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0 1992

The Japanese Society of Pathology

Pancreatic Islet Abnormalities in Sudden Infant Death Syndrome Qualitative and Quantitative Analyses of 15 Cases

Masa no ri Hisao ka I, Joji Ha rata ke', Yasu hiro Na ka mura2, and Yohko Itoh3

The pancreata of 15 autopsy cases of sudden infant death syndrome (SIDS) and those of 14 age-matched controls were examined qualitatively and quantitatively to re-evaluate the relationship between pancreatic islet abnormalities and sudden death in infancy. Histopathologically, a diffuse or focal form of nesidioblastosis and septal islets were frequently observed in the pancreata of both groups. Endocrine cell dysplasia was found only in 2 infants who had died of SIDS. Quantitatively, there was little difference of islet cell composition between the SlDS cases and the controls. A relatively high proportion of islet cell area to total pancreatic tissue area was demonstrated in the SlDS group (8.46+4.90% in the pancreatic head ; 8.66+4.23% in the pancreatic body to tail) in comparison with the controls (5.32k 1.77% ; 5.63?1.60%). Although nesidioblastosis and septal islets were considered to be within the limits of normal variation during pancreatic development, endocrine cell dysplasia and quantitatively unusual proliferation of the pancreatic endocrine tissue suggest the possibility that abnormalities in the endocrine pancreas may be causally related to sudden death in infancy. Acta Pathol Jpn 42: 870-875, 1992. Key words : Sudden infant death, Pancreatic islet, Nesidio-

blastosis, Quantitative analysis

Sudden infant death syndrome (SIDS) has been generally defined as the death of an infant or a young child, which is unexpected on the basis of history and where a -

Received August 3, 1992. Accepted for publication October 12, 1992. 'Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, *Department of Pathology, St. Mary's Hospital, Kurume, and 3Department of Legal Medicine, Kurume University School of Medicine, Kurume. Mailing address : Masanori Hisaoka, M.D., Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807, Japan.

thorough necropsy examination fails to reveal a cause of death(1). Although the incidence of SlDS in Japan, 1.2/1,000 live births, is lower than the figure of about 3/ 1,000 in Europe (2, 3), thorough investigation and appropriate measures for prevention of SlDS are urgently required. Although previous extensive studies have considered various plausible or possible causes of death in SIDS, including asphyxia, infection, abnormal respiratory physiology, and metabolic disorder (4-7), 60-70% of deaths are still unexplained (8, 9). Polak et a/. and some other investigators have found islet cell hyperplasia or nesidioblastosis in the pancreata of some SlDS cases, and suggested that hyperinsulinemic hypoglycemia due to abnormal 6-cell (insulinsecreting cell) proliferation could be related to the cause of sudden death (10-13). However, these sporadic case studies seem to be insufficient for establishing the cause of sudden death in infancy. In order to confirm the relationship between such islet cell abnormalities and SIDS, we examined qualitatively and quantitatively the pancreatic endocrine tissue of 15 infants who had died of SlDS and 1 4 age-matched co ntroIs.

MATERIALS AND METHODS SlDS cases Fifteen infants who had died of SlDS a t 11 days to 7 months after birth were carefully selected from among infant autopsy cases seen at our hospitals. All of these cases satisfied the criteria of SIDS; the deaths were sudden and unexpected, without a history of significant abnormalities, i.e. major congenital abnormalities, extreme prematurity, severe infection or serious trauma, and thorough autopsy had failed to reveal any pathological finding considered to be related to sudden death. During life, clinical laboratory tests had not been per-


Acta Pathologica Japonica 4 2 (12): 1992

formed on most of the infants. Little abnormality was detected in the few examined, and all of the deaths of the infants selected were clinically "unexplained". In addition, these cases also conformed to the revised definition of SlDS drafted recently (14). Fourteen age-matched controls (aged 8 days to 8 months) were also selected from among infant autopsy cases seen at our hospitals. All of them were confirmed to have had a clear cause of death; sepsis or severe respiratory infection (5 cases), congenital cardiac anomalies (4 cases), hydrocephalus (2 cases), cystic dysplastic kidney (1 case), bronchopulmonary dysplasia (1 case) and acute monocytic leukemia (1 case). The duration of their clinical courses was generally short (mean, 37.4 days). Although exact clinical data on pancreatic hormones were unavailable, these controls showed no evidence of organic endocrine or metabolic diseases. No persistent abnormalities of glucose homeostasis were detected during their clinical courses. Corticosteroids were not administered except for two infants. Pancreatic sampling a n d immunohistochemistry Samples used in this study were obtained from formalin-fixed pancreatic tissues of subjects in both groups. Tissue specimens were cut from two discrete regions: the pancreatic head, and the body to tail region. Because of some sampling limitations, the total number of specimens obtained were 9 pancreatic head regions and 1 5 body to tail regions from SlDS cases (specimens from both regions were taken from each of 9 cases, and only one specimen of the body t o tail region was taken from each of 6 cases), and 14 head regions and 11 body to tail regions from controls (specimens from both regions were taken from each of 11 controls, and only one specimen of the head region was taken from each of 3 controls). Each specimen was embedded in paraffin and routinely processed for histological examination. In addition to HE staining, immunoperoxidase staining for insulin, glucagon, somatostatin and pancreatic polypeptide (PP) using the avidin-biotin complex method was performed respectively on serial sections of each tissue specimen. Furthermore, immunostaining with combined antisera against these four pancreatic hormones was done on other sections. The antisera employed were rabbit polyclonal ones obtained commercially from DAKO JAPAN Co., Ltd. (Kyoto, Japan). The PP-cell-rich region was identified in the pancreatic heads of 7 SlDS cases (47%) and 12 controls (86%). Quantitative analysis The relative proportion of the endocrine tissue area to

the total parenchymal area of the pancreas in each tissue section was calculated using an IBAS-2000 automatic image-analysis system (KONTRON Bildanalyse GmbH, Eching, Germany). Optical views of the sections immunostained with combined antisera against the four pancreatic hormones were projected through a microscope onto square fields of a TV monitor a t a magnification of x 185. Contours of the pancreatic islets (including endocrine cells clusters composed of 2 or more endocrine cells) in each field were traced on the monitor, and the total area of enclosed islets or cell clusters was summed automatically by the system. The relative proportion of the islet cell area was estimated by dividing the total summed area enclosed by the total parenchymal area, which was also calculated automatically. Twenty consecutive fields for each section were scanned, covering most of the parenchymal tissue area of the section. Although scanned total parenchymal areas were not markedly different among the subjects (about 17.6 mm2 per region), the number of pancreatic islets examined varied considerably among the subjects (about 30 to 1 5 0 islets per region). The area of isolated or single endocrine cells, observed sparsely in almost all of the specimens, was not evaluated in this analysis because of certain technical limitations in our method and the low contribution of such cell areas to the total measured endocrine tissue area. The populations of the four types of endocrine cells were also evaluated. Positively immunostained endocrine cells in 20 consecutive fields were counted microscopically at a magnification of x200 in each immunostained serial tissue section, and the relative proportion of each cell type was estimated in each pancreatic region. In total, about 1,200 to 5,500 endocrine cells per region were identified and counted. In the cases showing a PP-rich region in the pancreatic head, the cell composition was evaluated respectively in PP-rich and PP-poor regions in the same section. Differences between means were assessed by Welch's t test.

RESULTS P a thol o g ica I findings Microscopic examination of the pancreata from SlDS cases and controls revealed a smaller-sized lobular arrangement of acinar tissue and scattered pancreatic islets or small packets of endocrine cells within or outside the pancreatic lobules. Pancreatic islets varied in size and shape not only among the SlDS cases but also among the selected areas, even in a single case. A focal or diffuse form of unusual islet cell proliferation (focal or diffuse nesidioblastosis) was a common finding

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Pancreatic Islet Abnormalities in SlDS (Hisaoka et a / . )

Figure 1. Photomicrographs of various islet abnormalities observed in the pancreata of SlDS cases and controls. a : Focal nesidioblastosis (SIDS, pancreatic tail, immunoperoxidase staining with combined antisera). b: A septal islet (control, pancreatic head, HE). c : Endocrine cell dysplasia (SIDS, pancreatic tail, immunoperoxidase staining with combined antisera). d : Islet cell hypertrophy (arrows) (SIDS, pancreatic head, HE).

in both groups. Each focal lesion was composed of large islets and partly confluent endocrine cell clusters in restricted areas, being evident in 6 SlDS cases (40%) and 5 controls (36%) (Fig. l a ) . In each diffuse lesion, a large number of various-sized islets and small packets of endocrine cells were distributed evenly throughout the pancreatic tissue, being evident in 3 SlDS cases (20%) and 2 controls (14%). Septal islets, i.e. islets lying entirely within the septal connective tissue stroma of the pancreas, were constantly observed in both groups, and the sizes of the islets varied considerably (Fig. lb). This was evident in 13 SlDS cases (87%) and 13 controls (93%). lmmunohistochemically, the islets observed were composed of an admixture of four types of endocrine cells (B, A (glucagon-secreting), D (somatostatin-secreting) and

Table 1. Pancreatic Islet Abnormalities in SlDS and Control Infants Islet abnormalities Nesidio blastosis focal diffuse Septal islets Endocrine cell dvsalasia

SlDS (n=15)

6 (40%) 3 ~20%) 13 (87%) 2 (13%)

Controls (n=14) 5 (36%) 2 (14%) 13 (93%)


PP (PP-secreting) cells) with a relative predominance of B cells. The distribution of these cells within the islets showed no distinct abnormalities. Scattered endocrine cells or cell clusters within the acinar tissue were also immunostained positively for various types of hormones. Although a small number of immunostained endocrine cells were identified in the ductal epithelium in most of

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Acta Pathologica Japonica 42 (12): 1992

Table 2. Relative Proportions (mean%) of Pancreatic Endocrine Cells and Areas in SlDS Cases and Controls B cell

% Endocrine cells A cell D cell

PP cell

SlDS (n=15) head region (n=9) PP-rich (n=7) PP- poor (n=9) Body to tail region (n=15)

26.44 f6.25 57.73 f3.65

5.94 k2.10 18.00 f4.68

14.16 f4.66 23.24 i5.13

53.47 f8.05 1.03 f0.61

3562 f1064 3208 k2095

56.04 k8.23

19.35 k3.65

24.04 f6.03

0.57 1-0.29

4214 f1192

Controls (n=14) head region (n=14) PP-rich (n=12) PP-poor (n=14) body t o tail region (n=ll)

22.05 k7.62 56.49 f9.86

8.06 t7.00 18.63 1-7.72

10.95 k3.90 23.98 f7.91

58.95 k13.57 0.90 f0.65

3797 t1047 2884 f1484

58.23 k11.71

19.02 f8.77

21.98 f9.17

0.78 k0.58

4091 k1418

Total endocrine cells counted

% Endocrine cell area 8.46 k 4 . 9 0





Each value indicates mean+SD;



Difference statistically significant, P0.05; 5 . 6 3 2 1 . 6 0 s in the body to tail, P

Pancreatic islet abnormalities in sudden infant death syndrome. Qualitative and quantitative analyses of 15 cases.

The pancreata of 15 autopsy cases of sudden infant death syndrome (SIDS) and those of 14 age-matched controls were examined qualitatively and quantita...
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