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While most benign lesions of the adrenal glands represent either an adrenocortical adenoma or a myelolipoma, the advent and frequent use of high-resolution radiological investigations have led to relatively increased incidental discovery of rare adrenal lesions, specifically benign adrenal cysts, adrenal ganglioneuromas, adrenal schwannomas, adrenal hemorrhage, and adrenal calcifications. Radiological characteristics of the different rare benign adrenal lesions could vary from distinct to indeterminate. Though typically nonfunctional, these rare lesions require evaluation for adrenal hormone excess, as they may phenotypically appear similar to pheochromocytoma or adrenocortical carcinoma and could sometimes be associated with or conceal an underlying functional adrenal tumor. In this review, we discuss the various rare benign adrenal lesions, emphasizing a practical perspective.

ContextInflammatory infiltrates are sometimes present in solid tumors and may be coupled to clinical behavior or etiology. Infectious viruses contribute to tumorigenesis in a significant fraction of human neoplasias.ObjectiveCharacterize inflammatory infiltrates and possible viral transcription in primary hyperparathyroidism.DesignFrom the period 2007 to 2016, a total of 55 parathyroid tumors (51 adenomas and 4 hyperplasias) with prominent inflammatory infiltrates were identified from more than 2000 parathyroid tumors in the pathology archives, and investigated by immunohistochemistry for CD4, CD8, CD20 and CD45 and scored as +0, +1 or +2. Clinicopathological data were compared to 142 parathyroid adenomas without histological evidence of inflammation. Transcriptome sequencing was performed for 13 parathyroid tumors (four inflammatory, 9 non-inflammatory) to identify potential viral transcripts.ResultsTumors had prominent germinal center-like nodular (+2) lymphocytic infiltrates consisting of T and B lymphocytes (31%) and/or diffuse (+1–2) infiltrates of predominantly CD8+ T lymphocytes (84%). In the majority of cases with adjacent normal parathyroid tissue, the normal rim was unaffected by the inflammatory infiltrates (96%). Presence of inflammatory infiltrates was associated with higher levels of serum-PTH (P = 0.007) and oxyphilic differentiation (P = 0.002). Co-existent autoimmune disease was observed in 27% of patients with inflammatory infiltrates, which in turn was associated with oxyphilic differentiation (P = 0.041). Additionally, prescription of anti-inflammatory drugs was associated with lower serum ionized calcium (P = 0.037).ConclusionsNo evidence of virus-like sequences in the parathyroid tumors could be found by transcriptome sequencing, suggesting that other factors may contribute to attract the immune system to the parathyroid tumor tissue.

ObjectivePrimary hyperparathyroidism is usually characterized by a monoclonal parathyroid tumor secreting excess parathyroid hormone (PTH). The main regulator of PTH secretion is calcium and the calcium–PTH set point is shifted in parathyroid tumor cells. We sought to investigate the relationship between tumor PTH andPTHmRNA expression and clinical presentation as well as the regulatory factors including phosphate, vitamin D, and fibroblast growth factor 23.DesignA total of 154 parathyroid tumors were analyzed by PTH immunohistochemistry and chromogenicin situhybridization ofPTHmRNA. A subset of samples (n= 34) was analyzed using quantitative real-time PCR.ResultsLow tumorPTHmRNA level was significantly associated with low tumor PTH immunoreactivity (P= 0.026), but the two did not correlate with regard to histological distribution within individual tumors. Tumors displaying reducedPTHmRNA levels as compared with normal rim were significantly larger (P= 0.013) and showed higher expression of thecalcium-sensingreceptor(CASR) (P= 0.046). Weaker tumorPTHmRNA level was significantly associated with higher concentration of circulating 25-hydroxyvitamin D (P= 0.005). No significant correlation was seen between PTH immunoreactivity and patient biochemistry. Tumor weight was strongly associated with circulatory concentrations of calcium and PTH.ConclusionsNo areas with apparently higher PTH expression were identified, perhaps suggesting that hyper functioning parathyroid tumor subclones should be rare. Circulating 25-hydroxyvitamin D levels may influence tumorPTHexpressionin vivo. If PTH immunoreactivity reflects the tumor calcium–PTH set point, our data imply that the main determinant of disease severity should be tumor weight.

ObjectiveTumours in the adrenocortex are common human tumours. Malignancy is however, rare, the yearly incidence being 0.5–2 per million inhabitants, but associated with a very aggressive behaviour. Adrenocortical tumours are often associated with altered hormone production with a variety of clinical symptoms. The aggressiveness of carcinomas together with the high frequency of adenomas calls for a deeper understanding of the underlying biological mechanisms and an improvement of the diagnostic possibilities.MethodsMicroarray gene expression analysis was performed in tumours of adrenocortex with emphasis on malignancy as well as hormonal activity. The sample set consisted of 17 adenomas, 11 carcinomas and 4 histological normal adrenocortexes. RNA from these was hybridised according to a reference design on microarrays harbouring 29 760 human cDNA clones. Confirmation was performed with quantitative real time-PCR and western blot analysis.ResultsUnsupervised clustering to reveal relationships between samples based on the entire gene expression profile resulted in two subclusters; carcinomas and non-cancer specimens. A large number of genes were accordingly found to be differentially expressed comparing carcinomas to adenomas. Among these were IGF2, FGFR1 and FGFR4 in growth factor signalling the most predominant and also the USP4, UBE2C and UFD1L in the ubiquitin-proteasome pathway. Moreover, two subgroups of carcinomas were identified with different survival outcome, suggesting that survival prediction can be made on the basis of gene expression profiles. Regarding adenomas with aldosterone overproduction, OSBP and VEGFB were among the most up-regulated genes compared with the other samples.ConclusionsAdrenocortical carcinomas are associated with a distinct molecular signature apparent in their gene expression profiles. Differentially expressed genes were identified associated with malignancy, survival as well as hormonal activity providing a resource of candidate genes for an exploration of possible drug targets and diagnostic and prognostic markers.