Without Insular Hyperfunction
Nesidioblastosis in
PAUL N. KARNAUCHOW, M.D.
Examination of pancreases from a series of 207 autopsies of
adults without either clinical or autopsy evidence of insular
hyperfunction showed minimal nesidioblastosis in 36.7%. Ductulo-insular complexes, together with insular cells among the
acini, were found in 10.6% of the biopsy specimens. Nesidioblastosis was more frequent in men (61.8%), and the oldest
individual was an 84-year-old man. Ductulo-insular complexes
and the aggregations of insular cells in the exocrine parenchyma develop asynchronously and may have been initiated by
different stimuli. This series did not explain the possible causative factors. (Key words: Nesidioblastosis in adults; Ductuloinsular complexes) Am J Clin Pathol 1982; 78: 511-513
NESIDIOBLASTOSIS was a term used by Laidlaw15 to
describe " . . . a diffuse and disseminated proliferation
of islet cells . . . arising from pancreatic ducts or ductules." Later it was modified by Yakovac and co-workers23 to include ". . . beta cells scattered . . . in glandular acini," confining its use to the lesions associated
with hypoglycemia in infancy.
Although most authors 5 , 8 ' 9 " 1 9 , 2 0 believe that nesidioblastosis is responsible for the production of hyperinsulinemic hypoglycemia, Jaffe and colleagues14 questioned its role, after finding it in a series of 32 euglycemic
infants. In adults, nesidioblastosis is found not only in
hypoglycemia,12 but also in the Zollinger-Ellison3,4,22and
watery diarrhea13,17 syndromes, and in patients being
treated with sulfonylurea drugs.2,7 Whether this occurs
in adults without clinical and autopsy evidence of insular
hyperfunction is not known.
Materials and Methods
The materials consisted of slides and paraffin blocks
of pancreatic tissue from 207 selected autopsies from
616 cases in our files from 1975-1979. Autopsies were
performed on individuals who: (1) were 30 years of age
and older; (2) had no history of hypoglycemia, diabetes
mellitus, or severe diarrhea; and (3) did not have peptic
ulcers, pancreatic neoplasms (benign, malignant or secondary), chronic pancreatitis, or extensive pancreatic
fibrosis.
Received November 4, 1981; received revised manuscript and accepted for publication January 27, 1982.
Presented at the 1980 Meeting of the Society of Northern Ontario
Pathologists, November 1980.
Address reprint requests to Dr. Karnauchow: North Bay Civic Hospital, 750 Scollard Street, North Bay, Ontario P1B 5A4.
0002-9173/82/1000/0511 $00.95 ©
Unified Laboratory of North Bay's Hospitals, North Bay
Civic Hospital, North Bay, Ontario, Canada
Most of the pancreatic tissue consisted of a single slice
taken from the mid-portion of the gland's body. It was
fixed in 10% formalin, embedded in paraffin, and stained
with routinely employed Hematoxylin-Phloxin-Saffron
(H.P.S.) stain. A few selected blocks of tissue were cut
serially, and some sections were stained with P.A.S.,
P.T.A.H., and Gabe's stains, as well as with the silver
impregnation methods of Bielschowski and Hellman
and Hellenstrom.
Pancreatic sections measured 2.0-3.5 X 1.5-2.2 cm.
All were scanned microscopically at a magnification of
X100.
To obtain the mean number of islets and Langerhans
per section, the latter were counted at a magnification
of XI00 in 10 random fields in the first 85 autopsies of
the series.
Results
Nesidioblastosis was identified mainly by the presence
of ductulo-insular complexes (D-ICs), in which there
was a continuity between the epithelial elements of ductules and islets (Fig. 1). In all of these complexes the
basement membranes of the ductules are either absent
or loosened. Occasionally the ductules showed ball-like
aggregations of islet epithelium that pushed their basement membrane outwards (Fig. 2). Although D-ICs occasionally were found within the pancreatic lobules, they
were seen mostly in the expanded periductal connective
tissue, and frequently were associated with proliferation
of ductules.
Of the 207 autopsies, the pancreata of 76 (36.7%)
showed varying numbers of D-ICs. In seventy of the 76,
there were 1 -6 per section, and in six, 6 or more. They
were found in 29 women and in 47 men. The oldest
individual was an 84-year-old man.
Scattered insular cells, single or arranged in small
groups, were observed in 22 (28.9%) pancreata with DICs, and in 35 (16.9%) of the series. Serial sections of
one pancreas from the former group, showed that many
of these cellular aggregates were ordinary islets. The centro-acinar cells were prominent in 10 glands with D-ICs,
and in 17 without D-ICs.
erican Society of Clinical Pathologists
511
512
A.J.C.P. • October 1982
KARNAUCHOW
FIG. 1 (/e/?). (AJ-1682, male, 62 years old). Newly formed islet surrounding portions of a branching duct identified on serial sections.
Basement membrane of the duct is either absent or loosened. Combined HPS and Bielschowski's stains (X400).
FIG. 2 (right). (Same case as in Fig. 1). A ball of islet cells arising from the epithelium of a duct. Basement membrane of the latter is pushed
outwards. PAS (X400).
There was no relationship between the presence of
either D-ICs or insular cells in the acinar parenchyma
and the causes of death or other pathologic states found
in this series. In 44, the D-ICs were associated with fibrosis. However, there was no correlation between their
number and the degree of fibrosis. In fact, there were
80 pacreata which showed varying degrees offibrosisbut
no D-ICs. Thus, their occurrence in 124 fibrotic glands
was only 35.5%. There was no correlation between them
and dilatation of ducts, since the latter was present in
five glands with D-ICs and in seven without D-ICs. Likewise, there were 30 showing amyloidosis of the islets of
which only 14 were associated with these complexes.
The mean number of islets of Langerhans in the 85
pancreata was 65. When sections of the glands contained
100 islets or more, they were considered to show insular
hyperplasia. This was found in 39 pancreata with D-ICs
and in 48 without D-ICs.
P.T.A.H., Gabe's and Hellman and Hellenstrom's
stains demonstrated that the complexes and the aggregates within the acinar tissue contained variable proportions of alpha, beta, and delta cells, respectively.
Discussion
Minimal nesidioblastosis was found in 36.7% of this
series of autopsies, and in 28.9% of these, the D-ICs were
associated with insular cells among the acini. In all instances the morphologic changes could not have influenced the individuals' physiologic well being, and may
be interpreted as either a variant of "normal" or as an
effect of mildly abnormal stimulation. The latter is probably closer to the truth.
This study does not suggest possible stimuli that might
produce either of the two morphologic changes of nesidioblastosis. Such factors as exaggeration or prolongation of normal fetal development of insular tissue in
infants,8'20 persistence or lack of inhibitory mechanism
for this process,14 or the presence of some genetic defect10"'1619 considered in infantile hypoglycemia, could
not apply to adults. It seems that neither the ligation of
pancreatic ducts in the dog21 nor cystic fibrosis618 and
chronic pancreatitis in humans313 could be held entirely
responsible for nesidioblastosis or for either of its two
morphologic components. Eighty glands (64.5%) with-
BRIEF SCIENTIFIC REPORTS
Vol. 78 • No. 4
out D-ICs in this series demonstrated mild to moderate
fibrosis, and seven had dilatation of ducts. This is in
accord with the findings of Bartow and co-workers.' In
their series of 70 pancreata with fibrosis, atrophy, chronic pancreatitis, and duct obstruction, only 20 (18.5%)
showed nesidioblastosis. Thus, dilatation of ducts and
fibrosis may well be merely concomitant features within
the otherwise stimulated glands. Brown and associates
suggest that secretin4 and leucine5 may stimulate the
development of nesidioblastosis, while other researchers
implicate syulfonylurea,2,7 and even phenolic laxatives.17
Yang and Hunter24 suggest cachexia as a possible factor,
while Bloodworth and Elliot3 speak of yet unknown
stimuli.
This series does not show a relationship between nesidioblastosis or the presence of D-ICs and other morphologic abnormalities in the pancreas. And, strangely
enough, this applies to the presence of insular cells
within the exocrine tissue as well. It seems that insular
cells and the D-ICs develop asynchronously, and that
their development was initiated by different stimuli.
Also, there was no relationship between the described
morphologic changes and either the diseases responsible
for the deaths, or those that were of secondary and tertiary importance.
Since the work of preceding authors indicates that
beta814 and non-beta813 cells take part in nesidioblastosis, and since the latter occurs with other than hyperinsulinemic syndromes, extensive histochemical studies
were not undertaken. Nevertheless, the limited investigation of a few glands showed that there were variable
numbers of alpha, beta, and delta cells within the D-ICs
and in the insular aggregates among the acini.
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