumors of the adrenal gland, composite pheochromocytoma, and composite paraganglioma. The state of knowledge regarding this group of tumors has been profoundly influenced by recent developments in the field of molecular genetics. In her review, Dr Kimura summarizes these new discoveries. In particular, genetic studies have furthered our understanding of the biology of pheochromocytoma and paraganglioma. At least 30% of these tumors are now known to be hereditary. Germline mutations in at least 19 hereditary susceptibility genes have been recently reported, and somatic mutations of some of these genes have been identified in sporadic tumors. Genotype-phenotype correlations determine tumor distribution, hormonal function, multiplicity, risk of metastasis, and syndromic associations. Mutations in genes encoding succinate dehydrogenase subunits—the SDH gene family—have been identified as the most common cause of hereditary pheochromocytoma and paraganglioma. Thus, the expanded genetic landscape presents new challenges and opportunities to both clinicians and pathologists. Pathologists should play an important role in identifying cases of potential hereditary disease. INHERITED ENDOCRINE TUMOR SYNDROMES Dr Mete has devoted his exhaustive and extremely well-organized review to the epidemiological, clinical, morphological, and genetic characteristics of inherited tumor syndromes that involve endocrine organs. These syndromes are varied and complex. The 2017 WHO Classification includes updates on our state of knowledge of the known syndromes; in addition, 3 new syndromes were added: multiple endocrine neoplasia (MEN) type 4, DICER1 syndrome, and glucagon cell hyperplasia and neoplasia. The review covers all these syndromes; in particular, MEN1, MEN2, hyperparathyroidism–jaw tumor syndrome and von Hippel-Lindau syndrome are discussed in detail. With the accumulation of our knowledge of genetic alterations in various syndromes, pathologists should be prepared not only to make a morphologic diagnosis but also to suggest and pursue genetic analyses in order to ensure the most appropriate pathological diagnosis and genetic workup for the patients. CONCLUSIONS As guest editors for issues devoted to Tumors of Endocrine Organs Part 1 and Part 2, we hope these reviews corresponding to specific chapters in WHO Classification 2017 will enable surgical pathologists and other medical professionals to better understand the disease processes, diagnosis, prognosis, and treatment of neuroendocrine neoplasms.