ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 10, No. 1 Copyright© 1980, Institute for Clinical Science, Inc. Endocrine Pancreatic Tumors: Ultrastructure MERY KOSTIANOVSKY, M.D. Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107 ABSTRACT Endocrine pancreatic tumors are frequently multicellular and produce several hormones and peptides. A review of the basic concepts of hormone secretion, pancreatic islet cell composition and ultrastructural make-up of tumors is presented. The importance of correlating ultrastructural, immuno- cytochemical and biochemical studies of these tumors is emphasized. Introduction Morphofunctional Aspects of Pancreatic Islets During the last few years a great amount of information was accumulated regarding At the present time four different types the mechanisms of synthesis, storage and of cells have been described in the pan­ release of hormones.14,28,31 The use of ex­ creatic islets,17,33 each having a specific perimental in vitro m odels21,25,26,28 was secretory product (table I). A variety of very helpful in clarifying the participation other cells possibly exists, although of different organelles in the biosynthesis, further identification is awaited. By light cellular “packaging” and emyocytosis of microscopy, it is not possible to distin­ the secretory products. In a review, Lacy31 guish one type of cell from the other. has proposed a working model for hor­ Histochemical procedures are of help, mone secretion, describing the sim­ however, and B cells are easily stained ilarities between different endocrine with aldehyde fuchsin. The dicferent pro­ glands. Some of this information was ob­ cedures and empiric nature oi the silver tained through the studies of endocrine stain22 added confusion in the nomen­ pancreatic tumors as in the case of the clature of the cells (as seen in table I) discovery of pro-insulin in a beta cell where the same cell has been described adenoma.62 The purpose of this paper is to by different names. illustrate the ultrastructural observations Immunofluorescent studies have dem­ of pancreatic tumors and to review the onstrated that B cells contain insulin. A literature. Attempts are made to correlate, cells contain glucagon and somatostatin wherever possible, the ultrastructural was localized in the D cells.57 Although, morphology of these tumors with normal some investigators20 found gastrin in the pancreatic islets cells and their possible D cells, this finding was not corroborated histogenesis. by others44 and the cell source of gastrin in 65 0091-7370/0100-0065 $01.80© Institute for Clinical Science, Inc. 66 KOSTIANOVSKY T A B L E I Normal Islet Cell Population Type of Cell & Secretory Frequency Electron Microscopy Topographic Product (Percent} Histochemistry Size Shape Localization B cells (B) Aldehyde 200 - 250 nm Insulin fuschsin + A cells (&2> 20 - 25 Argyrophilic 250 - 200 nm Glucagon reaction Grimelius + Argyrophilic 300 - 350 nm Somatostatin reaction Uellerström and Heilman Human pancreatic Not present Grimelius + 100 - 150 nm polypetide in every 4th type islet Acinar cells Ductal cells A fifth type of cell (D1) is omitted since the relation with V.I.P. is still in dispute. the pancreatic islets is not known. In addi­ a central homogenous cell population as tion, a fourth type of cell containing small composed of B cells, and a peripheral granules54 has been shown to store human zone of heterogenous cell population con­ pancreatic polypeptide, (HPP), a secre­ taining A, D and HPP cells or the fourth tory product whose physiological role has type of cells. These authors suggested that not yet been determined.1 this cellular distribution has functional Recently, a fifth type of cell (Dl) was implications. Since each cell produces a described, and there is some indication hormone which is influencing the which correlates this cell with the produc­ neighboring cells in related functions, it tion of vasoactive intestinal polypeptide was hypothesized that this action is local (VIP) or VIP-related molecule.60 In addi­ or “paracrine” in nature, without entering tion, cells similar to the enterochromaffin the general circulation.50 The finding of gastro-intestinal cells were rarely re­ junctional intercellular attachments of ported in human islets.6 Except for the B tight and gap type66 reinforced their and A cells, most of the cells described in hypothesis. the pancreatic islets are also present in the Intracellular Aspects of gastro-intestinal tract. This morphological the Secretory Process and functional overlap between gut endocrinology and pancreatic islets Hormonal synthesis occurs in the rough emphasizes the common embryological endoplasmic reticulum in the form of origin and probably functional inter­ pro-hormones (pro-insulin, pro-gluca- relationship. gon) and by an energy requiring mecha­ Unger et al63 have described a topo­ nism transferred to the Golgi-Complex. In graphic localization of the different cells the Golgi-Complex, the big molecules are in the pancreatic islets. Using immuno- split by an enzymatic mechanism and histochemical methods,50 Orci described converted to the mature hormone. A ENDOCRINE PANCREATIC TUMORS ULTRASTRUCTURE 6 7 membranous sac derived from the Golgi abundance of granules by electron mi­ Complex is added35 and the final product croscopy without evidence of hormonal is condensed in a visible form.25 From the secretion clinically. In vitro studies of Golgi Complex, the mature secretory insulinoma corroborated the assumption products are channeled to the periphery that these tumor cells have the capacity for of the cells where, with the participation a higher turnover of proinsulin and in­ of the microtubular-microfilamentous sulin compared to normal beta cells. system, secretion takes place. The secre­ Hence, insulinoma cells may display a tory mechanism occurs by fusing the decrease storage capacity.10 granule membrane with the plasma membrane of the cell in a process called The Histogenesis of the emiocytosis or exocytosis without loss Pancreatic Islet Cell Tumors of granular membrane (figure 1). The understanding of the secretory The histogenesis of pancreatic islet cell process in the normal cell is important, tumors have been the source of con­ since the neoplastic cell might suffer al­ troversy. Two main theories exist regard­ terations in the different steps of this nor­ ing the cell of origin, one claiming an mal process.19 Tumors usually secrete endodermal origin from a putative pluri- hormone in an “autonomous” fashion un­ potential ductal cell.37 The authors based responsive of stimulatory or inhibitory their hypothesis on morphological obser­ mechanisms. There are few cases in the vations55 of fetal pancreas, as well as on literature of insulinoma retaining the comparative endocrinological studies.12 normal capacity to respond to different The second theory proposed by concentrations of glucose.58 Certain Pearse53 places the islet cells as a part of tumors secrete mainly the immature a big family of cells which appear to be of secretory product as in the case of an neuroectodermal derivation having insulinoma and glucagonoma which pro­ APUD(Amine content and/or Amine Pre­ duced pro-insulin and pro-glucagon, re­ cursor Uptake and Decarboxylation) spectively.12 This would explain the var­ characteristics. Their theory is based on iability of the histochemical reactions in cytochemistry and ultrastructural endocrine pancreatic tumors and the studies52 (figure 2). M icro tu bular m ic ro f il am e nts s y s te m C a p illa ry F I G U R E 1. Schem atic representation of the se­ S e c r e to ry G ra n u le quence of events leading to endocrine secretion. Fndothelial R.E.R. = Rough endo­ CeU plasmic reticulum. N u cleu s B asal M em b ra n e 68 KOSTIANOVSKY HISTOGENESIS OF PANCREATIC ENDOCRINE TUMORS logical behavior of these tumors could be understood better and possible tumor Endodermal Origin Ectodermal Origin markers could be recognized. These (neural crest) tumor markers could be of help in diag­ I i nosis, especially in non-functional tu­ Pluripotential Amine Precursor mors, and in monitoring the treatment of Ductal Cells Uptake and Decarboxylation possible recurrences. Cell Series One such study56 demonstrated in­ I I creased pancreatic polypeptide levels in Pancreatic Endocrine Pancreatic Endocrine Tumors Tumors plasma of patients with different types of pancreatic endocrine neoplasms. How­ F ig u r e 2. A.P.U.D. = Amine Precursor l/ptake ever, it was recently shown in many cases and Decarboxylation (see references 52 and 53). that the increase of pancreatic polypep­ tide levels are due to islet hyperplasia in the peripancreatic region and not to the Creutzfeld recently8,9 described a type presence of pancreatic polypeptide cells in of cell found in different types of pancrea­ the tumor itself.38 tic endocrine tumors which has atypical Several clinical syndromes have been secretory granules unlike any other type produced by endocrine pancreatic tu­ of cell in the normal islet. He concluded mors. Ultrastructurally, these tumors con­ that these cells may represent a precursor tain a variety of granulated and agranu- or stem pluripotential cell type, present lated cell types. The prevailing cell type also in cases of ductular proliferation. in most cases correlated with the clinical Ductular proliferation and nesidio­ symptoms of hormone secretion (tables II blastosis (neoformation of islets) have and III). been recently described in the peritu- moral pancreatic tissue.9,39 Experimental