Introduction
Rare neoplasia of the adrenal gland such as ganglioneuroma, ganglioneuroblastoma, neuroblastoma, schwannoma and malignant peripheral nerve sheath tumors may arise as stand-alone entities or as composite tumors intermingled with pheochromocytoma. Whereas the definitions of some of these lesions have been widely accepted, the histological, molecular and clinical parameters of these entities are somewhat obscure.
Schwannoma is a peripheral nerve sheath tumor originating from Schwann cells. Although reported in a wide variety of ages, the incidence seems to be highest in middle-aged patients. Schwannomas are mostly sporadic tumors arising predominantly on the limbs or in the head and neck region, but cases have been reported for many parenchymatous organs as well as the retroperitoneum [
1‐
3]. Subsets of cases may develop as part of an underlying syndrome, such as neurofibromatosis type 2 (NF2), Carney complex and familial schwannomatosis [
4‐
6]. The vast majority of tumors are benign and patient outcome is excellent. From a histological context, schwannomas are subdivided based on their growth patterns; including conventional, ancient, cellular, plexiform, epithelioid and microcystic subtypes [
7‐
9]. Malignant transformation is exceedingly rare and may be related to previous radiation therapy [
10,
11]. Subsets of cases have been reported to display inactivation of the
NF2 and/or
SMARCB1 tumor suppressor genes [
12‐
14].
Adrenal schwannoma (AS) is defined as a schwannoma arising in the adrenal medulla. If the schwannoma develops in close proximity to the adrenal gland, the suggested terminology is periadrenal schwannoma (PAS). AS/PAS are rare lesions, with less than 200 cases published to date [
15]. Notably, the bulk of scientific descriptions is derived from single-institution case series, and extensive molecular characterization of these entities is lacking. Given the lack of clinical, histological and genetic data, we sought to describe institutional cases from our department including findings from imaging, histopathology, molecular work-up and follow-up data.
Materials and methods
In total, we found three AS cases and one PAS case during 1992 to 2022 (with 1992 as the starting year given the earliest inputs in our electronic search system). We used the Systematized Nomenclature of Medicine (SNOMED) code T93*** to retrieve all 1248 histopathologically diagnosed adrenal lesions during these years, specifically looking for M956** (including “neurilemmoma”, the SNOMED assigned term for schwannoma). This search function generated four cases corresponding to 0.32% of diagnosed cases. The patient charts and pathology reports of each case were reviewed. As the quality of the staining may deteriorate over time, blocks were recut and restained for hematoxylin-eosin (H&E). We defined AS as a schwannoma arising within the adrenal medulla, and PAS as schwannoma arising in peripheral nerves in close association to the adrenal gland. We considered SOX10, S100 and GFAP immunohistochemistry essential to the diagnosis, and therefore stained any case lacking one or several of these markers in their original report. Furthermore, all four cases were subjected to molecular characterization using an established next-generation sequencing (NGS) pipeline (Oncomine Childhood Cancer, Thermo-Fisher Scientific, Waltham, MA, USA) used in clinical routine at the Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden. In brief, this platform interrogates DNA and RNA extracted from formalin-fixated paraffin embedded tissue for mutations in 126 genes (full exon coverage of 44 genes and hotspot coverage of additional 82 genes) and >1700 gene fusion variants in 88 genes. The methodology regarding nucleic acid extraction and sequencing has been previously published [
16].
Discussion
AS and PAS are infrequently encountered lesions in the clinical setting, and hence the data regarding histological attributes, molecular drivers and clinical presentation is limited. A recent meta-analysis from 2022 identified 169 published AS cases [
15]. The majority of AS and PAS present as incidentalomas either due to radiological investigations or due to symptoms of mass effect. The typical AS patient is middle-aged, and exhibits a unilateral, non-functioning adrenal mass with a median size of 60 mm [
15]. AS usually presents as a solitary and encapsulated mass with a homogenous appearance on a CT scan, and the mean attenuation is slightly over 30 HU, thus most often making AS readily distinguishable from adrenal cortical adenoma and myelolipoma [
15,
17]. The attenuation of the tumors in our series ranged from 11–28 HU. Case 3 presented with a hypervascular lesion on imaging, thus radiologically suspicious for pheochromocytoma or adrenocortical carcinoma (ACC). As AS and PAS are large lesions that often present with cystic degeneration and/or necrosis, non-functioning ACCs could constitute a potential differential diagnosis in the radiological work-up. It is also worth stressing the fact that ACCs might be more common than AS and PAS in the general populace, thereby also highlighting the clinical need to distinguish these entities rapidly. Other imaging techniques, such as
18F-FDG PET/CT, are rarely used in the diagnostic work-up of AS and PAS, and the few reported cases investigated with this modality show a widespread distribution in terms of uptake, possibly due to differences in histological subtyping and cellular composition [
18]. In our case series, the PAS of patient 2 had peripheral
18F-FDG uptake only, most likely correlating to the wide-spread central degeneration of tumor tissue, while the
18F-FDG uptake in patient 4 was enhanced.
Histologically, most AS and PAS cases are described as either conventional or cellular, while other histological subtypes are rare. A conventional AS/PAS exhibits hypercellular areas (denoted as “Antoni A”) intermingled with palisading spindle cells (Verocay bodies) as well as various amounts of hypocellular areas (“Antoni B”). Cellular AS/PAS cases, however, usually lack Antoni B areas and the Verocay bodies that are seen in conventional AS [
19]. In our series, histological subtyping revealed that 3 cases were subtyped as cellular AS or PAS, and a single case was annotated as microcystic AS. Of note, the hypercellular appearance and the lack of loosely populated Antoni B areas and classic Verocay bodies led to extensive immunohistochemical analyses of these three cases, and a number of markers were assayed in order to rule out neurofibroma (CD34), leiomyosarcoma (desmin), angiosarcoma (CD34 and ERG), metastatic GIST (c-kit, DOG1), malignant melanoma (Melan A), pheochromocytoma (chromogranin A) as well as adrenal cortical tumors (SF1, Alpha-inhibin). It seems appropriate to include a wide variety of differential diagnoses in the clinical work-up of AS and PAS, given the rarity of the disease and the existing palette of malignant lesions with morphological similarities [
20,
21]. In our experience, typical morphology in addition to positive staining for SOX10, S100 and GFAP is diagnostic for AS/PAS.
The focused NGS screening did not detect any pathogenic variants or gene fusion events in this small case series. Although
NF2 and
SMARCB1 mutations have been reported in schwannomas from other anatomical sites [
12‐
14], we did not observe these aberrations. Hence, the molecular background of AS/PAS remain elusive, and pan-genomic analyses could be required to identify potential driver events.
As expected, all patients in this series were free of metastatic disease. In fact, only a few cases of AS with malignant transformation have been reported [
22,
23]. Two of our cases (cases 3 and 4) exhibited substantially higher Ki-67 indices than cases 1 and 2, but there was no clear-cut correlation between the mitotic activity and this labeling index or any other histological parameter. While Ki-67 has been proposed as a predictive marker for recurrence in vestibular schwannoma, little is known regarding the potential value of this analysis in terms of AS/PAS [
24].
We conclude that AS and PAS are rare lesions with a radiologically heterogenous presentation. As the lesions might be misinterpreted as malignant during preoperative workup, increased knowledge of these entities is of importance for radiologists, endocrinologists, surgeons and pathologists alike.
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