Sudden unexpected death after initial infusion of rituximab for Waldenström macroglobulinemia/lymphoplasmacytic lymphoma: an autopsy case.

BACKGROUND: Waldenström's macroglobulinemia (WM) is defined as a lymphoplasmacytic lymphoma (LPL) involving the bone marrow (BM) with presence of IgM monoclonal protein, and comprises > 95% of all LPL cases. Rituximab-based regimens have been predominant in the management of WM. Infusion-related reactions (IRRs) are a primary concern with rituximab, although it is generally better tolerated with less toxicity than conventional anticancer agents. Here, we present an autopsy case of an elderly man who died suddenly after receiving the initial infusion of rituximab for WM/LPL. CASE PRESENTATION: An 84-year-old man was found dead in his bedroom. He had undergone the initial intravenous rituximab infusion for progressive anemia related to Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) approximately 15 h before death. Although the protocol for rituximab administration and additional medication was considered appropriate, he exhibited several symptoms consistent with infusion-related reactions (IRRs) during the infusion. Autopsy revealed monotonous proliferation of small-to-medium-sized lymphocytic cells in the bone marrow, consistent with the premortem diagnosis of WM/LPL. Additionally, immunoglobulin λ-light chain-derived amyloid (ALλ) deposition was identified in all organs other than the brain. Although ALλ deposition and LPL infiltration were found in the heart, they were not severe enough to cause severe functional impairment. Severe congestion and/or edema were observed in the lungs, liver, and brain. Although significant inflammatory cell infiltration was not found in any organs, laboratory tests revealed elevated serum levels of inflammatory cytokines, including interleukin-1ß, interleukin-6, tumor necrosis factor-α and the presence of IgM-λ monoclonal protein. CONCLUSION: Acute IRRs associated with the initial rituximab infusion were the major contributing factor to his sudden unexpected death. The autopsy findings of present case suggest the necessity for thorough monitoring of older patients with WM/LPL undergoing rituximab treatment, particularly when pronounced IRRs occur during the first administration, in addition to investigating complications of WM/LPL before infusion.

Amyloid-Forming Corpora Amylacea and Spheroid-Type Amyloid Deposition: Comprehensive Analysis Using Immunohistochemistry, Proteomics, and a Literature Review.

This study aimed to elucidate the similarities and differences between amyloid-forming corpora amylacea (CA) in the prostate and lung, examine the nature of CAs in cystic tumors of the atrioventricular node (CTAVN), and clarify the distinctions between amyloid-forming CA and spheroid-type amyloid deposition. We conducted proteomics analyses using liquid chromatography-tandem mass spectrometry with laser microdissection and immunohistochemistry to validate the characteristics of CAs in the lung and prostate. Our findings revealed that the CAs in these organs primarily consisted of common proteins (ß2-microglobulin and lysozyme) and locally produced proteins. Moreover, we observed a discrepancy between the histopathological and proteomic analysis results in CTAVN-associated CAs. In addition, while the histopathological appearance of the amyloid-forming CAs and spheroid-type amyloid deposits were nearly identical, the latter deposition lacked ß2-microglobulin and lysozyme and exhibited evident destruction of the surrounding tissue. A literature review further supported these findings. These results suggest that amyloid-forming CAs in the lung and prostate are formed through a shared mechanism, serving as waste containers (wasteosomes) and/or storage for excess proteins (functional amyloids). In contrast, we hypothesize that while amyloid-forming CA and spheroid-type amyloid deposits are formed, in part, through common mechanisms, the latter are pathological.

Transthyretin-derived amyloid (ATTR) and sarcoidosis: Does ATTR deposition cause a granulomatous inflammatory response in older adults with sarcoidosis?

This study aimed to assess the frequency and association between transthyretin-derived (ATTR) amyloidosis and sarcoidosis in a large autopsy cohort including many cases of sudden cardiac death (SCD). We identified 73 sporadic ATTR amyloidosis cases and 11 sarcoidosis cases, among which we found two cases with concomitant ATTR amyloidosis and sarcoidosis (2.4% of all cases; 2.7% within the sporadic ATTR group). The first case involved a 92-year-old man who experienced SCD. In this patient's heart, we observed ATTR deposition and noncaseating epithelioid granulomas consistent with sarcoidosis. Focally, ATTR deposits and granulomas co-localized, with histiocyte phagocytosis of transthyretin-immunoreactive fragments. However, in most lesions, they were distributed independently. The second case was that of an 86-year-old woman who also experienced SCD. In this patient, we detected ATTR deposition in the heart and lung, while noncaseating epithelioid granulomas were only observed in the lung, liver, kidney, and thyroid. Furthermore, no co-localization of the two lesions was observed. Based on these findings, we concluded that the coexistence of ATTR amyloidosis and sarcoidosis was likely coincidental. Nevertheless, despite the rarity of the combination of these two diseases, it should be recognized as a potential cause of SCD, especially among elderly people.

Sudden unexpected death of a young adult due to subarachnoid hemorrhage associated with polyarteritis nodosa: Clinicopathological appearance and literature review.

A 28-year-old male was found dead in his bedroom. There were no anomalies in his birth and medical history, and there was no family history of sudden unexpected death (SUD). Autopsy showed subarachnoid hemorrhage (SAH) with basilar top inflammatory pseudoaneurysm rupture accompanied by fibrinoid necrosis in the aneurysm wall. Active and healed arteritides in small- to medium-sized arteries were identified in the brain, heart, and systemic connective tissue, which was consistent with polyarteritis nodosa (PAN). Furthermore, pneumatosis cystoides intestinalis was observed in the ascending colon. Hepatitis B virus infection and antineutrophil nuclear antibodies were negative. Genetic investigation using whole-exome sequencing showed no mutations among autoinflammatory-related genes, including UBA1, MEFV, and ADA2. SAH due to rupture of a pseudoaneurysm formed by PAN was considered as the cause of death in the present case. Although myocardial ischemia linked to coronary arteritis is a recognized trigger for SUD in PAN, our study showed that rupture of inflammatory pseudoaneurysm in the cerebral artery can also cause SUD in younger subjects with PAN, even if prodromal symptoms are not evident before death.

An autopsy case of infective aortic aneurysm with Pasteurella multocida infection: clinicopathological appearance and a review of literatures.

Here, we showed our clinicopathological findings of infected aortic aneurysm (IAA) with Pasteurella multocida, which is a Gram-negative coccobacillus and is part of the normal oral flora of many animals. The patient was a 76-year-old male animal owner with a history of diabetes mellitus, alcoholic liver damage, and laryngeal cancer. He died 16 days after admission without undergoing operation because of poor general condition. Autopsy showed saccular outpouching with loss of the existing aortic wall and marked neutrophilic infiltration in the suprarenal abdominal aorta. Rupture was not evident. A polymerase chain reaction assay using DNA extracted from formalin-fixed paraffin-embedded specimen of the aneurysmal wall detected the Pasteurella multocida gene, therefore we conclude that the present case was IAA of native aorta with Pasteurella multocida infection. A review of the literature showed that IAA of native aorta with Pasteurella multocida infection is opportunistic and that liver disorder, alcohol addiction, diabetes mellitus, and animal bite may increase its risk. On the other hand, aortic endograft infection with Pasteurella multocida frequently occurred without an immunocompromised state. Pasteurella multocida may be a distinct causative microorganism in IAA, and/or sepsis when the participant is an animal owner.

Calcifying pseudoneoplasm of the neuraxis (CAPNON) associated with neurenteric cyst. An autopsy case showing unusual fatal outcome.

A 53-year-old man with a history of an untreated brain mass was taken to Toyama Prefectural Central Hospital by emergency transport. Computed tomography revealed an intracranial hypo-attenuated lesion exhibiting mass effect. Several calcified foci were observed around the lesion. His radiographical diagnosis was meningioma with calcification and edema. He suddenly showed tonic seizure after admission; therefore an emergency craniotomy was performed. However, he unfortunately died due to advanced cerebral edema. Microscopic findings of the surgically obtained materials were consistent with neurenteric cyst (NC). Intracranial hard masses were found adjacent to NCs, and the masses were composed of fibrous cartilage-like matrix with extensive linear calcification and the presence of surrounding round-to-oval epithelioid cells. Thus, calcifying pseudoneoplasm of the neuraxis (CAPNON) associated with NC was considered the most appropriate diagnosis of the present case. To the best of our knowledge, this is the first report of such a case. The present case suggests that delay of treatment might cause a poor outcome, at least in CAPNON associated with NC. Careful investigations, including the underlying pathology, may be essential when considering the etiology of CAPNON and its treatment strategies.

A Novel NKX2-5 Variant in a Child with Left Ventricular Noncompaction, Atrial Septal Defect, Atrioventricular Conduction Disorder, and Syncope.

The NKX2-5 gene encodes a transcription factor and is actively involved in heart formation and development. A pediatric case with its variant and left ventricular noncompaction (LVNC) has not been reported. A 12-year-old girl with a history of a surgery for atrial septal detect was referred because of syncope during exercise. The electrocardiogram showed atrioventricular block, and the echocardiogram revealed prominent trabeculations in the left ventricular wall, suggesting LVNC. A novel heterozygous variant in the NKX2-5 gene (NM_004387.1: c.255_256delCT, p.Phe86fs) was identified. NKX2-5 variants should be considered in cases with LVNC, congenital heart disease, arrhythmia, and syncope to prevent sudden cardiac death.

Clinicopathologic Appearance of Advanced Ketoacidosis With Basal Vacuolation in Renal Tubules.

CONTEXT.­: Basal vacuolization (BV) in renal tubules is a histopathologic hallmark of advanced ketoacidosis that enables us to retrospectively diagnose these cases. OBJECTIVE.­: To clarify the pathologic background and serologic findings of ketoacidosis with BV, and to reveal the pathologic findings by each pathologic background. DESIGN.­: We examined 664 serial autopsy cases. A systemic histopathologic examination and measurement of serum ß-hydroxybutyrate concentration were performed for the cases with BV. The extent of steatosis and fibrosis in the organs and the degree of coronary artery stenosis were semiquantitatively investigated. Immunohistochemistry for adipophilin was also performed to analyze its usefulness for the pathologic diagnosis. RESULTS.­: Basal vacuolization was found in 16 cases, all of which showed a pathologic serum ß-hydroxybutyrate concentration. The main background of ketoacidosis was considered as alcohol abuse in 6 cases, diabetes in 5, malnutrition in 3, and hypothermia and infection in 1 case each. Severe hepatic fibrosis was observed only in the alcohol-abuser group. Moreover, cardiac steatosis was more severe in patients with possible alcohol abuse than in those with other causes. Immunohistochemistry for adipophilin showed immunoreactivity consistent with BV in 13 of 16 cases. There was no correlation between ß-hydroxybutyrate concentration and either the postmortem or storage interval. CONCLUSIONS.­: Basal vacuolization may be a useful finding for detecting ketoacidosis cases in a postmortem investigation. Serum ß-hydroxybutyrate was a stable and reliable compound for the definitive diagnosis of ketoacidosis in such cases. The present study showed that pathologic changes in some organs may vary by each pathologic background of ketoacidosis with BV.

Effects of sporadic transthyretin amyloidosis frequently on the gallbladder and the correlation between amyloid deposition in the gallbladder and heart: A forensic autopsy-based histopathological evaluation.

The aim of the study is to evaluate the clinicopathological features of cholecystic ATTR deposition in patients with cardiac involvement, investigate the correlation of amyloid deposition severity in the gallbladder and the heart, and compare its prevalence in the gallbladder and other organs. Fifty patients with sporadic ATTR amyloidosis were identified. Of these, we evaluated 15 patients who underwent gallbladder sampling accurately. Among 10 patients (67%) with cholecystic deposition, six exhibited detectable deposition in the hematoxylin and eosin-stained specimens, and all of them displayed obstructive vascular deposition (VD). The severity of gall bladder VD was statistically correlated with that of cardiac VD and atrial interstitial deposition (ID). Additionally, all patients exhibiting cholecystic ID displayed severe ventricular and atrial IDs. In visceral organs excluding the heart, amyloid deposition was commonly observed in the lungs (93%), followed by the gastrointestinal tract (47%-80%), liver (60%) and periosteal tissues (53%). The involvement of the gallbladder was prevalent and comparable to that of the gastrointestinal tract. Moreover, the severity of cholecystic deposition was correlated with that of cardiac deposition. Therefore, pathologists should be aware that sporadic ATTR amyloidosis is a common condition and should not be overlooked.

Clinicopathological features of clinically undiagnosed sporadic transthyretin cardiac amyloidosis: a forensic autopsy-based series.

OBJECTIVE: To investigate the clinicopathological features of sporadic amyloid transthyretin (ATTR) amyloidosis. METHODS: We evaluated 1698 serial Japanese forensic autopsy patients. The extent and amount of ATTR deposition in the 16 cardiac regions, including the conduction system, were semiquantitatively evaluated. Ward's hierarchical cluster analysis was applied to classify the cases into subgroups. Also, the relationship between ATTR and amyloid atrial natriuretic factor (AANF) was evaluated. RESULTS: Forty-four cardiac ATTR amyloidosis patients (mean age 85.4 ± 5.7 years; 22 men) without history of hereditary polyneuropathy were identified (2.6% of all patients, 8.8% of those aged ≥80 years). All the 44 patients were not in the bedridden state and died-out-of-hospital scenarios. Of these, 10 (23%) were sudden death. Cluster analysis classified the patients into three groups (mild, atria-predominant and the severe deposition group). Amyloid deposition had already started simultaneously from each atrium and ventricle; however, the atrial septum and basilar ventricular septum were the sites that revealed the most frequent deposition. Also, a possible association between ATTR and AANF deposits was identified. CONCLUSIONS: Sporadic ATTR amyloidosis patients might already be susceptible to a risk for sudden death even from an early-phase. Also, ATTR amyloid deposition in such cases might progress with a certain degree of regularity.

Sex-dependent expression of prostatic markers and hormone receptors in cystic tumor of the atrioventricular node: A histopathological study of three cases.

We pathologically investigated three autopsy cases of cystic tumor of the atrioventricular node (CTAVN) with sudden death. Case 1 was a 36-year-old woman without any clinical history. Case 2 was a 76-year-old man with an implanted pacemaker for complete atrioventricular block. Case 3 was a 45-year-old man with a history of first-degree AV block and sinus bradycardia. Microscopically, all three cases showed the bilayered structure of tumor glands and corpora amylacea in the glandular lumens. Immunohistochemically, the inner cells of the tumor glands were positive for cytokeratin CAM5.2, CEA, EMA, olfactomedin-4 and alpha-methylacyl-coenzyme A racemase; the outer cells were positive for p63 and cytokeratin high molecular weight. In Case 1, androgen receptor and estrogen receptor were negative; progesterone receptor was focally positive in both the inner and outer cells. In Case 2, androgen receptor showed intermediate positivity in the inner cells; estrogen receptor and progesterone receptor were positive in the outer cells. Positive expression of both prostate-specific antigen and prostate-specific acid phosphate were found in the inner cells of both male cases. Because CTAVN cells exhibit different degrees of the prostatic phenotype depending on the patient's sex, we believe that CTAVN may originate from urogenital sinus tissue in some cases.

Left Ventricular Noncompaction and Congenital Heart Disease Increases the Risk of Congestive Heart Failure.

BACKGROUND: Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy that is associated with high morbidity and mortality rates. Recently, LVNC was classified into several phenotypes including congenital heart disease (CHD). However, although LVNC and CHD are frequently observed, the role and clinical significance of genetics in these cardiomyopathies has not been fully evaluated. Therefore, we aimed to evaluate the impact on the perioperative outcomes of children with concomitant LVNC and CHD using next-generation sequencing (NGS). METHODS: From May 2000 to August 2018, 53 Japanese probands with LVNC (25 males and 28 females) were enrolled and we screened 182 cardiomyopathy-associated genes in these patients using NGS. RESULTS: The age at diagnosis of the enrolled patients ranged from 0 to 14 years (median: 0.3 months). A total of 23 patients (43.4%) were diagnosed with heart failure, 14 with heart murmur (26.4%), and 6 with cyanosis (11.3%). During the observation period, 31 patients (58.5%) experienced heart failure and 13 (24.5%) developed arrhythmias such as ventricular tachycardia, supraventricular tachycardia, and atrioventricular block. Moreover, 29 patients (54.7%) had ventricular septal defects (VSDs), 17 (32.1%) had atrial septal defects, 10 had patent ductus arteriosus (PDA), and 7 (13.2%) had Ebstein's anomaly and double outlet right ventricle. Among the included patients, 30 underwent surgery, 19 underwent biventricular repair, and 2 underwent pulmonary artery banding, bilateral pulmonary artery banding, and PDA ligation. Overall, 30 genetic variants were identified in 28 patients with LVNC and CHD. Eight variants were detected in MYH7 and two in TPM1. Echocardiography showed lower ejection fractions and more thickened trabeculations in the left ventricle in patients with LVNC and CHD than in age-matched patients with VSDs. During follow-up, 4 patients died and the condition of 8 worsened postoperatively. The multivariable proportional hazards model showed that heart failure, LV ejection fraction of < 24%, LV end-diastolic diameter z-score of > 8.56, and noncompacted-to-compacted ratio of the left ventricular apex of > 8.33 at the last visit were risk factors for survival. CONCLUSIONS: LVNC and CHD are frequently associated with genetic abnormalities. Knowledge of the association between CHD and LVNC is important for the awareness of clinical implications during the preoperative and postoperative periods to identify the populations who are at an increased risk of additional morbidity.

An autopsy case of amyloid tubulopathy exhibiting characteristic spheroid-type deposition.

An 84-year-old woman with a history of haemodialysis for renal failure from approximately 1 year before death. Autopsy revealed numerous spheroid-type amyloid deposits in the kidney that were observed mainly in the interstitium but not the glomeruli and vessels. In addition, intracytoplasmic small globular amyloid deposits in the proximal tubules in addition to amyloid casts were identified. Immunohistochemistry and proteomic analyses indicated these deposits were composed of λ light chains. Amyloid deposition was also found in the lung and heart. λ-type monoclonal protein was detected in her serum and increased numbers of CD138-positive cells with λ-restriction was observed in the bone marrow. The case was diagnosed as amyloid tubulopathy (AT) associated with systemic ALλ amyloidosis related to plasma cell neoplasm. This case indicates that AT is associated with ALλ amyloidosis, which developed systemically with characteristic amyloid deposition forms. These pathological features may be associated with her rapid progressive renal failure.

Autopsy of a multiple lobar hemorrhage case with amyloid-ß-related angiitis.

A 92-year-old man died of multiple lobar hemorrhage with amyloid-ß protein (Aß)-related angiitis (ABRA) with an unusual pathological appearance. Although he had shown relatively rapid progressive dementia, starting 1 year before death, there was no detailed clinical investigation, and no immunosuppressive or anticoagulant therapy, because of his advanced age. The autopsy showed two lobar hemorrhagic lesions in the right parietal lobe and temporal lobes. Microscopically, almost all the brain's blood vessels showed cerebral amyloid angiopathy with many foci of transmural vasculitis. Infiltrating cells were predominantly CD8-positive T-lymphocytes, but we observed no granulomatous inflammation with appearance of multinucleated giant cells. We found fibrinoid necrosis in some blood vessels and disruption of these blood vessels in the arachnoid space-cerebral cortex junction in the hemorrhagic lesion at the temporal lobe. We also observed an unusual, neutrophil-predominant, abscess-like vasculitis in the subarachnoid space; almost all such unusual vasculitides were located at a short distance from the two lobar hemorrhagic lesions. Serum anti-neutrophil cytoplasmic myeloperoxidase and proteinase-3 antibodies were negative, and the genotype of the apolipoprotein E (ApoE) gene (ApoE) was ε2/ε3. Although we did not observe some of ABRA's typical histopathological findings, transmural and vascular destructive inflammation with Aß deposition was consistent with ABRA. Vulnerability of blood vessels to fibrinoid necrosis might be associated with disruption of the relevant blood vessels, leading to lobar hemorrhage. ABRA exhibits various clinical and histopathological findings, depending on the patient's age, immune function status, treatment, and ApoE genotype. This is the first case and the oldest (92 years old) autopsy of ABRA associated with ApoE-ε2/ε3 genotype.

An autopsy case of sudden unexpected death with loxoprofen sodium-induced allergic eosinophilic coronary periarteritis.

Although the cause of eosinophilic coronary periarteritis (ECPA) remains unclear, an allergic background is present in fewer patients than expected. A 50-year-old man with no history of allergy or symptoms suggestive of cardiac or respiratory disorders suddenly died shortly after oral administration of loxoprofen sodium. Autopsy showed eosinophilic coronary periarteritis in three main branches of the coronary arteries, characterized by eosinophil-predominant inflammation without fibrinoid necrosis or granulomatous change in the adventitia and its surroundings of the three main branches of the coronary arteries, in addition to the localized sign of bronchial asthma in the lung. Immunohistochemical examination showed that many mast cells positive for human mast cell tryptase were evident in the perivascular tissue containing peripheral nerve trunks. Whereas the blood concentration of loxoprofen sodium was within the therapeutic range, significant elevation of the serum histamine and tryptase levels was found. The present case suggests that eosinophilic coronary periarteritis may be caused by a type I allergic reaction in some patients and that loxoprofen sodium can trigger a life-threatening type I allergic reaction, including eosinophilic coronary periarteritis, leading to sudden unexpected death.

Sudden unexpected death with rare compound heterozygous variants in PRICKLE1.

Progressive myoclonus epilepsy-ataxia syndrome (EPM5) is an autosomal recessive form of progressive myoclonus epilepsy that has been associated with a homozygous missense mutation in PRICKLE1. We report a 23-year-old male who died shortly after refractory convulsion and respiratory failure. Autopsy showed unilateral hippocampal malformation without significant neuronal loss or gliosis. Genetic analysis that targeted both epilepsy and cardiac disease using next-generation sequencing revealed two variants of PRICKLE1. Additional investigation showed that the patient's father (p.Asp760del) and mother (p.Asp201Asn) each had a mutation in this gene. The present case shows that EPM5 can also be caused by compound heterozygous mutations.

Sudden unexpected death with primary adrenal lymphoma.

An 82-year-old man was found dead on the road near his home with unwitnessed interval of 3 h from final witness. He had been diagnosed with hypertension and mild aortic stenosis (AS) 13 years before death, and was continuously followed up with medication. Although a recent medical check-up related to cardiac function was stable and consistent with moderate AS, he sometimes complained of general fatigue, anorexia associated with intermittent mild fever and rare vomiting in the weeks before death. At autopsy, no lethal injury or drug intoxication was found, but congenital bicuspid aortic valve (BAV) with central rache was found. Although calcification was found in a restricted area of one cusp, valvular structural deformity was clearly milder than in typical severe AS cases. Moderate left ventricular hypertrophy without coronary disease was found. A brownish-red, soft nodular lesion was found in both adrenal glands, but no other tumorous focus was evident in any other organs. Immunohistochemical examination showed that B-lymphocyte-derived markers (CD20, melanoma associated antigen (mutated) 1, and CD79a) were exclusively positive. Therefore, we diagnosed primary adrenal lymphoma (PAL), diffuse large B-cell lymphoma phenotype. We concluded that the cause of sudden unexpected death (SUD) was adrenal insufficiency associated with PAL, with a background of moderate AS related to BAV.

Intramyocardial bronchogenic cyst: histological appearance and a review of the literature.

We report histological appearance of a bronchogenic cyst that was incidentally found in a 78-year-old man who died from drowning related to a traumatic accident. The cyst was found in the posterior edge of the interventricular septum and was monolocular with a 5-mm diameter. The cystic wall was not associated with cartilage or the smooth muscle layer, and was lined by ciliated respiratory epithelium. Immunohistochemistry showed that many of these epithelial cells were positive for cytokeratin 7 and thyroid transcription factor-1. A few of the cells were positive for CA19-9, chromogranin A, synaptophysin, and S-100. No cells were positive for cytokeratin 20, p63, bcl-2 and napsin A. This feature was compatible with bronchogenic cyst, and is not common compared with previously reported immunohistochemical features of cystic tumors of the atrioventricular node. A low prevalence of p53, single strand-DNA, and Ki-67 indicated modest cell turnover in the epithelial cells of present case. Our survey of the English literature showed 23 cases of intramyocardial bronchogenic cyst. Although asymptomatic cases were dominant in the literature, some intramyocardial bronchogenic cysts showed life-threatening arrhythmia, which could cause sudden unexpected death.