Nakagawa et al. Diagnostic Pathology(2023) 18:115
https://doi.org/10.1186/s13000-023-01403-y

Diagnostic Pathology

Open Access

RESEARCH

Circularity of islets is a distinct marker for thepathological diagnosis of adult non-neoplastic
hyperinsulinemic hypoglycemia using surgical
specimens
Ryota Nakagawa1,2, Sachiko Minamiguchi1*, Tatsuki R. Kataoka2, Junji Fujikura3, Toshihiko Masui4,
Masakazu Fujimoto1, Yosuke Yamada1, Yasuhide Takeuchi1, Yuki Teramoto1, Hiroaki Ito1, Manduwa Saka1,
Kyohei Kitamura1, Shinya Otsuki1, Ryohei Nishijima1 and Hironori Haga1
Abstract
Background Adult non-neoplastic hyperinsulinemic hypoglycemia (ANHH), also known as adult-onset
nesidioblastosis, is a rare cause of endogenous hyperinsulinemic hypoglycemia in adults. This disease is characterized
by diffuse hyperplasia of pancreatic endocrine cells and is diagnosed by a pathological examination. While diagnostic
criteria for this disease have already been proposed, we established more quantitative criteria for evaluating islet
morphology.
Methods We measured the number, maximum diameter, total area, and circularity (representing how closely islets
resemble perfect spheres) of islets contained in representative sections of ANHH (n = 4) and control cases (n = 5)
using the NIS-Elements software program. We also measured the average cell size, percentage of cells with enlarged
nuclei, and percentage of cells with recognizable nucleoli for each of three representative islets. We also assessed theinterobserver diagnostic concordance of ANHH between five experienced and seven less-experienced pathologists.
Results There was no significant difference in the number, maximum diameter, or total area of islets between
the two groups, even after correcting for these parameters per unit area. However, the number of islets with low
circularity (< 0.71) per total area of the pancreatic parenchyma was significantly larger in ANHH specimens than incontrols. We also found that the percentage of cells with recognizable nucleoli was significantly higher in the ANHH
group than in the controls. There were no significant differences in the average cell size or the number of cells withenlarged nuclei between the groups. The correct diagnosis rate with the blind test was 47.5% ± 6.12% for experienced
pathologists and 50.0% ± 8.63% for less-experienced pathologists, with no significant differences noted.
Conclusions Low circularity, which indicates an irregular islet shape, referred to as “irregular shape and occasional
enlargement of islets” and “lobulated islet structure” in a previous report, is a useful marker for diagnosing ANHH. An*Correspondence:
Sachiko Minamiguchi
minami@kuhp.kyoto-u.ac.jp
Full list of author information is available at the end of the article© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use,sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) andthe source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in thisarticle are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not includedin the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you willneed to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The
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Nakagawa et al. Diagnostic Pathology(2023) 18:115

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increased percentage of recognizable nucleoli, corresponding to “macronucleoli in β-cells,“ has potential diagnostic
value.
Keywords Adult non-neoplastic hyperinsulinemic hypoglycemia (ANHH), Circularity, Digital pathology, Image
analysis, Islets, Nesidioblastosis, NIS-Elements, Quantitative criteria

Introduction
Persistent hyperinsulinemic hypoglycemia (PHH) iscaused by impaired control of insulin release from nonneoplastic and neoplastic β-cells of the pancreatic islets[1]. The primary cause of PHH in infants is nesidioblastosis, while that in adults is insulinoma [1]. Nesidioblastosis is histologically characterized by diffuse or focal
hypertrophic β-cells in the pancreas, [2, 3] first describedin infants [4]. Adult-onset nesidioblastosis was firstreported in 1975, [5] and only a small number of adultonset nesidioblastosis cases have since been described[1]. Adult-onset nesidioblastosis has recently beenreferred to as adult non-neoplastic hyperinsulinemic
hypoglycemia (ANHH) [6] and is estimated to accountfor 0.5-5% of adult PHH cases [7].
The hypertrophic β-cells in ANHH are thought to bedysregulated in their function as a result of abnormal
pathological features [8]. Anlauf et al. proposed diagnostic criteria for this disease, as shown in Table 1 [9]. Eachof the major criteria as well as the minor criterion “macronucleoli in β-cells” seem to be objectively confirmed bya careful microscopic examination supported by insulin
and Ki-67 immunohistochemistry. However, we believethat inter- and intraobserver variability can exist in theconfirmation of the minor criteria “irregular shape andoccasional enlargement of islets,” “increased number ofislets,” and “lobulated islet structure,” owing to the lack ofa quantitative standard for these items.
Therefore, we established more quantitative criteria toevaluate the morphology of islets in ANHH specimens bycomparing them with those in control specimens.

Table 1 Histopathologic criteria for the diagnosis of diffuse
nesidioblastosis in adults (recently known as ANHH) proposed byAnlauf et al.
MAJOR CRITERIAMINORCRITERIA
Exclusion of an insulinoma by macroscopic, microIrregular shapescopic, and immunohistochemical examinations
and occasional
enlargement of
isletsMultiple β-cells with an enlarged and hyperchromatic Increased numnucleus and abundant clear cytoplasm
ber of islets
Islets with normal spatial distribution of the various
Lobulated islet
cell types
structure
No proliferative activity of endocrine cells
Macronucleoli
in β-cells

Materials and methods
Patients

We identified four cases of ANHH in the pathological
database of Kyoto University Hospital between 1988 and2022. The clinicopathological features of the patients are
summarized in Table 2A. All four cases had PHH. Two of
the four cases (Cases 1 and 3) were suspected of having
ANHH owing to the lack of tumor-like nodules on computed tomography (CT), and the other two cases (Cases 2
and 4) were suspected of having an insulinoma or ANHH
before distal pancreatectomy. Two cases of the ANHH
specimens used for the evaluation were from the pancreatic tail (cases 1 and 2), and the other two were from thepancreatic body (cases 3 and 4).
Controls were obtained from autopsied pathological specimens at the Department of Diagnostic Pathology, Kyoto University Hospital, and the Department of
Pathology, Iwate Medical University. Suitable conditions
for controls were as follows: (1) no pancreatic tumor(including neuroendocrine tumor); (2) no metastasis orinvasion of the tumor into the pancreatic parenchyma or
peripancreatic tissue (adipose tissue, blood, or lymphatic
vessels); (3) no history of diabetes; (4) no chronic pancreatitis; (5) no intensive systemic treatment; and (6) good
fixation and no advanced autolysis. One control specimen was obtained from the pancreatic tail (cases 1 and2), two from the pancreatic head (case 3), and two fromthe pancreatic body (cases 4 and 5). Clinicopathologicalfeatures of the control cases are summarized in Table 2B.
Pathological diagnoses

The pancreas in all four ANHH cases was entirely
resected and examined (representative case shown in
Fig. 1). All pancreatic specimens were cut perpendicular
to the main pancreatic duct and preserved as formalinfixed paraffin-embedded (FFPE) samples. Hematoxylineosin (H&E) staining and immunostaining for insulin(guinea pig polyclonal, Cat# A05664; DAKO, Glostrup,
Denmark), glucagon (rabbit polyclonal, Cat# N1541;
DAKO), pancreatic polypeptide (rabbit polyclonal, Cat#
A0619; DAKO), somatostatin (rabbit polyclonal, Cat#N1551; DAKO), Ki-67 (mouse monoclonal, Cat# M7240;
DAKO), and proliferating cell nuclear antigen (PCNA)(rabbit monoclonal, Cat# 13,110; Cell Signaling Technology, Boston, MA, USA) were performed using a Ventana
Benchmark Ultra autoimmunostainer (Roche Diagnostics, Mannheim, Germany) according to the manufacturer’s protocols. H&E staining was also performed on all

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Table 2 Clinicopathological features of the current cases(A) ANHH cases.

Clinical Diagnosis
CT scan
Surgical procedure
Postoperative course

ANHH
No noduleDP
No hypoglycemic
symptom

CASE 2
54/M
Hypoglycemia with
LOC
Insulinoma
No noduleDP
Occasional hypoglycemic symptom

Type
Site of the pancreas in a representative section(B) Control cases.

Diffuse
Tail

DiffuseTail

CASE 3
49/F
Hypoglycemia with headache and LOC after TG
ANHH
No noduleDP
Repeated hypoglycemic
symptoms
12 years after operation,
she died of ischemic heartdisease
DiffuseBody

CASE 1

CASE 2

CASE 3

CASE 474/F
pulmonaryvascular injury,
AAV, HLH, aspergillosis, pulmonary
nocardiosis
Tail

46/F
Ruptured esophageal varices, PSC,
UC, LC

65/M
Systemic metastasis of
prostate cancer

69/M
ICH, HT

Tail

Head

Body

Age (years)/Gender
Symptom

Age (years)/GenderDiseases

Site of the pancreas in a representative section

CASE 1
24/M
HH

CASE 434/F
HH witharrhythmia
Insulinoma
No noduleDP
No data

Diffuse
Body
CASE
5
65/M
AP,
peritonitis,
ALS
Body

AAV, anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis; ALS, amyotrophic lateral sclerosis; ANHH, adult nonneoplastic hyperinsulinemic
hypoglycemia; AP, aspiration pneumonia; DP, distal pancreatectomy; HH hyperinsulinemic hypoglycemia; HLH, hemophagocytic lymphohistiocytosis; HT,
hypertension; ICH, intracerebral hemorrhaging; LC, liver cirrhosis; LOC, loss of consciousness; PSC, primary sclerosing cholangitis; TG, total gastrectomy; UC,
ulcerative colitis

FFPE samples in the control cases, and immunostaining
for insulin was performed in some cases. A microscopic
examination was performed according to the criteria
proposed in Ref. 8.
The measurement of the numbers, maximum diameters,
total areas, and circularities of the islets

Representative sections of ANHH and control specimens
were digitized using whole-slide imaging (WSI) (Nanozoomer RS or Nanozoomer S360; Hamamatsu Photonics
KK, Hamamatsu, Japan). The number, maximum diameter, perimeter, and area of each islet in each specimen
were measured using an image analysis system (NISElement D software program, version 5.30.00; Nikon,
Tokyo, Japan). Islets of any size were evaluated. The measurement method is shown in the schematic illustration(Fig. 2A). The cross-sectional area of pancreatic parenchyma was measured in the same manner. The circularity
ranged from 0 to 1.0, with a higher circularity meaningthat the shape of the given islet was closer to a circle [9–11]. In this study, circularity was calculated using the following formula: 4π × (area of islet) / (perimeter of islet)2.
We adopted 0.71 as a threshold value because it was thevalue that generated the largest statistically significant
difference.

The measurement of cell size, the percentage of cellswith enlarged nuclei, and the percentage of cells withrecognizable nucleolus of the representative islets

For each of the three representative islets, we measured
the average cell size (number of cells in the islet divided
by the area of the islet), percentage of cells with enlarged
nuclei (nucleus size: ≥9 μm), and percentage of cells inwhich the nucleoli could be recognized (nucleolus size:≥1.5 μm) using the virtual slides above.
Interobserver analyses

We conducted a blind assessment of the virtual slides
of four ANHH cases (cases 1–4) and four control cases(cases 1–4) to evaluate interobserver diagnostic concordance. The evaluations were performed by 5 experienced
pathologists (≥ 10 years’ experience) and 7 less-experienced pathologists (< 10 years’ experience). After presenting the diagnostic criteria in Table 1, pathologists
were asked to identify whether they were ANHH orcontrols. The number of ANHH and controls are notpresented.
Statistical analyses

Data in Table 3; Fig. 3 are expressed as the mean ± standard error. Differences between the groups were examined for statistical significance using an unpaired t-test

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The measurement of the numbers, maximum diameters,
total areas, and circularities of the islets in adult-onset
ANHH

We measured and compared the number, maximum
diameter, total area, and circularity of the islets in ANHH
(n = 4) and control specimens (n = 5). No significant differences were noted in the number, maximum diameter,or total area of islets between the two groups (Table 3).
We also compared these parameters when correcting
per unit area of the pancreatic parenchyma, with no significant differences observed in the corrected parameters(Table 3). The average number of islets per specimen in
the ANHH cases was 417 ± 67.8, and the average area was
199 ± 8.29 mm2; the average number of islets per specimen in the control cases was 501 ± 90.0, and the averagearea was 247 ± 27.7 mm2.
Next, we evaluated the circularity of the ANHH andcontrol specimens, as in previous reports [9–11]. The
number of islets with circularity < 0.71 per total areaof the pancreatic parenchyma was significantly greaterin the ANHH specimens than in the control specimens(Table 3; Fig. 3).

Fig. 1 Pathological features of ANHH. (A) Macroscopic and (B) microscopic examinations (H&E) and (C) insulin immunostaining reveal no mass lesion in the sections of the resected pancreas. (D) Ductuloinsular complex.
H&E. (E) Multiple β-cells with an enlarged and hyperchromatic nucleus
and abundant clear cytoplasm. H&E. (F) Macronucleoli in β-cells. H&E. (G-J)
Immunostaining. Islets with normal spatial distribution of the various cell
types. (G) Insulin, (H) Glucagon, (I) Somatostatin, and (J) Pancreatic polypeptide staining. (K) Ki-67 immunostaining reveals no proliferative activityof the islet cells. Scale bars in B, C, G-K are 250 μm; the scale bar in D is
100 μm; the scale bar in E is 50 μm; and the scale bar in F is 25 μm(Excel; Microsoft, Redmond, WA, USA). P was set at
p < 0.05.

Results
Macroscopic and microscopic examinations of the four
ANHH cases

Macroscopically, all four cases lacked tumor-like nodules(representative case in Fig. 1). Immunohistochemically,
proliferation markers, Ki-67 and PCNA were negative inislets of four ANNH cases (Fig. 1K and Supplementary
Figure S1). Three of the four examined ANHH specimens met all major diagnostic criteria, and the remainingcases met three of the four major criteria (Table 4). Twocases met the minor criterion “macronucleoli in β-cells”(Table 4), and three cases showed “ductuloinsular complex”, which is non-specific but characteristic of ANHH
(Table 4) [8]. The histopathological images are shown in
Figs. 1 and 2.

The measurement of the cell size, percentage of cells withenlarged nuclei, and percentage of cells with recognizable
nucleoli of the representative islets

We found that the percentage of nucleoli of islet cellswith a recognized size in ANHH specimens was significantly higher than that in the control specimens (Supplementary Table S1). There was no significant difference inthe average cell size or cells with enlarged nuclei of islet
cells between ANHH and control cases.
Interobserver analyses

The experienced pathologists correctly diagnosed ANHH
in 47.5% ± 6.12% of cases, while the less-experienced did
so in 50.0% ± 8.63% of cases, resulting in an overall correct diagnostic rate of 49.0% ± 5.43%, showing no significant differences (p = 0.83) (Supplementary Table S2).

Discussion
ANHH is subclassified into focal and diffuse types, andalmost all reported adult cases are of the diffuse type [2,3, 8]. The current cases were all classified as the diffuse
type. Therefore, our conclusion might be inappropriate
for focal-type ANHH, which is difficult to differentiate
from insulinoma [12, 13].
Anlauf et al. proposed the diagnostic criteria of adultonset nesidiobalstosis (recently known as ANHH) [8].
All of the major criteria and the minor criterion “macronucleoli in β-cells” seemed to be objectively confirmed
by a careful macroscopic examination and supported byinsulin and Ki-67 immunohistochemistry. The percentage of recognizable nucleoli (nucleolus size: ≥1.5 μm)

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Fig. 2 Measurement procedure of the islets (A), representative images with each circularity value (B) and representative images showing an irregularshape of the islets in ANHH cases compared to controls (insulin immunostaining) (C)in representative islet cells of ANHH cases in the present study was significantly higher than that in the control
cases. However, inter- and intraobserver variability may
exist in efforts to confirm the minor criteria “irregularshape and occasional enlargement of islets,” “increased
number of islets,” and “lobulated islet structure.” It isdifficult to diagnose ANHH correctly, regardless of thepathologist’s experience. This may be due to a lack ofprior clinical information and limited experience indiagnosing ANHH. Therefore, we explored quantitative

assessment methods to help improve the diagnostic rateof ANHH.
The degree of circularity can reflect an “irregular shapeand occasional enlargement of islets” and “lobulated islet
structure” Thus, our finding that circularity is a marker
for the diagnosis of ANHH seems acceptable. In contrast,
an “increased number of islets” may not be useful for
diagnosing ANHH. Circularity is calculated by the areaand perimeter, which can be easily measured using animage analysis software program, such as NIS-Elements,
ImageJ (https://imagej.nih.gov/ij/), or NDP viewer.

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Table 3 The measured parameters and aspect ratio of the islets
of ANHH and control cases
ANHH (n = 4)
Number of islets
417 ± 67.8
Number of islets per total
211 ± 38.6
area of pancreas [/cm2]
Total area of islets [cm2]0.0403 ± 0.0119
Total area of islets per
2.07% ± 0.661%
total area of pancreas
Maximum diameter [µm]107 ± 14.0
Number of islets with82 ± 19.0
circularity < 0.71

Control (n = 5)
501 ± 90.0
200 ± 25.4

P
value
0.50
0.80

0.0474 ± 0.00916
1.92% ± 0.315%

0.64
0.833

105 ± 8.97
30 ± 5.71

0.89
0.023

However, if no such program is available, the images
depicting different degrees of circularity in Fig. 2B C may
help pathologists diagnose ANHH morphologically.
There was no significant difference in the percentage of cells with enlarged nuclei between ANHH andcontrol specimens, but the percentage of islet cells withrecognizable nucleoli was significantly higher in ANHH
specimens than in control specimens. An increased

percentage of islet cells with recognizable nucleoli may
be a useful marker for diagnosing ANHH.
Extremely large islets, called “islet clusters”, have an
area greater than 100,000 µm2 as defined in Ref. 14 andare sometimes found in the normal pancreas. In the current study, there was 1 islet with an area greater than
100,000 µm2 in the ANHH group and 5 in the control
group. There was no marked difference in the islet size
between ANHH and control specimens, and the average size of islets in the control cases was comparable topreviously reported values [11, 14]. The presence of islet
clusters might render “increased number of islets” and“occasional enlargement of islets” not useful for diagnosing ANHH.

Conclusions
Circularity can be easily measured using digital slide
images and an image analysis system. Low circularity (< 0.71) in islets should be considered to indicate anirregular islet shape and be taken as a useful marker for
diagnosing ANHH, in contrast to the number, density,

Fig. 3 Number of islets with circularity < 0.71 per total area of pancreas parenchyma in patients with diffuse adult-onset ANHH compared with control
specimens

Table 4 Concordance with each major and minor diagnostic criteria of ANHH in the current cases
Criteria
Case
Exclusion of an insulinoma
Multiple β-cells with an enlarged nucleus(Diameter of nucleus is more than 15 μm)
Multiple β-cells with a hyperchromatic nucleus
Multiple β-cells with an abundant cytoplasm
Islets with normal spatial distribution of the various cell types
No proliferative activity of endocrine cells
Macronucleoli(Diameter of nucleolus is more than 5 μm)
Ductuloinsular complex

ANHH
1
P
P

2
P
N

3
P
P

4
P
P

Control
1
2
P
P
N
P

3
P
P

4
P
P

5
P
P

P
P
P
P
P

P
P
P
P
N

P
P
P
P
P

P
P
P
P
N

N
P
P
P
N

P
P
P
P
P

P
P
P
P
P

P
P
P
P
N

N
P
P
P
N

N

P

P

P

N

N

N

N

N

ANHH, adult nonneoplastic hyperinsulinemic hypoglycemia; N, negative; P, positive

Nakagawa et al. Diagnostic Pathology(2023) 18:115

area, or maximum diameter of the islets, subsequent tothe confirmation of PHH and the following major criteria: exclusion of insulinoma; multiple β-cells withenlarged and hyperchromatic nuclei and abundant, clear
cytoplasm; islets with normal spatial distribution of various cell types; and no proliferative activity of endocrine
cells. An increased percentage of recognizable nucleoli,
corresponding to the minor criterion “macronucleoli in
β-cells,“ thus has potential diagnostic value.
Abbreviations
AAV	Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis
ALS	Amyotrophic lateral sclerosis
ANHH	Adult nonneoplastic hyperinsulinemic hypoglycemia
AP	Aspiration pneumonia
DP	Distal pancreatectomy
HH	Hyperinsulinemic hypoglycemia
HLH	Hemophagocytic lymphohistiocytosisHT	Hypertension
ICH	Intracerebral hemorrhage
LC	Liver cirrhosis
LOC	Loss of consciousness
PCNA	Proliferating cell nuclear antigen
PSC	Primary sclerosing cholangitis
SE	Standard error
UC	Ulcerative colitis

Supplementary Information

The online version contains supplementary material available at https://doi.
org/10.1186/s13000-023-01403-y.
Supplementary Material 1: Supplementary table S2 Interobserver
Analyses.
Supplementary Material 2: Supplementary table S1 The measured cellparameters for each of the three representative islets of the ANHH andcontrol groups.
Supplementary Material 3: Supplementary figure S1 (A) Islets of ANHH.
H&E. (B) Proliferating cell nuclear antigen (PCNA) immunostaining reveals
no proliferative activity of the islet cells. Scale bars = 250 μm.
Acknowledgements
This study was financially supported by JSPS KAKENHI (Grant Number
21K06909).
Authors’ contributions
SM and HH conceived of and designed the study. RN, SM, JF, TM, MF, YY, YT, YT,
HI, MS, KK, SO, RN, and HH acquired data. RN, SM, and TRK analyzed the data.
RN, SM, TRK, and HH drafted the manuscript and the figures. All authors haveread and agreed to the published version of the manuscript.
Funding
Not applicable.
Data Availability
The dataset supporting the conclusions of this article is included within thearticle.

Declarations
Competing interests
The authors declare no competing interests.

Page 7 of 7

Ethics approval and consent to participate
Informed consent was obtained following the local ethical guidelines and the1975 Declaration of Helsinki.
Author details
1
Department of Diagnostic Pathology, Kyoto University Hospital, Sakyoku, Kyoto 606-8507, Japan2
Department of Pathology, Iwate Medical University, Yahaba-cho, Shiwagun, Iwate 028-3694, Japan3
Department of Diabetes, Endocrinology and Nutrition, Kyoto University
Hospital, Sakyo-ku, Kyoto 606-8507, Japan
4
Department of Department of Hepatobiliary Pancreatic Surgery andTransplantation, Kyoto University Hospital, Sakyo-ku, Kyoto
606-8507, Japan
Received: 18 August 2023 / Accepted: 17 October 2023

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