Individual Keratinocyte Necroses in the Epidermis Are Apoptotic Keratinocytes in the Skin.

The patient was a 44-year-old woman with Stevens-Johnson syndrome due to receiving Baktar® (sulfamethoxazole trimethoprim) medication at our outpatient dermatology clinic. The epidermis, dermis, and subcutaneous adipose tissue samples showed numerous necrotic keratinocytes in the epidermis. Apoptotic nuclei were visualized as diaminobenzidine brown deposits with immunoperoxidase staining for cleaved caspase-3. The cleaved caspase-3-positive findings were consistent with eosinophilic material that appeared to be necrotic cells within the epidermis. Therefore, these eosinophilic materials may be apoptotic bodies. Generally speaking, eosinophilic cells are considered necrotic keratinocytes, especially in Japan. To the best of our knowledge, no studies have used apoptotic immunohistochemical markers to examine whether these structures are apoptotic in a human specimen.

Colloid Carcinoma Arising in an Intestinal-Type Intraductal Papillary Mucinous Neoplasm with High-Grade Dysplasia Appearing as Signet-Ring Cells of the Pancreas by Serial Pancreatic Juice Aspiration Cytology: A Case Report.

We report a case of colloid carcinoma (CC) arising from an intestinal-type intraductal papillary mucinous neoplasm with high-grade dysplasia (IPMNHGD) of the pancreas, diagnosed with serial pancreatic juice aspiration cytological examination (SPACE). A rapidly growing intraductal papillary mucinous neoplasm (IPMN) in a 71-year-old Japanese man accelerated his hospitalization in our institute. Clinically, a large, ruptured pancreatic cyst was suspected. Cytologically, several mucin-positive signet-ring cells were scattered in the inflammatory, necrotic, or mucinous background. Signet-ring cells in cell block specimens were immunoreactive for MUC2, MUC5AC, maspin, S100P, and claudin-18. The final cytologic diagnosis was CC arising in an intestinal-type IPMNHGD with intraperitoneal penetration. The patient died two months after an explorative laparotomy. The cytologic diagnosis was achieved through SPACE, and the presence of signet-ring cells was characteristic. Anti-claudin-18.2-specific monoclonal antibody therapy will likely be used to treat patients with IPMNHGD in the future. This case highlights the diagnostic utility of SPACE, with particular emphasis on the characteristic presence of signet-ring cells. Furthermore, it anticipates the potential use of anti-claudin-18.2- specific monoclonal antibody therapy in the management of IPMNHGD patients.

Systemic amyloidosis with amyloid goiter: An autopsy report.

Systemic amyloidosis is a rare but potentially lethal disease characterized by amyloid accumulation in all organs. Amyloid goiter is an extremely rare pathological lesion characterized by thyroid gland enlargement with fat deposition due to local or systemic amyloidosis. A 60 s woman with rheumatoid arthritis was found unconscious on her bed and declared dead after failed cardiopulmonary resuscitation. Postmortem computed tomography showed severe enlargement of the heart and thyroid glands, suggestive of cardiac hypertrophy and thyroidism. Histological examination revealed amorphous eosinophilic deposits with parenchymal cell destruction in all organs, including the heart and thyroid gland. Abnormal amorphous deposits in the tissues were positive for amyloid A as noted upon Congo red immunohistochemical staining and birefringence microscopy, confirming systemic amyloidosis with amyloid goiter. Serum biochemical analysis revealed increased levels of C-reactive protein; anti-cyclic citrullinated peptide antibody; creatinine kinase-myoglobin binding and N-terminal pro-brain natriuretic peptide; and thyroglobulin, free triiodothyronine, and free thyroxine, indicating systemic inflammation, active rheumatoid arthritis, heart failure, and destructive hyperthyroidism, respectively. These findings suggested that the cause of death was undiagnosed heart failure due to secondary systemic amyloid A (AA) amyloidosis related to rheumatoid arthritis. In addition, destructive hyperthyroidism caused by systemic AA amyloidosis may have also been one of the causes of death as indicated by cardiac overload. To the best of our knowledge, this is the first forensic autopsy report of cardiac amyloidosis with amyloid goiter. In conclusion, this autopsy report highlights the importance of increased awareness and early intervention for severe but treatable complications of systemic amyloidosis.

Mitochondrial fission in hepatocytes as a potential therapeutic target for nonalcoholic steatohepatitis.

AIM: The mitochondria are highly plastic and dynamic organelles; mitochondrial dysfunction has been reported to play causative roles in diabetes, cardiovascular diseases, and nonalcoholic fatty liver disease (NAFLD). However, the relationship between mitochondrial fission and NAFLD pathogenesis remains unknown. We aimed to investigate whether alterations in mitochondrial fission could play a role in the progression of NAFLD. METHODS: Mice were fed a standard diet or choline-deficient, L-amino acid-defined (CDAA) diet with vehicle or mitochondrial division inhibitor-1. RESULTS: Substantial enhancement of mitochondrial fission in hepatocytes was triggered by 4 weeks of feeding and was associated with changes reflecting the early stage of human nonalcoholic steatohepatitis (NASH), steatotic change with liver inflammation, and hepatocyte ballooning. Excessive mitochondrial fission inhibition in hepatocytes and lipid metabolism dysregulation in adipose tissue attenuated liver inflammation and fibrogenesis but not steatosis and the systemic pathological changes in the early and chronic fibrotic NASH stages (4- and 12-week CDAA feeding). These beneficial changes due to the suppression of mitochondrial fission against the liver and systemic injuries were associated with decreased autophagic responses and endoplasmic reticulum stress in hepatocytes. Injuries to other liver cells, such as endothelial cells, Kupffer cells, and hepatic stellate cells, were also attenuated by the inhibition of mitochondrial fission in hepatocytes. CONCLUSIONS: Taken together, these findings suggest that excessive mitochondrial fission in hepatocytes could play a causative role in NAFLD progression by liver inflammation and fibrogenesis through altered cell cross-talk. This study provides a potential therapeutic target for NAFLD.

A proof-of-concept study to construct Bayesian network decision models for supporting the categorization of sudden unexpected infant death.

Sudden infant death syndrome (SIDS) remains a leading cause of infant death in high-income countries. Supporting models for categorization of sudden unexpected infant death into SIDS/non-SIDS could reduce mortality. Therefore, we aimed to develop such a tool utilizing forensic data, but the reduced number of SIDS cases renders this task inherently difficult. To overcome this, we constructed Bayesian network models according to diagnoses performed by expert pathologists and created conditional probability tables in a proof-of-concept study. In the diagnostic support model, the data of 64 sudden unexpected infant death cases was employed as the training dataset, and 16 known-risk factors, including age at death and co-sleeping, were added. In the validation study, which included 8 new cases, the models reproduced experts' diagnoses in 4 or 5 of the 6 SIDS cases. Next, to confirm the effectiveness of this approach for onset prediction, the data from 41 SIDS cases was employed. The model predicted that the risk of SIDS in 0- to 2-month-old infants exposed to passive smoking and co-sleeping is eightfold higher than that in the general infant population, which is comparable with previously published findings. The Bayesian approach could be a promising tool for constructing SIDS prevention models.

Fatal Dieulafoy lesion with IgG4-related disease: An autopsy case report.

Dieulafoy lesions are rare vascular malformations of the gastrointestinal tract; however, they can lead to fatal vascular bleeding. Immunoglobulin G4-related disease (IgG4-RD) is a rare systemic fibroinflammatory disease involving multiple organs, including the vasculature. To date, no autopsy reports of Dieulafoy lesions with IgG4-RD have been described in the literature. A 48-year-old man was found dead in his home with hematochezia. Postmortem computed tomography revealed high-density gastric contents and an enlarged iso-density area in the pancreas, indicating gastric hemorrhage and mass-forming lesions. Macroscopic and histological examinations revealed an ulcer of the body of the stomach with a large amount of hemorrhage from the enlarged artery in the submucosal layer, confirming the rupture of the Dieulafoy lesion. Moreover, lymphocyte infiltrations with increased IgG4 positive cells were found in the pancreas, thyroid gland, and arteries in non-ulcer regions of the stomach, suggesting IgG4-RD. Serum biochemical analysis showed elevated levels of inflammatory mediators, such as IgE, soluble-interleukin-2 receptor, and C-reactive protein. These findings suggest that systemic inflammation caused by IgG4-RD could, at least in part, contribute to the development of Dieulafoy lesions and fatal rupture of the lesion. This case report highlights the importance of autopsy research focusing on Dieulafoy lesions and IgG4-RD to promote awareness and a better understanding of the relationships between these treatable diseases to establish earlier and effective interventional strategies for better patient outcomes.

Circumstances and factors of sleep-related sudden infancy deaths in Japan.

BACKGROUND: Sudden unexpected death in infancy (SUDI) comprises both natural and unnatural causes of death. However, few epidemiological surveys have investigated SUDI in Japan. OBJECTIVE: This retrospective study was conducted to investigate the latest trends of circumstances and risk factors of SUDI cases in which collapse occurred during sleep. METHODS: Forensic pathology sections from eight universities participated in the selection of subjects from 2013 to 2018. Data obtained from the checklist form were analyzed based on information at postmortem. RESULTS: There were 259 SUDI cases consisting of 145 male infants and 114 female infants with a mean birth weight of 2888 ± 553 and 2750 ± 370 g, respectively. Deaths most frequently occurred among infants at 1 month of age (18%). According to population data as the control, the odds ratio (95% confidence interval) of mother's age ≤19 years was 11.1 (6.9-17.7) compared with ages 30-39. The odds ratio for the fourth- and later born infants was 5.2 (3.4-7.9) compared with the frequency of first-born infants. The most frequent time of day for discovery was between 7 and 8 o'clock, and the time difference from the last seen alive was a mean of 4.1 h. Co-sleeping was recorded for 61%, and the prone position was found for 40% of cases at discovery. Mother's smoking habit exhibited an odds ratio of 4.5 (2.9-5.8). CONCLUSION: This study confirmed the trends that have been observed for sudden infant death syndrome; particularly, very high odds ratios were evident for teenage mothers and later birth order in comparison with those in other developed countries. Neglect was suspected in some cases of the prolonged time to discovery of unreactive infants. To our knowledge, this is the first report of an extensive survey of SUDI during sleep in Japan.

Fatal Mumps Myocarditis Associated with Left Ventricular Non-Compaction.

BACKGROUND Myocarditis is a rare but potentially fatal complication of mumps virus infection. Left ventricular non-compaction (LVNC) is a rare congenital abnormality that can lead to development of low cardiac output, cardiac dysfunction, arrhythmias, or sudden cardiac death. To the best of our knowledge, no autopsy cases of mumps myocarditis with LVNC have been reported in the literature. Here, we report an autopsy case of a 21-month-old girl who died due to mumps myocarditis associated with an undiagnosed LVNC. CASE REPORT Postmortem computed tomography demonstrated bilaterally enlarged parotid glands. Serum analysis of anti-mumps IgM titer was positive. Macroscopic and histological examinations revealed glandular destruction with massive inflammatory cell infiltration of the enlarged parotid glands and mild inflammatory cell infiltration of the heart, which showed prominent trabeculations and deep intra-trabecular recesses, indicating LVNC. Immunohistochemical analyses showed positive immunostainings for mumps in the cardiac and salivary gland tissues. CONCLUSIONS These findings suggest that mumps myocarditis associated with LVNC contributed to this patient's death. Myocarditis patients with other comorbidities, including LVNC, may be at higher risk of sudden death. Further reports of mumps myocarditis and LVNC are needed to better understand the mechanisms of sudden unexpected deaths in children.

Presence of Citrullinated Histone H3-Positive Neutrophils in Microscopic Polyangiitis from the Early Phase: An Autopsy Proven Case.

A 76-year-old man was admitted with general fatigue, weight loss, fever, headache, renal failure, and a high serum level of myeloperoxidase-antineutrophil cytoplasmic antibody. Biopsy revealed citrullinated histone H3 (citH3)-positive neutrophils adherent to the temporal artery endothelium. Three days after completing pulse steroid therapy, he suffered from a sudden disturbance of consciousness and died. On autopsy, the kidneys showed the most severe vasculitis with dense infiltration of citH3-positive neutrophils. The lungs showed intra-alveolar hemorrhage due to capillaritis. Severe brain hemorrhage was found in the left frontal lobe and putamen with uncal herniation. No vasculitis or thrombi was observed in the brain. The right dura mater was thickened due to fibrosis and inflammation. In conclusion, autopsy revealed systemic vasculitis with infiltration of abundant citH3-positive neutrophils, suggesting that the neutrophil extracellular trap formation and citH3 might play important roles in the early phases and development of microscopic polyangiitis.

Clinicopathological Features of 15 Occult and 178 Clinical Pancreatic Ductal Adenocarcinomas in 8339 Autopsied Elderly Patients.

OBJECTIVE: The aim of the study was to investigate the clinicopathological features of pancreatic cancer at different stages using autopsy results. METHODS: We retrospectively evaluated 8399 consecutive cases of autopsy performed between 1972 and 2013 at our geriatric hospital. RESULTS: Macroscopic pancreatic lesions were detected in 6.13% of the cases. Primary and secondary pancreatic tumors were observed in 2.88% and 2.10% of the cases, respectively. Most primary tumors were invasive ductal adenocarcinomas (193 cases [2.31%]; mean patient age, 78.09 years) with a peak incidence at 50 to 59 years. Occult invasive ductal adenocarcinoma was discovered incidentally in 15 cases, with distant metastasis present in 26.67% of those. Microscopically, occult and advanced tumors exhibited similar characteristics such as hyalinized fibrous stroma, necrosis, invasion into vessels, peripancreatic fat tissues, and extrapancreatic nerve plexus. Mucin 1 and 2 immunohistochemical expression levels were also similar. Occult cancer incidence increased with age. Patients aged 85 years or older had shorter survival, a small tumor size, and a low incidence of lymph node metastasis. Approximately 8% of pancreatic invasive ductal adenocarcinomas progressed asymptomatically and were discovered incidentally at autopsy. CONCLUSIONS: Pancreatic cancers in elderly patients tend to progress asymptomatically, but once symptoms develop, they are more often fatal than those in younger patients.

Gradual telomere shortening and increasing chromosomal instability among PanIN grades and normal ductal epithelia with and without cancer in the pancreas.

A large body of evidence supports a key role for telomere dysfunction in carcinogenesis due to the induction of chromosomal instability. To study telomere shortening in precancerous pancreatic lesions, we measured telomere lengths using quantitative fluorescence in situ hybridization in the normal pancreatic duct epithelium, pancreatic intraepithelial neoplasias (PanINs), and cancers. The materials employed included surgically resected pancreatic specimens without cancer (n = 33) and with invasive ductal carcinoma (n = 36), as well as control autopsy cases (n = 150). In comparison with normal ducts, telomere length was decreased in PanIN-1, -2 and -3 and cancer. Furthermore, telomeres were shorter in cancer than in PanIN-1 and -2. Telomere length in cancer was not associated with histological type, lesion location, or cancer stage. PanINs with or without cancer showed similar telomere lengths. The incidences of atypical mitosis and anaphase bridges, which are morphological characteristics of chromosomal instability, were negatively correlated with telomere length. The telomeres in normal duct epithelium became shorter with aging, and those in PanINs or cancers were shorter than in age-matched controls, suggesting that telomere shortening occurs even when histological changes are absent. Our data strongly suggest that telomere shortening occurs in the early stages of pancreatic carcinogenesis and progresses with precancerous development. Telomere shortening and chromosomal instability in the duct epithelium might be associated with carcinogenesis of the pancreas. Determination of telomere length in pancreatic ductal lesions may be valuable for accurate detection and risk assessment of pancreatic cancer.