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"Severe acute respiratory syndrome" (SARS) due to coronavirus (SARS-CoV-2) infection is a well-known cause of death. Sometimes, demise can occur unexpectedly in apparently previous healthy individual after a brief period of trivial flu-like symptoms. In these doubtful cases, the forensic pathologist could be requested to define the cause of death occurred outside the hospital. In this report, the authors describe two autopsied cases of SARS-CoV-2-related deaths which occurred suddenly at home and were not preceded by hospitalization, highlighting associated histopathologic patterns and correlating them to pathophysiology of viral infection.

Purpose: Adrenocortical tumors (ACT) occur rarely in pediatric age group. Pediatric ACTs behave differently from their histologically similar adult counterparts and standard adult criteria often cannot accurately predict their clinical behavior. The aim of the present study was to document the clinicopathologic spectrum of pediatric ACTs and to assess the utility of Wieneke scoring system in predicting clinical behavior of these tumors., Methods: This multi-institutional study comprised of 13 cases of pediatric ACTs from January 2005 to May 2014. Clinical features and gross pathologic characteristics were obtained from records. Comprehensive analyses of microscopic features were performed. Each tumor was assessed according to criteria proposed by Wieneke et al. and was assigned to benign, intermediate for malignancy or malignant group. The standard adult Weiss criteria were also applied for comparison., Results: There were total 6 cases of adrenocortical adenomas and 7 cases of adrenocortical carcinomas. Most of the children (76.9%) presented with endocrine dysfunction. Lower age of presentation was significantly associated with better prognosis. Applying Wieneke criteria, there were 6 benign and 6 malignant cases and one case was assigned to intermediate for malignancy group. The clinical behavior of all the cases was consistent with Wieneke criteria categorization. Applying Weiss criteria, 3 cases with benign clinical behavior were assigned to malignant group., Conclusion: Our study validates the reliability of Wieneke scoring system in predicting malignancy in pediatric ACTs. It is simple and easy to use and therefore useful in day-to-day practice.

Adrenal cortical tumors, particularly oncocytic tumors, have been reported to contain a variety of intracytoplasmic and intramitochondrial inclusions. Oncocytic cortical tumors can also morphologically mimic pheochromocytomas. We report an unusual, partially oncocytic cortical neoplasm with nesting architecture, intranuclear inclusions, and hyaline globules reminiscent of pheochromocytoma, together with numerous, small, brightly eosinophilic, periodic acid-Schiff-positive cytoplasmic inclusions and typical cytoplasmic lipid droplets. Ultrastructural study revealed oncocytes containing numerous mitochondria with intramitochondrial crystals and lipid droplets. Immunohistochemistry and immunoblots were utilized to further characterize the tumor. Immunohistochemistry demonstrated immunoreactivity of both the eosinophilic inclusions and the hyaline globules for adipose differentiation-related protein (ADRP), which is one of a group of proteins associated with storage of neutral lipids in many cell types. Immunoblots confirmed the presence of ADRP and demonstrated an imbalance between ADRP and perilipin, another neutral lipid-associated protein, in tumor tissue compared to normal adrenal cortex. The findings suggest that mitochondrial dysfunction in oncocytic cortical tumors may lead to abnormal processing of proteins related to the lipid-storing functions of the adrenal cortex, resulting in unusual cytoplasmic inclusions and extracellular globules resembling the globules in pheochromocytomas. The finding of ADRP as a constituent of inclusions in adrenal cortical tumors has not been previously reported.

The increasing occurrence of incidentally discovered benign adrenocortical tumors has become a clinical dilemma because of the difficulties in differentiating them from their malignant counterpart. Adrenocortical tumors are associated with familial cancer syndromes such as the Beckwith-Wiedemann syndrome, the Li-Fraumeni syndrome, the Carney complex, multiple endocrine neoplasia type 1, congenital adrenal hyperplasia, and the McCune-Albright syndrome. Genetic events are known to take place on the chromosomal and gene level in sporadic adrenocortical tumors.

The present study systematically investigated the expression and distribution of the major histocompatibility complex (MHC) classes I and II in the rat. About 150 native tissue probes from eight adult Lewis rats were taken, representative for most organs, tissues, and the vascular system. MHC expression was analyzed by two monoclonal antibodies (mAb) generated against the non-polymorphic determinants of rat MHC class I (Ox-18) and class II (Ox-6). Immunoreactivities were compared to those of different endothelial (HIS52, TLD-3A12, Ox-43, REHA-1 antigen), histiocytic (ED1, ED2), B-cell (RLN-9D3), and T-cell (MRC Ox-52) markers. A nonspecific mAb (MR12/53) served as a negative control. Pretested concentrations on various tissues and the alkaline phosphatase-anti-alkaline phosphatase technique allowed semiquantitative evaluation of serial cryostat tissue sections. MHC class I expression was detected on most immunocompetent cells. Endothelial cells were stained heterogeneously along the vascular system and the organ-specific microcirculation. Furthermore, some organs showed staining of parenchymal cells. MHC class II was found on all immunocompetent cells positive for the B-cell marker and about 15% of cells positive for the histiocytic markers. Besides the well-known expression of MHC class II in the outer zone of the renal proximal tubule, further organ-specific cell forms were found positive. In conclusion, the present study outlines tissue-specific distribution of MHC I/ II and implies that each organ carries a variable immunologic burden that needs to be considered for any transplantation model.

The innervation of the human adrenal gland and of cortical lesions was studied in sections of cortical tissue (n=10), hyperplastic cortical tissue (n=3), and tissue from cortical adenomas (n=5) and carcinomas (n=6). The presence and distribution of nerve structures containing neuronal markers indicating sympathetic and parasympathetic innervation were studied by immunohistochemistry and the co-existence and co-localization patterns of the different markers by immunofluorescence. The cortex and hyperplastic cortical tissue had a moderate to rich supply of nerve structures containing the typical neuronal markers: protein gene product 9.5 (PGP 9.5), neuron-specific enolase (NSE), small vesicle synaptic protein type 2 (SV2), and nerves showing immunoreactivity to the adrenergic marker tyrosine hydroxylase (TH). All these immunoreactive nerves were located predominantly adjacent to blood vessels, but also among parenchymal cells. The cortex showed numerous nerve structures containing the neuropeptide substance P (SP), neuropeptide Y (NPY) and vasoactive intestinal protein (VIP), but few nerves containing these peptides were seen in hyperplastic cortical tissue. Typical markers were occasionally observed in cortical adenomas but were not found in carcinomas, except in a few cases where PGP 9.5 and NSE were present, but only adjacent to necrotic areas. Nerves containing NPY and VIP occurred in varying numbers in both adenomas and carcinomas. NPY- and VIP-immunoreactive nerve structures were seen mostly alongside blood vessels. There were several types of co-existence. For instance, NSE/VIP-, TH/VIP- and TH/NPY-immunoreactive nerve structures were often seen in the same trunk, but were only partly co-localized.

The vasculature of the adrenal gland has been studied by microinjection techniques in a variety of species. While there is general agreement about the overall patterns, some uncertainty still exists over the structure of medullary arteries and the connections between the sinusoids of the cortex and medulla. We have taken a new approach to these problems by applying immunohistochemical techniques to the human adrenal gland, identifying overall vascular patterns by endothelial expression of CD34 and muscular channels by smooth muscle actin. We have also examined adrenal nodules, adenomas and carcinomas to see whether these can be differentiated on the basis of their vascular patterns. The general pattern in the normal gland was similar to that found in injection studies, but there appeared to be more connections between sinusoids of the zona fasciculata than previously reported. There was direct continuity between cortical and medullary sinusoids. Medullary arteries were demonstrated as thin-walled vessels. Immunopositivity for smooth muscle actin was present in sinusoids, apparently in endothelial cells, suggesting that they may express this protein and thus have a contractile function. Macronodules and adenomas could not be reliably distinguished, both showing a rich network of sinusoidal vessels. Carcinomas showed marked disorganization, with large-calibre vessels interspersed with irregular networks of vessels of very small calibre.

A 12-year-old female suffering from adrenocortical insufficiency showed symptoms similar to a gastro-enteritis, and severe electrolytic and acid/base disturbances which progressed into cerebral oedema and death. Autopsy findings included depletion of the adrenal cortex, with enlargement and eosinophilia of surviving cells. In ante-mortem blood, anti-adrenal auto-antibodies were found and elevated levels of ACTH and cortisol with a low level of aldosterone.

A case of adrenocortical adenoma containing small adipose foci is presented. A small amount of fat within the mass led to an erroneous preoperative diagnosis of myelolipoma. Adrenal adenoma should be included in the differential diagnosis of adrenal mass containing fat.

Detection of fat within an adrenal primary mass is virtually pathognomonic of myelolipoma, and in most cases such a diagnosis excludes any further diagnostic and therapeutic approaches. We report our findings, with computed tomography (CT) and magnetic resonance (MR), of the first, to our knowledge, pathologically proven case of fat tissue within an adrenal cortical carcinoma. We also discuss the possible origin of fat within such malignancies and the potential diagnostic dilemmas it might cause.

The sudden infant death syndrome (SIDS) is at present based on unknown pathogenetical mechanisms but in industrial nations is the most common cause of death in infancy after the perinatal period. Studies of a large number of adrenal glands in this syndrome have not been reported. Therefore, we evaluated 146 SIDS cases (85 males, 61 females, aged 14-465 days) and 24 control cases (17 males, 7 females, aged 18-623 days) by light microscopy, morphometry and immunocytochemistry (anti-chromogranin A and anti-S100 protein). Our data revealed a normal maturation of the adrenal glands in SIDS cases. Necroses, extensive hemorrhages or inflammation were not found. A focal lipid depletion of the zona fasciculata was seen in 92% of the adrenal glands of the SIDS and control cases. We found a siderosis (in 33% of the SIDS cases and 4% of the control cases) and calcium deposits (13% and 12% respectively) due to hyperemic involution of the fetal zone. The medulla, including the sustentacular cells (S 100 protein-positive cells) and chromaffin cells (chromogranin A-positive cells) was unchanged. Our results indicate that the few morphological alterations of the adrenal glands in SIDS cases are the effect of the underlying disease and not the cause of the sudden death.

In cortical adrenal gland tumours there are discrepancies between morphological criteria for malignancy and biological behaviour. This makes it difficult to select the appropriate treatment. We have studied morphometric and DNA densitometric features of 24 adrenal proliferative lesions (hyperplasia, adenoma, and carcinoma) by means of slide cytometry. All variables have been correlated with pathological diagnosis. The samples were selected from paraffin-embedded tissue, and representative lesions were Feulgen stained. Densitometric study showed aneuploid cell lines in every carcinoma, 5 of 8 adenomas, and 5 of 10 hyperplastic lesions. Both DNA nuclear content (mean ploidy of 2.11 c, 2.41 c, and 3.05 c) mean nuclear area (average of 31.26 microns 2, 35.92 microns 2, and 42.39 microns 2) showed progressive increase from hyperplasia to adenoma, and carcinoma. Mean shape factors were lowest in adenomas (1.69) and highest in carcinomas (1.82). Those karyometric variables which showed statistically significant differences (p < 0.05) among diagnostic groups were included in a stepwise three-way discriminant analysis. Only three parameters, shape factor (p = 0.0008), mean ploidy (p = 0.0012), and adrenal weight (p = 0.0055) persisted as independent predictive factors. Using the three variables selected by discriminant analysis on our cases, 100% of the adenomas were correctly classified, 83% of the carcinomas, and 80% of the hyperplasias. Tumour weight and nuclear shape factor differentiated adrenal cortex adenoma from carcinoma, while mean ploidy distinguished adrenal cortical hyperplasia from carcinoma. Nuclear pleomorphism (shape factor) and DNA-ploidy are the most important nuclear features in predicting the biological course of proliferative adrenal cortex lesions, although by themselves they are not bona-fide discriminators.

In a 52-year-old Caucasian man osteopoikilosis had been misdiagnosed roentgenologically 2 years before his death. Gradually he developed Cushing's syndrome and ultimately superior vena caval obstruction. At autopsy a primary thymic carcinoid with extensive osteoblastic bone metastasis was found. Immunohistochemically the tumor was shown to be positive for adrenocorticotropic hormone (ACTH), cytokeratin (KL1), neuron-specific enolase, synaptophysin, chromogranin and glucagon. Remarkably the tumour was negative for serotonin despite high urinary hydroxyindolacetic acid levels. Bilateral hyperplasia of the adrenal cortex was found. The adenohypophysis showed a considerable reduction of ACTH-producing cells and numerous Crooke's cells with a characteristic immunohistochemical pattern.

A boy born to healthy, unrelated parents, presented at birth with hypotonia and seizures. Very long chain fatty acids in the plasma were strongly elevated; bile acid intermediates and plasmalogen biosynthesis were normal. Acyl-CoA oxidase activity was normal. The patient died at the age of 3 months. The cerebellum and medulla oblongata showed neuronal migration defects. The specific biochemical basis for the impaired peroxisomal beta-oxidation has not been found. The three immunoreactive peroxisomal beta-oxidation enzymes and catalase were localized in the hepatocellular peroxisomes. Aberrant features of the peroxisomes included: a subpopulation of organelles larger than 1 micron, an amorphous nucleoid in many organelles, and invaginations of the peroxisomal membrane into the matrix. Peroxisomes in the proximal renal tubules also contained the three immunoreactive beta-oxidation enzymes. Regularly spaced trilamellar inclusions were seen in hepatic macrophages; they were much more abundant in adrenocortical macrophages. The inclusions were birefringent and resistant to acetone extraction. Distinct hepatic fibrosis had developed over a period of 2.5 months. We speculate that the impaired beta-oxidation is due to a defect at the level of the peroxisomal carnitine octanoyl or -acetyl transferase, responsible for the export of beta-oxidation products.

Adrenal glands from eight patients with the cerebro-hepato-renal syndrome, a disease in which there are no morphologically demonstrable peroxisomes, were studied histologically; one of the eight was also examined ultrastructurally. Seven of the eight demonstrated striated adrenocortical cells in the inner portion of the adrenal cortex. Ultrastructural examination confirmed that the striated cells contained the lammellae and lamellar-lipid profiles of very long chain fatty acids-cholesterol esters that are characteristic of adreno-leukodystrophy. This morphologic observation further emphasizes the common pathogenetic features of the cerebro-hepato-renal (Zellweger) syndrome and adreno-leukodystrophy.

Cytochrome P-450 specific for steroid 11 beta-hydroxylation (P-45011 beta) was immunohistochemically demonstrated in the adrenal glands of human, pig and bovine and of mineralo- and glucocorticoid excess using a specific monoclonal antibody against P-450 11 beta of bovine adrenocortical mitochondria. P-450 11 beta was present in all three cortical zones of the histologically normal adrenal glands of bovine, pig and human, particularly in the zona fasciculata (ZF) and reticularis (ZR). The P-450 11 beta immunoreactivity was intensive in cortical micronodules and inner ZF and ZR in Cushing's disease, and relatively intensive in the zona glomerulosa (ZG) and outer ZF in idiopathic hyperaldosteronism (IHA), corresponding to the sites of active steroidogenesis. In adenomas with Cushing's syndrome and primary aldosteronism, compact cells were generally stained well. In the adrenal glands attached to the adenomas, immunoreactivity was observed only focally in ZG cells but not in ZF and ZR cells.

Five cases of adrenal cortical carcinoma examined with magnetic resonance (MR) are presented. Clinical histories, computed tomographic (CT) scans, and final pathologic findings were reviewed in each case. All masses were hypointense compared to the liver on T1-weighted images and became hyperintense compared to the liver on T2-weighted images. Signal intensity of adrenal masses, fat, and liver were measured. Adrenal/liver and adrenal/fat signal intensity ratios were then calculated. All the masses were readily identified with MR. The MR also demonstrated displacement or invasion of adjacent organs, as well as liver metastases. The inferior vena cava was also identified in each case. Even though there were no consistent MR findings to diagnose adrenal cortical carcinomas accurately, superior blood vessel identification and multiplanar capabilities may make MR the imaging modality of choice in evaluating the extent of disease and in planning surgical excision.

Applications of nuclear magnetic resonance (NMR) to the adrenal gland have received considerable attention in recent years. Using high field strength magnets and surface coil technology, images of normal and abnormal adrenal glands have been obtained that compare favorably, and in some instances excel, computed tomography (CT) with respect to both image quality and, to a greater degree, differentiation of pathology. This article reviews the current state of magnetic resonance (MR) imaging of normal and abnormal adrenal glands, compares MR with CT imaging, and indicates where NMR spectroscopy has been of greatest value to date in the study of adrenal gland disease.