Hypoglycemia and Insular Hyperplasia:

Review of 148 Cases

PARIDE STEFANINI, M.D., MANLIO CARBONI, M.D., NERI PATRASSI, M.D.,ANTONIO BASOLI, M.D.

On the bases of personal experience and the series of 148cases from an international inquiry and a review of theliterature, the relation between insular hyperplasia andhypoglycemia was examined. The fundamental points in thisinvestigation included: age, diagnostic investigations, histo-logical findings and postoperative results. The data on thepatients with insular hyperplasia indicates that 83% wereof adult age. Insular hyperplasia was the only abnormalfactor determined to be present. Through treatment a highpercentage of cases (71% ) was cured. From a practical sur-gical point of view, differentiation between occult insulomasand insular hyperplasia is not critical. Consequently, goodresults can be achieved in botlh diseases by practicing a pro-gressive blind resection guided by examination of the op-erated specimen and by intra-operative blood sugar levels.

H YPERINSULINISM of pancreatic origin may be causedby either a benign 8 cell adenoma, carcinoma, or

diffuse hyperplasia of the islet cells. Of these causes, theadenoma is by far the most common.

Occasionally however, the only recognizable patho-logic lesion in the pancreas is islet hyperplasia. Manycases of hypoglycemia with islet hyperplasia have beenreported. Some authors hesitate to accept islet cell hyper-plasia as the cause of hypoglycemia. When only diffusehyperplasia of the islets is found they feel that thehypoglycemia is caused by a missed insuloma. In thechild, however, the existence of islet hyperplasia and itscapacity to determine hypoglycemia is generally ac-cepted.42 Cases have been reported in which pancreatichypoglycemia exists with insular hyperplasia in the ab-sence of insulomas and other hypoglycemia-inducing

Submitted for publication June 12, 1973.Address correspondence to: Paride Stefanini, M.D., 2nd Surgical

Clinic of The University of Rome Medical School, PoliclinicoUmberto 10, 00161, Rome, Italy.

From the 2nd Surgical Clinic and Surgical Anatomyof the University of Rome Medical School, Rome, Italy

diseases.29 Many authors have reported relief of hypo-glycemia after pancreatic resections without finding abeta islet-cell tumor.8644'49'3Our experience in management of hyperinsulinism of

pancreatic origin consists of 11 adenomas, one carcinomaand five insular hyperplasias. The observation of thesecases of hyperplasia induced us to investigate this stillmuch discussed topic. We reviewed the literature andcarried out an international inquiry (Table 1). An anal-ysis of these cases and of our own experience is reportedin this paper.

Material

On the basis of our research we observed that of atotal of 1137 cases of organic hypoglycemia, 1067 (93.8%)were caused by insulomas and 70 (6.2%) by insular hy-perplasia. In seven cases (0.6%) there was a combina-tion of the two diseases.Of the 149 authors who communicated their experi-

ence on hypoglycemia of pancreatic origin, 30 (20%)report cases of insular hyperplasia. Yet seven (4%) ofthese have doubts on the connection between hypo-glycemia and insular hyperplasia in their patients.Of 148 cases of insular hyperplasia documented from

a histological and clinical point of view, 122 had under-gone surgical intervention with immediate and long termrelief of hypoglycemia.

In the series collected from 140 cases documented,there were 78 (56%) females and 62 (44%) males: only16 were children, while all the others were adults withan age ranging from 19 to 65 years.

130

HYPOGLYCEMIA AND INSULAR HYPERPLASIA

TABLE 1. Insular Hyperplasias: Case Material

No. ofSeries Cases Authors (cases)

Gathered by 65 Biancalana 1, Blomquist 1, Bloodworth 1,Internat. Inquiry Carrington 1, Creutzfeldt 1, De Cesare 1,

De Peyster 5, Fonkaisrud 1, Fraser 1, Fuchsig2, Goffrini 3, Hess 1, Huguet 1, Juvara 7,Leger 15, Mandache 1, McGarity 1, Mc-Govern 1, Passaro 1, Pellegrini 1, Poli 1,Porter 6, Ritchie 1, Saegesser 1, Sato 2,Shamiyeh 1, Singleton 1, Solcia 1, White 3,Zenker 1

Gathered from 78 Auguston 1,1 Barbarino 1,2 Becker 6,3-4 BellReview of the 1,5 Bernhard 3,6 Boone 1,7 Broq 6,9 CallawayLiterature 1,10 Conn 1,11 David 1,12 Deucher 2,14 Deuil

1,'5 Edwards 1,16 Fish 1,17 Geraud 1,19Gilchrist 1,29 Graham 1,21 Greenle 1,22Grotzinger 2,23 Haworth 8,25 Hellstrom 1,26Hill 1,27 Holman 1,28 Kalbfleisch 1,30 Kjaer-gaard 2,32 Koutras 4,33 Leriche 1,37 Linder1,38 McCaughan 4,3940 Magner 1,"3 Martin1,46 Maxeiner 1,47 Mengoli 1,48 Milone 1,49Mosenthal 1,50 Orr 1,12 Pfeiffer 1,53 Phillips1,54 Richardson 1,55 Sawyer 1,57 Sendrail 2,69Simon 1,60 Sloper 2,61 Spencer 1,62 Walters 1,64Whipple 365

Personal Cases 5Total 148

Our patients had an average age of 35 years. Fourwere females and one was a male.The symptomatology of our cases with insular hyper-

plasia was practically the same as that presented bypatients with insulomas. The only conclusion we can

draw from our experience is that, in comparison to in-sulomas, patients with hyperplasia presented hypogly-cemia crises at less frequent intervals. However, cardio-vascular and gastrointestinal symptoms were more oftennoted (Table 2). Neurological symptoms were frequentand often resulted in diagnostic errors, with admittanceof patients to mental hospitals. Gastrointestinal symp-

toms, consisted mainly in hunger while the cardiovas-cular symptoms consisted mainly of sinus tachycardia.On the average, there elapsed four-and-a-half years

from the onset of symptoms to the diagnosis of hypogly-cemia. Epilepsy was diagnosed three times and numer-

ous E.E.G.'s were carried out with negative results.The same investigations were useful in evaluating

patients with hyperplasia and in those with insulomas.In particular, the prolonged fasting test (five out of five)and the tolbutamide test (three out of four) had a

high degree of diagnostic accuracy. Blood insulin levels,measured by radioimmunological assay, were very highin the three cases tested. The clinical symptoms and thebiochemical data of our patients do not differ greatlyfrom those communicated to us by the authors. Twenty-one reported that in their opinion, clinical findings andlaboratory data showed no differences between theircases of insulomas and those of hyperplasia.The surgical treatment of our patients is summarized

in Table 3. The preoperative diagnosis in our patientshas always been that of hypoglycemia from insulomaand the finding of insular hyperplasia was unexpected.The type of intervention, the death rate, and longterm

results which were obtained from the different authors,are summarized in Table 4. The types of operation mostused were corpocaudal pancreatectomy (63.8%) and sub-total pancreatectomy (24.3%). Twice, following a sub-total resection, a total resection was carried out withrecovery in one case and the persistence of hypoglycemiain the other. The follow up period was of six months tofive years except in five cases. Pancreatic biopsy led tothe diagnosis of insular hyperplasia in four cases. Oneof these cases had insular carcinoma associated withhyperplasia.

In four cases, insular hyperplasia was diagnosed atpost-mortem examination.

Case Report

L.G., a 32-year-old woman had experienced increasingly fre-quent episodes of wealness, memory loss, mental confusion andcoma over a 5-year period.Her symptoms were most prominent when fasting and after

physical effort. The first physician she consulted diagnosed epi-lepsy. She was admitted to the 2nd Surgical Clinic of the Uni-versity of Rome in September 1969. There were no significantphysical findings, except tachycardia during hypoglycemic attacks.An oral glucose tolerance test, tolbutamide test, prolonged fasting

TABLE 2. Insular Hyperplasias: Symptoms and Diagnosis (personal cases)

Previous PreviousCase Age Sex Principal Symptoms Diagnosis Admissions Blood Sugar IRI Fasting Tolbutamide

1 50 M 5 years neuropsychic epilepsy 2 0.30 +cardiovascular

2 39 F 11 years neuropsychic epilepsy 4 0.40 + +3 36 F 7 months neuropsychic 0.45 69 + i

gastrointest.4 32 F 4 years neuropsychic epilepsy 3 0.25 91 + +

cardiovascular5 20 F 4 years neuropsychic 1 0.40 72 + +

cardiovasculargastrointest.

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TABLE 3. Insular Hyperplasias: Interventions and Results (personal cases)

Postoperative Glycemia

Case Type of Intervention Mortality 1st 3rd 6th Long-Term Results

1 blind distal resection 1.80 1.20 1 cure at 1 year, paradiabetic2 blind distal resection 2 1.50 1 cure at 1 year3 blind distal resection 0.80 0.80 0.60 hypoglycemia

subtotal pancreatectomy 2 0.95 1.10 cure at 6 months, paradiabetic4 blind distal resection 1.60 1.30 0.90 cure at 1 1/2 years5 blind distal resection 1 .95 1 .20 0.95 cure at 9 months

test and glucagon test were diagnostic of functioning beta celltumor of the pancreas.

The fasting serum insulin level was elevated at 91l,uU/ml. OnNovember 22, 1969 she underwent exploratory laparotomy. Thepancreas and sites of aberrant pancreatic tissue were carefullyexamined and no tumor could be found. Therefore, a blind distalresection was performed. Histological examination of resectedspecimen showed insular hyperplasia (Figs. 1 and 2). Her bloodsugar rose to 160 mg/100 on the first postoperative day andgradually returned to normal by the 6th day. She was dischargedon the 18th postoperative day. She has had no recurrence of hypo-glycemia and has done well over a three-year period of followup.

DiscussionThe diagnostic and therapeutic problems of insular

hyperplasia are not very different from those of occultinsulomas. From a clinical and biochemical point ofview it is not possible to differentiate the two diseases.The only possible way might be selective arteriographywhich, in spite of the high percentage of success (66%in our inquiry), may not always demonstrate a tumor ofsmall dimension and of sparse vascularity.As for surgical treatment, at present a progressive re-

section of the pancreas guided by the blood sugar levelsand by histological examination of the removed specimenis advised by some authors in the management of occultinsulomas'3 24813'41 rather than blind distal resection.

This procedure can also be successfully applied incases of insular hyperplasia. Exploration of the pancreasand common sites of aberrant pancreatic tissue shouldbe carried out as there exists, though rarely, the possi-bility of a hyperplasia-insuloma association.

Therefore, from a practical point of view, in the ab-

sence of a tumor a blind resection should be carriedout, this will have a beneficial effect in both diseases.From the analysis of our patients and of the series

gathered, the relationship between hypoglycemia andinsular hyperplasia appears well demonstrated.There were five points noted in the majority of the

collected cases: 1) adult age; 2) absence of other dis-eases producing hypoglycemia; 3) positive diagnostictests for organic hypoglycemia; 4) histological findingsof insular hyperplasia; and 5) recovery after operativeresection of the pancreas.

Regarding the first point, only 16 cases (13%) con-cerned children. Four of these were communicated to us

by Porter who, on the bases of his cases, doubts anyconnection between hyperplasia and hypoglycemia. Theaverage age of the subjects taken into consideration was39 years and 6 months; this was only slightly lower thanour patients with insulomas (45 years and six months).The possibility that other pancreatic and extrapan-

creatic diseases may cause hypoglycemia is generallyaccepted.

Chronic pancreatitis complicated by the presence ofhypoglycemia, is reported in the literature.18,3436,66 How-ever, these reports lack histological confirmation. More-over it cannot be excluded that some of these casesshould be interpreted as examples of functional hyper-insulinism. In chronic pancreatitis hypoglycemia hasbeen attibuted to an obstruction of the excretory ductswith a consequent hypertension effect.45 The observa-tions of recovery with simple sphincterotomy,34 externalbiliary drainage,44 or with simple cholecystectomy58 cast

TABLE 4. Insular Hyperplasias: Interventions and Results (115 completely documented cases)

Long-Term Results*

Mortality Poor Fair Good

No. of No. of No. of No. of No. ofCases % Cases % Cases % Cases % Cases %

Caudal Pancreatectomy 5 4.4 4 80Corpocaudal Pancreatectomy 76 66 2 2.7 9 11.8 9 11.8 53 69.8Subtotal Pancreatectomy 29 25.2 1 3.4 4 13.7 1 3.4 22 75.7Laparotomy 5 4.4 1 20 4 80

* In 5 cases long-term results were not specified.

132 STEFANINI AND OTHERS Ann. Surg. * July 1974

HYPOGLYCEMIA AND INSULAR HYPERPLASIA 133doubts on organic hypoglycemia as the cause of hypo-glycemia in these patients.

Extrapancreatic tumors, such as mesenchymal tumors,hepatomas, pseudomyxomas, epithelial tumors and thoseof the adrenal cortex, are important and convincingcauses of hypoglycemia.

In these cases the differential diagnosis can often bemade by routine x-ray investigations. Also the plasmainsulin levels are normal during fasting and during anoral glucose tolerance test. In 84 mesenchymal tumors,40 hepatomas, 19 adrenal cortex tumors, and 13 epithelialtumors, the only exception was a patient reported byOleesky in 1962.51 The patient was a male of 62 yearswith pelvic spindle cell fibrosarcoma. The insulin levelwas 860/ml and blood sugar 23 mg%. This hypoglycemiadisappeared after radiotherapy.

Functional hypoglycemias from other diseases of thedigestive system are easily distinguishable from organicpancreatic ones. In fact, provocative tests are sufficient toexclude this possibility.The histological examination carried out on 144 op-

erated and four autopsy specimens, allows the demon-stration of hyperplasia, occult insulomas, or chronic pan-creatitis. The pathological findings also demonstrate thatin six cases an adenoma was associated with insularhyperplasia. In one case, hyperplasia co-existed with aninoperable carcinoma. In two cases, hyperplasia andinsuloma were treated at the same time and in two casesa blind distal resection was followed by enucleation ofthe adenoma. In one case, operation for the adenoma

la.FIGS. la. and lb. Case 4. Histological examination of resectedspecimen. Fig. la shows an increase in number of islet ofLangerhans (x60). Fig. lb shows an increase in size (X250).

lb.

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Ann. Surg. * July 1974

was carried out and subsequently reoperation with thediagnosis of hvperplasia. The long term results in thisgroup of patients, records two failures; one of whichrelated to exploratory laparotomv for insular carcinoma,and five recoveries.Considering the results of surgical treatment the per-

centage of recoveries were 71%. Mortality of operationwas 4.5%. In many cases, surgical failure, after corpo-caudal resection can be attributed to an inadequate re-section of the pancreas. Yet one cannot deny that occultinsulomas could have been present in the 24.5% of thecases where hypoglycemia persisted.

AcknowledgmentsWe are greatly indebted to all those authors who sent us their

personal communications and to all those who collaborated withtheir valid information.

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