HPB Surgery, 1997, Vol.10, pp. 201-209 (C) 1997 OPA (Overseas Publishers Association) Reprints available directly from the publisher Amsterdam B.V. Published in The Netherlands Photocopying permitted by license only by Harwood Academic Publishers Printed in India

Nesidioblastosis in the Adult Surgical Management J. PALLA GARCIA, TERESA FRAN(A, CONSIGLIERI PEDROSO, CARLOS CARDOSO and M.aOLMPIA CID

St. Martha's Hospital General Surgery and Histopathology Wards (Rua de Santa Marta, 1100 Lisboa, Portugal)

(Received 21 July 1995)

Nesidioblastosis is an exceedingly rare occurrence in Three types of diffuse changes of the islet the adult and, when it appears, it is usually part of a cells are and either at MEAl syndrome. known, they may appear We present a .case of nesidioblastosis in a young random, or by genetic determinism: islet cell woman, with no concurrent endocrine pathology, adenomatosis, islet cell hyperplasia and nesi- while we discuss in detail the diagnostic and thera- dioblastosis[2]. peutic problems posed by this condition. The selected treatment was sub-total pancreatectomy The word "nesidioblastosis" comes from the (70-80%) and the histopathologic and immunohisto- Greek "vecn&v" (nesidiu), which means "islet", chemical tests of the surgical specimen showed: and was originally proposed by Leidlow[3] and "Diffuse Nesidioblastosis'. The histopathologic and immuno-histochemical fea- used by Vance[4] in reference to a diffuse lesion tures of the resected pancreas are analysed in detail. of the islets. It is worth noting that nesidioblastosis is a Keywords: Nesidioblastosis, pancreatectomy, Hyperinsulin- developmental phase of the foetal pancreas and ism/hypoglycaemia not an autonomous histopathologic entity, an impairment of the insulin storage and release capabilities being the best explanation for the INTRODUCTION hyperinsulinism found in these patients[5]. It's also worth mentioning that nesidio- In the adult, the syndrome involving hypo- blastosis in the adult is an extraordinarily rare glycaemic crisis associated with primary occurrence and, when one is found, it's usually hyperinsulinism, immediately evokes the pos- part of the MEA syndrome. sibility of an insulinoma however, 10-15% of the adult patients with autonomous hyper- insulinism will have diffuse lesions to the is- lets, rather than a solitary adenoma[1]. In these MATERIALS AND METHODS situations of hyperinsulinism with diffuse le- in which the sions, the external appearance of Clinical Case pancreas, as well as the imaging techniques, will not show any changes, the experience and We report a thirty years old female caucasian skill of the histopathologist will constitute a patient, with a history of hypoglycaemic crisis. major factor to the recognition and diagnosis of She first presented in 1987 with bouts of intense the actual lesions. sudoresis, tremor, loss of consciousness and

201 202 J. PALLA GARCIA et al. transient right hemiparesis. She was diagnosed autonomous hyperinsulinism, the possibility as having hypoglycaemic crisis, with a blood of nesidioblastosis was considered. In this con- glucose of 2.2 mmol/L (normal 3.9-6.1) dition, usually, the pancreas; appears normal Later she had two similar bouts, with similar and microscopic examination is not capable of hypoglycaemia. defining this pathological process. In May 1990 she had an inconclusive fasting The decision to perform pancreatectomy in test, but subsequently had two more crisis of seri- this case was based mainly on the clinical and ous hypoglycaemia with loss of consciousness. laboratory features, and not on the surgical find- In January 1991 she was admitted to the Gen- ings. We performed a sub-total pancreatectomy eral Surgery Department of St. Martha's Hospi- of 70% and splenectomy. tal, for a fasting test, which was inconclusive The sub-total pancreatectomy, measuring 7 x except for the very high levels of insulin. In 3.5 cm, was serially sectioned, with an average May 1991 she was re-admitted, repeating the thickness of 0.5 cm. The cut surface of the slices fasting test, which showed irregular changes in showed the usual appearance of pancreatic glycaemia, insulinaemia and the corrected ratio lobulation and no tumours were seen. of the two variables. A large number of paraffin sections were ex- Previous personal history and physical exami- amined these under optical microscopy stained nation were non-contributors. From the avail- by Haema-toxilin-Eosin. Some of the slices were able data we diagnosed a probable insulinoma. observed with histochemical techniques, by the Following this diagnosis we performed some Grimelius method, and also immuno-histo- imaging of the pancreas, aimed at identifying chemically by the immunoperoxydasis method, the insulinoma, but this was inconclusive. various hormonal anti-bodies were used: insulin In January 1991 an abdominal CAT-scan ( cells), glucagon (0 cells), somatostatin ( cells), showed "discreet nodularity of the pancreas tail": VIP ( cells), Substance-P, Bombesine, Gastrine abdominal CAT-scan of May 1991 revealed that and Chromogranine, as an anti-body for endo- "the nodularity of the pancreas tail is still crine cells. present". NMR-imaging of the pancreas showed no changes. At angiography of the celiac branch (May 1991), RESULTS showed a "tenuous venous flush in the transition area between the and tail". pancreas body Histology In spite of the problems posed by this lack of a sure pre-surgical identification of the insu- Pancreatic parenchyma had no changes in the exo- linoma, we decided to proceed with surgery, crine tissue, but the endocrine tissue was both with both diagnostic and therapeutic purposes. morphologically and topographically altered, with We believed that the patient had a small and variation in the size and number of islets, with loss solitary insulinoma, which we had to precisely of their normal centro-lobular distribution. localise and resect, its precise localisation being With immuno-histochemical staining for the first major surgical difficulty. With a complete insulin an unusual diffuse proliferation of marker- and optimal exposure we went on to its syste- positive cells, was seen with a random distribution matic exploration, by visual inspection, careful within the pancreatic lobule, either isolated, or in palpation and pre-operative ultrasonography, small aggregates of 2 or more ceils (Fig. la, b). we did not find an insulinoma. Insulin-positive cells were also seen, not only In the absence of a detected insulinoma, but in the epithelium of pancreatic ducts, but also in with a sure diagnosis of hypoglycaemia with their proximity, in the form of cell conglomerates, NESIDIOBLASTOSIS 203

FIGURE 1A Diffuse proliferation of small endocrine cell conglomerates and islets. H.E., x40. (See Color Plate I). sometimes multiple, but often as duct-endo- Bombesine (-) crine proliferations (Fig. 2). An enormous size is Gastrine (-) reached by some islets which also have an ir- Chromogranine (++++) regular shape. There is occasional nuclear vari- The immediate post-operative period was ability, both in size and staining (Fig. 3). without event. Four months later she had a ab- The hormonal tests, besides insulin, included dominal CAT-scan (September 1991) which other hormonal markers for which we estab- showed "post surgical status, with normal topo- lished a ranking between one (+) and four graphic organ arrangement". (++++) proportional to the number of cells However, during the first year post-surgery, that had cytoplasm positive to each marker. A the patient had two new crisis of hypo- negative immuno-marker response was assumed glycaemia with blood glucose about 2 mmol/L. in the absence of brown cytoplasmic staining. Glycaemia and insulinaemia levels between The following results were thus obtained: crisis were normal. It was decided to start medi- Insulin ([ cells) (++++) cal therapy with infused long-acting somato- Glucagon (0 cells) (+++) statin, for periods of 5 days, with good results Somatostatin ( cells). (+++) during 1992/93, during which she had no more VIP (52 cells) (++) crisis. Early in 1994, two and a half years after 204 J. PALLA GARCIA et al. the pancreatic resection, she received a long producing cells. Until 1981 nesidioblastosis in acting somatostatin, Sandostatin(R) (octreotide) adults[6] had always been described in sub-cutaneously, 100 g t.i.d., as an outpatient. association with other diseases, such as: At the end of 1995- four years after operation Zollinger-Ellison syndrome, multiple endo- she was quite well, without further hypoglycaemic crine adenomatosis, congenital neuroblastoma, crisis. Lindau's disease, chronic pancreatitis and cysticfibrosis. In the last 12 years a very small number of cases of nesidioblastosis in the adult, unassociated with other diseases, has DISCUSSION been described in the literature. It was George F. Leidlow[3] who, for the first Nesidioblastosis is the main cause of time in 1938, defined the morphological lesion of hyperinsulinism/hypoglycaemia in new-borns nesidioblastosis as a "diffuse or disseminated and children, being a very rare condition in proliferation of the islet cells originating in the adults. In these, as in adolescents, the main ductules or pancreatic ducts"[6]. Later, Yakovac cause of hyperinsulinism/hypoglycaemia is the (1986) wrote that: "nesidioblastosis consists of presence of a pancreatic adenoma of insulin- insulin-producing cells, either isolated, or in

FIGURE 1B Minuscule cell aggregates enhanced by the insulin-sensitive immuno-peroxydasis technique, x40o (See Color Plate II). NESIDIOBLASTOSIS 205 small groups of 2-6 cells, dispersed throughout d) changes in the functional regulation of cells the parenchyma, often in relation to the epithe- impairing the storage and release of insulin. lium of exocrine ducts"[7]. These morphological The increase in the mass of islet cells associ- changes, with distortion of the pancreatic ated with the anatomical findings of adeno- lobular architecture, due to endocrine cell proli- matosis, hyperplasia and nesidioblastosis, men- feration, had been previously mentioned by some tioned by various authors[9,10,11] has not been authors under the name of nesidiodysplasia[6]. confirmed, however, using histometry para- Later this designation was attributed to other meters[12,13,14]. morphological criteria: increase in nuclear dia- The relative increase of cells with reduction meter and staining, in islet endocrine cells[8]. In of the glucagon and somatostatin secreting our case all these morphological criteria, distor- cells[15,16] has also not been found. Depsite tion of the lobular architecture, endocrine duct/ abnormal islet architecture and impairment of ductule proliferation, changes in size and irregu- the para-endocrine function having been re- larity of the islets were present and we also ferred to as a possible mechanism for hyper in- found discret occasional changes in nuclear dia- sulinism[17] this has also been found in normal meter and staining, i.e., cell hypertrophy. controls. The impairment of storage and release This disease of the Langerhans Islets of the of insulin remains the possible mechanism for pancreas, represents an entity difficult to treat, the clinical manifestation. and difficult to understand. The awkward histo- The fact that the correction of hypoglycaemia logic appearance of nesidioblastosis, chains of is only temporary, with recurring bouts of cells along the pancreatic ducts while real islets hypoglycaemia in patients subjected to 70% are not to be found, has lead some authors to pancreatic resection may be explained because consider these lesions as a block to islet differ- such resections have reduced the total mass of entiation during foetal life. But with foetal de- islet cells, but left behind cells that apparently velopment and islet embryogenesis better still have a flaw in the regulation of insulin understanding due to advances in microscopy and production, and are capable of hypersecretion biochemistry, it became obvious that nesidio- with the resulting hypoglycaemia. blastosis, hyperplasia of the islet cells and Near-total pancreatectomy frequently seems adenomatosis, are phases in the foetal develop- to be necessary and, even in some of these pa- ment of the pancreas and represent different tients submitted to an extensive pancreatic aspects of a common condition, resulting from resectoin and left only with a small number of the incomplete islet maturation. remaining islets, the incidence of Diabetes The symptomatology present in these rare mellitus is surprisingly low. situations resutls from the intermittent and In spite of the best surgical treatment not yet variable insulin hypersecretion. The patho- having been completely established neither die- physiological relationship between the structural tary measuresnor insulin suppressing drugs have changes of the islets and hyperinsulinism is as shown an efficacy comparable to resection sur- yet unclear. Four mechanisms have been pro- gery. Total pancreatectomy will, however, al- posed[5] to explain hyperinsulinism in interest ways lead to endocrine and exocrine impairment, hypoglycaemia associated with nesidioblastosis: which may be badly tolerated by children and a) increase in the number of cells within the islets; adolescents. b) relative increase in the number of cells and a Early trends in the management of this condi- reduction of the glucagon and somatostatin secret- tion were relatively conservative, limiting the ing cells; c) changes in islet architecture resulting extent of the resection to 70-80% (sub-total pan- in impairment of their para-endocrine function; createctomy); however the frequent recurrence 206 J. PALLA GARCIA et al. of hypoglycaemia, mainly in infants and small subtle and islet irregularity, with mixed children, made re-operations frequent, and there endocrine and exocrine tissues, only became is now a marked trend towards near-total pan- obvious with special histochemical techniques createctomy 95%. and more thorough searching. However all of Scott-Bjerk[17] says that, in his experience of Norton' s work[ 19,20,21 underlines the need for babies with 70-80% pancreatic resection, all near-total pancreatectomy (95%), preserving had to be reoperated with 90-95% resection to the spleen, as the definitive treatment of control hypoglycaemia. With older children he nesidioblastosis in the child, this guideline to had better results with 70-80% resection, but be followed from early childhood, even when a they required post-surgery adjunct therapy. normal looking pancreas is found. Kramer[18] found more extensive structural In the adult, due to the great rarity of this lesions of the islets in the younger patients, condition, there are no available data in the consisting of a massive increase of endocrine literature to allow for any conclusions to be cells, with absence of normal secretion by this drawn; we should, however, think from its late endocrine tissue. In older children and adults onset that the islet lesions should be less hyper- the structural changes in the islets were more functioning and, that in the adult having all its

FIGURE 2 Duct-islet proliferation. Insulin-sensitive immuno-peroxydasis technique, 100. (See Color Plate III). NESIDIOBLASTOSIS 207

FIGURE 3A Duct-islet proliferation with very large and irregular Langerhan islet, H.E., xl00. (See Color Plate IV). systems fully developed, the consequences of other peptides, would have a palliative effect hypoglycaemia would be more attenuated. and, although a decrease in the growth of endocrine It should be noted, however, that the current tumours has been shown experimentally in the management in the child, and possibly in the rat, its effects are currently still under evaluation. adult, is the need for an early diagnosis and Clinically octeotride has been shown to be early aggressive surgical treatment, with exten- effective in the management of hypoglycaemia sive resection, saving the patient from the risks in children with nesidioblastosis, although it and complications of recurring hypoglycaemia. has not been as effective in adults with insu- Our patient, with a sub-total 70% pan- linoma[22,23]. Occasional hypoglycaemia control createctomy, is still under follow-up therapy and in a few patients with long term octeotride has has had, in the 5 following years, 4 milder bouts also been mentioned by some investigators[24]. of hypoglycaemia, apparently controlled and We recognise the need to keep our patient prevented by therapy with octreotide. under close follow-up and, if hypoglycaemia Long-acting somatostatin, which is described bouts recur, we will have to re-evaluate her and as having an inhibitory action on the release of plan a possible reoperation for near-total pan- insulin, growth-hormone, glucagon, gastrin and createctomy. 208 J. PALLA GARCIA et al.

FIGURE 3B, C Nuclear changes in size and staining H.E., x400. (See Color Plate V).

Human Pathology, 19, 1215-1218 by Sauders Company. References [9] Heitz, R.V., Klappel, G., Hacki, W.H., Polack, J.M. and Pearse A.C. (1977). Nesidioblastosis: the pathologic [1] Keivunun, D.G. and Harrison T. (1990). The basis of persistent hyperinsulin6mia hyp0glic6mia in Hypoglicemic Syndrome: Endogenous Hyper- infants. Diabetes, 26, 632. insulinismo in: Surgical Endocrinology Clinical-Syn- [10]Shermetta, D.W., Mendelsh Haller (1980). Hyper- drome Stanley Friesen Norman Tompson pag. 223, insulinemia hypoglyc6mia of the neonate associated Editor J.B. Lippincett. Comp. with persistent fetal histology and function of pan- [2] Friesen (1990). Editorial Comment in: Surgical creas. Ann. Surg., 191, 182. Endocrinology Clinical Syndromes by Stand Friesen [11] Gouldl, V.E., Memeli, V.A., Dardi, L.E. and Goudel Norman Tompson pag. 229, Editor J.B. Lippincett N.S. (1981). Nesidiodysplasia and nesidioblastosis of Comp. infancy: Ultrastructural and immunohistochemical [3] Laidlaw G.F. (1938). Nesidioblastoma the islect tumeur analysis of islet cell alterations with and without of the pancreas. Am. J. Pathology, 14, 125. associated hyperinsulinemic hipoglycaemic. Scand J. [4] Vance J.E. (1972). Familiar nesidioblastosis as the pre- Gastroenterolog., 70,129. dominant manifestation of the multiple endocrine [12] White, A.P., Greider, M.H. and DE Sehrgver k. kissane adenomatosis. Am. J. Med., 52, 211. (1990). The juvenile human endocrine pancreas: Nor- [5] Thomas, G.G., Guenco. R.E., Azigklin, R.G. and mal versus idiopatic hypereinsulinemic hypoglycemia. Underward L.E. (1988). Changing concepts of islect cell Semin. Diag. Patholog, 1,130. dysplasia in neonatal and infantile hyperinsulinism. [13] Jaffe, R., Hashide, Y. and Yunis E. (1986). Pancreatic pa- World J. Surg., 12, 598. thology in hiperinsulinemic hypoglycemia of infancy. [6] Jay, K. Harness et al. (Nesidioblastosisin adults) 1981. Lab. Invest, 42, 356. (May) Arch. Surg, 116, 575. [14] Simmons, P.S., Talander, R.L., Carney, J.A., Walel, L.E. [7] Goudswaard et at (1986). (Nesidioblastosis and Endo- and Haymond M.W. (1984). Surgical management of crine Hyperplasia of the Pancreas: A secondary Phe- hyperinsulinemic hypoglycemia in children. Arch. nomenon) Human Pathology, 17, 46-53. Surg., 119, 520. [8] I. Ariel. al. (Nesidiodysplasia. A histologic Entity?) [15] Bishop, A.E., Polak, J.M., Chese, P.G., Timsen, C.M., NESID OBLASTOSIS 209

Bryant, M.G. and Bloom S.R. (1981). Decrease of pan- endocrine system In de Vito Cancer: principles and prac- creatic somatostatin in neonatal nesidioblastosis. Dia- tice of oncology Philadelphia Lippincott. 1269-1344. betes, 30, 122. [20]Bolande R.P. (1974). The neurocrestopathioes: a [16] Falkmer, S. Svik, O. and Vidnes J. (1981). Immunohisto- unyfrying concept of disease arising from neural crest chemical, morphometric and clinical studies of the pan- maldevelopment Human. Pathol., 5, 409. creatic islects in enfants with persistent neonatal [21] Pearse (1980). The APUD concept and hormone produc- hypoglycemia. Acta Bol. Med. Gerieat, 40, 39. tion. Clin. Endocrinol. Metab., 9, 211. [17] H. Scott Bjerka et al. (1990). Oct (Surgical Management [22] Maton R.M. (1989). The use of the long acting somato- of islect cell Dysmaturation syndrome in young chil- statin analogue, octeotride in patients with islect cell dren). tumuers Gastroenterology. Clin. N.A., 18, 897-922. [18] Kramer, J. Martin Bell, De Schryver, Richard Bower, [23] Glaser, B., Rosler, A. and Halperin Y. (1990). Chronic Jessie Ternberg and Neil Withe (1982). Clinical and treatment of benign insulinoma using the long-acting Hystologic indications for extensive pancreatic resec- somatostatin analogues SMS Isr. J. Med., 26, 16-9. tion in Nesidioblastosis Am. J. Surg. 143-116-8 [24] Laron Z. et al. (1990). Somatostatin analogues in the [19]Norton. Doppman and Jansen (1989). Cancer of the management of benign insulinomas.Isr. J. Med.,26,1-2. M EDIATORSof INFLAMMATION

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