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Editorial |
The Barbara Davis Center for Childhood Diabetes, and the Department of Pathology, University of Colorado Health Science Center, Aurora, Colorado 80045; and the Department of Pathology, Children’s Hospital, Denver, Colorado 80202.
Address all correspondence and requests for reprints to: Dr. Roberto Gianani, The Barbara Davis Center for Childhood Diabetes and the Department of Pathology at the University of Colorado Health Science Center, 1775 N. Ursula Street, Aurora, Colorado 80045. E-mail: roberto.gianani{at}uchsc.edu.
Multiple endocrine neoplasia (MEN) syndromes are a group of genetic diseases characterized by proliferative lesions (hyperplasia, adenoma, and in some cases carcinoma) arising in several endocrine tissues (1). The endocrine tumors in MEN syndromes are not histologically different from their sporadic counterparts, but they are often multifocal and preceded by endocrine hyperplasia that in some cases is the only manifestation of the disease. The neoplastic glandular lesions can develop either at the same time (synchronously) or at different times (metachronously).
There are two major types of MEN (1): MEN-1, or Wermer syndrome, and MEN-2.
MEN-2 is subclassified in MEN-2A, or Sipple Syndrome characterized by parathyroid hyperplasia, pheochromocytomas, and C-cell hyperplasia or carcinoma (2), and MEN-2B, in which parathyroid hyperplasia is absent but multiple mucocutaneous ganglioneuromas can occur (3). A variant of MEN-2A, termed familiar medullary thyroid cancer, is distinguished by a strong predisposition for medullary cancer but the absence of the other features of the syndrome (4).
This editorial, accompanying the paper by Perren et al. (5) published in this issue, will focus on the genetic and molecular pathology of MEN-1 as well as the histological changes occurring in the pancreas of patients with this syndrome and their possible relevance to the ability of this organ to undergo islet remodeling.
MEN-1 consists of the association of pituitary, parathyroid, and pancreatic hyperplasia or neoplasia sometimes accompanied by gastroenteric endocrine tumors. More rarely, MEN-1 patients develop thymic carcinoids (which for unknown reasons occurs only in males) and lipomas or connective tissue tumors.
Clinically the most common presentation of MEN-1 is hyperparathyroidism usually due to hyperplasia rather than adenoma of the parathyroid glands (6). The second most common manifestation is neoplasia of the pancreatic islets that eventually occurs in 80% of the patients (7). These tumors are often multicentric, making surgical therapy particularly difficult, and can undergo malignant transformation and metastasize. In most of these tumors there is hyperplasia of multiple cell types even though the clinical manifestation are usually caused by hyperproduction of a single hormone. The most common islet tumor in MEN-1 is gastrinoma associated with the Zollingher-Ellison syndrome (8). Glucagonoma is a fairly rare tumor in this syndrome despite the frequent presence of numerous glucagon cells within other islet tumors (7).
MEN-1 is caused by a heritable germ-line mutation in the MENI gene located in the long arm of chromosome 11 (11q13) accompanied by a somatic deletion leading to loss of the wild-type allele (this process is generally termed loss of heterozygosity or LOH) (9). More rarely, the wild-type allele is inactivated by a somatic mutation resulting in loss of function. The loss of heterozygosity for chromosome 11q13 represents a necessary step for the development of endocrine neoplasms in the majority of MEN-1-related lesions. The MEN1 gene is a classical tumor suppressor gene in that its normal function in the cell prevents hyperplastic and/or neoplastic transformation, and this occurs only when both alleles are inactivated. The product of the MEN1 gene is a 610-amino-acid nuclear protein termed menin that regulates cell cycle and transcription (9, 10).
The exact role of menin in preventing tumorigenesis remains unknown, but a number of studies are beginning to elucidate the role of this molecule. Numerous proteins with roles in DNA cell cycle regulation, proliferation, and DNA damage repair interact with menin. The first menin-interacting protein is JunD, a transcription factor that is part of the activator protein 1 family (11). The activator protein-1 is a dimeric transcription factor formed by members of the Jun and Fos protein family that is important in the regulation of cell proliferation and differentiation. Another mechanism of menin tumor suppressor function is the activation of other tumor suppressor genes such as the cyclin-dependent kinase inhibitor p18INK4c (12). In a recent review, Dreijerink et al. (13) proposed that menin links transcriptional regulation and chromatin modification by binding to both transcription factors and chromatin modifying proteins. This hypothesis is supported by the observation that menin is a component of human histone methyltransferase, which can methylate the lysine 4 residue of histone H (13).
The study of Perren et al. (5) clearly defines the spectrum of histological and molecular lesions observed in the pancreata of subjects with MEN-1. The histological lesions in the MEN pancreata consist of macroadenomas (>5 mm) and microadenomas (multicentric and <5 mm). Microadenomas can be recognized histologically by their trabecular, gyriform, or solid architectural patterns with and without sclerosis. It is generally thought that in MEN-1 there is a progression from hyperplasia to adenomatous transformation (first micro- and then macroadenoma) and eventually, in some instances, frank carcinoma. This study shows that LOH is already present in clusters of endocrine cells (termed by the authors "monohormonal endocrine cell clusters") morphologically similar to normal islet tissue but identifiable by predominant or exclusive expression of one islet hormone (which, in the majority of cases, was glucagon). The implication of these findings is that menin LOH is a very early lesion, which per se does not cause adenomatous transformation (as defined by morphology) of the endocrine tissue. It is likely that the initial defect (i.e. LOH for the menin gene), possibly leading to proliferation of a single-cell type, is followed by additional events leading to adenoma formation. The other important conclusion of this study is that hyperplastic islets (defined by enlarged islets with an increased ratio of glucagon to insulin cells) do not show menin LOH, and, thus, islet hyperplasia is not likely to represent an obligatory step of the progression from normal tissue to neoplasm.
The pathogenesis of islet hyperplasia in MEN-1 is not known. It is possible, as suggested by the authors of the manuscript, that hyperplasia is a consequence of germ-line mutation (i.e. not requiring a second somatic menin mutation). An alternative hypothesis could be that the multicentric adenomatous lesions present in these pancreata secrete one or more factors that stimulate islet proliferation or neogenesis. Gastrin production is increased in approximately 60% of patients with MEN-1 even in the absence of clinical manifestation of hypergastrinemia (8). In humans there is increased islet ß-cell replication adjacent to intrapancreatic gastrinomas (14), and combination therapy with epidermal growth factor and gastrin induces neogenesis of human islet ß-cells from pancreatic duct cells (15). Thus, it is possible that gastrin production by pancreatic (or intestinal) tumors might at least in part be responsible for islet hyperplasia. The identification of factors promoting islet hyperplasia in MEN-1 might lead to the development of strategies to restore ß-cell mass in type 1 diabetic patients.
This study also shows that monohormonal endocrine cell clusters lesions and, thus, presumably also adenomatous lesions can derive from both islets and diffuse endocrine tissue associated with ducts. In contrast, a previous report by Vortmeyer et al. (16) suggested that islet tumors do not derive from pancreatic islet cells but from the pancreatic ductal/acinar compartment. In particular, Vortmeyer et al. speculated that islet tumors derive from pluripotent precursor cells that become committed to neoplastic proliferation after inactivation of the residual wild-type MEN allele by a somatic mutation. Further studies aimed at identifying the cells of origin of islet tumors may provide insights into the possible existence of pluripotent progenitor cells in both the islet and the ductal/acinar compartment.
Footnotes
Abbreviations: LOH, Loss of heterozygosity; MEN, multiple endocrine neoplasia.
Received January 15, 2007.
Accepted January 16, 2007.
References
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