MINI REVIEW
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Adrenal schwannoma: why should endocrinologists be aware of this uncommon tumour?
Giuseppina Incampo1 . Luigi Di Filippo1 . Erika Maria Grossrubatscher2 . Paolo Dalino Ciaramella2 . Stefano Frara1 . Andrea Giustina1 . Paola Loli 11
Received: 28 December 2021 / Accepted: 23 January 2022 / Published online: 12 February 2022 @ The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
Abstract
Purpose Adrenal schwannomas (AS) are rare tumours arising from Schwann cells. Due to the high prevalence of adrenal incidentalomas, running into very rare adrenal tumours has become a possibility for high volume expert centres. So far, the clinical behaviour and the radiological characteristics of AS make the pre-operative diagnosis of AS extremely challenging. Due to limited information available, we wanted to summarise the main features of this tumours, in order to raise the profile of an uncommon disease.
Methods We performed a MEDLINE and EMBASE research to review the literature. We found 57 case reports and case series and a total of 169 cases, including 2 more cases found in our Institutions. We collected data regarding year of publication, sex, age, and, when available, clinical presentation, hormonal data, radiological features, tumour site and size, treatment, histology and follow-up.
Results We analysed and discussed the clinical, radiological and pathological characteristics of cases identified, underlying the critical aspects of assessment and management of these tumours which still remain questioned, as, currently, pathologic examination is the only way to make the diagnosis.
Conclusions The pre-operative diagnosis of AS is more than challenging and pathologic examination is so far the only way to make a certain diagnosis. Therefore, it is important to consider also the AS in the list of possible diagnoses when faced with a large not secreting adrenal tumour, with suspicious radiological features.
Keywords Schwannoma · Adrenal incidentaloma · Adrenocortical carcinoma . Pheochromocytoma . Adrenal gland
Introduction
The spreading use of diagnostic imaging has led to an increased detection of adrenal incidentalomas, concerning 4% of all abdominal computed tomography (CT) scans and rising up to 7-10% in the elderly [1]. Most of the adrenal incidentalomas are benign adenomas, but 4-13% are more severe diseases such as pheochromocytomas and adreno- cortical carcinomas.
Schwannomas are rare tumours arising from Schwann cells in myelin sheaths of nerves. In particular,
retroperitoneal schwannomas comprise almost 1% of all retroperitoneal masses, encompassing both rare benign tumours and primary or metastatic malignant neoplasms [2].
Juxta-adrenal schwannomas, which may be mis- diagnosed as adrenal tumours, have been rarely reported but visceral schwannomas, and adrenal schwannomas (AS), are extremely infrequent diseases.
So far, only single case reports or small series are reported in the literature.
Aim of our review was to summarise the main features of these tumours, in order to raise the profile of an uncommon
☒ Paola Loli
1 Institute of Endocrine and Metabolic Sciences, Università Vita- Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy
2 Endocrine Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
Articles selected on basis of title and abstract N=94 (N of total cases = 212)
Articles excluded: .Only title or abstract available N = 10 (N cases= 11)
Full-text articles assessed for eligibility N = 84 (N of total cases= 201)
Full-text articles excluded for reason:
·Articles referring to juxta-adrenal/ retroperitoneal schwannoma N=26 (N cases= 32)
.Articles ratracted N=1 (N case= 1)
Articles included in the review N = 57 (N of total cases = 168)
Cases excluded:
.Previously published N=1
Cases added:
.Reported in the present paper N=2
Articles included in the review N = 57 (N of total cases = 169)
disease, whose pre-operative diagnosis still remains extre- mely challenging.
Methods
A computerised literature search of MEDLINE and EMBASE database was performed; original articles were searched using the following terms: ‘adrenal’ or ‘suprarenal’ AND ‘schwan- noma’ or ‘neurilemmoma’, the latter two considered as acceptable synonyms by the most recent WHO Classification [3], from the inception up to the 31st October 2021. As we wanted to focus our review on visceral schwannomas of the adrenal gland, we ruled out the ‘juxta-adrenal schwannoma’ or ‘retroperitoneal schwannoma’.
At least an English translation of the title was required for the original research; no other language restriction was applied. In addition, we searched the reference lists of identified articles to find additional eligible reports.
We excluded articles with an unavailable full-text and one retracted article; one poster was included (Fig. 1).
We identified 57 articles (47 case reports and 10 case series), with a total of 169 AS cases, including two more patients (Case 1 and 2) treated at our Institutions, and excluding one case which had been previously reported.
We collected data regarding the year of publication, sex, age, and, when available, clinical presentation, hormonal data, radiological features, tumour site and size, treatment, histology and follow-up.
Table 1 summarises the characteristics of the identified cases including two unpublished cases managed in our Units.
Etiopathogenesis
More than 90% of schwannomas are sporadic; however, they can also occur as part of syndromes, most frequently Neurofibromatosis 2, schwannomatosis or Carney complex
| Author | Year | N. of pati- ents | Sex | Age | Clinical presenta- tion | Diagnostic modalities | Solid/ Cystic | Side | Hormon secretion | Treat- ment | Histo- logy | Size (cm) | Follow-up (months) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Wilson CS [27] | 1975 | 2 | F | 2 | AP | RX | S | L | NI | OL | AN | 15 | 72 |
| Wilson CS [27] | 1975 | M | 52 | AP | RX | S | R | NI | OL | NI | 12 | NI | |
| Bedard YC [23] | 1986 | 1 | F | 63 | AP | US, CT | S | L | NS | OL | CE | 9 | NI |
| Igawa T [68] | 1998 | 1 | M | 45 | AP | US, CT, MRI | S | L | NS | TR | CO | 6,5 | NI |
| Gonzalez | 2000 | 1 | F | 61 | AP | US, MRI | SC | R | NS | TR | CO | 7 | NI |
| Gonzalez A [50] | |||||||||||||
| Ikemoto I [69] | 2002 | 1 | F | 62 | AP | US, CT, MRI | S | R | NS | TR | AN | 12 | NI |
| Tezel GG [24] | 2005 | 1 | F | 46 | A | US, CT | S | L | NS | TR | CO+ MY | 8 | 12 |
| Lau SK [70] | 2006 | 1 | M | 73 | AP | CT | S | L | NS | TR | CO | 9 | 17 |
| Lau SK [70] | 2006 | 1 | F | 26 | AP | CT | S | L | NS | TR | CE | 10 | 9 |
| Gazula S [71] | 2007 | 1 | M | 42 | AP | US, CT | SC | R | NS | OL | NI + TBC | 12 | NI |
| Suzuki K [30] | 2007 | 1 | M | 33 | A | RX, US, CT, MRI, MIBG, COLSCIN | S | R | NS | TR | NI | 9 | NI |
| Korets R [72] | 2007 | 1 | M | 70 | UTD | CT,MRI | C | L | NS | LP | NI | 3 | NI |
| Jakowski JD [22] | 2008 | 1 | F | 51 | A | CT | SC | L | NS | LP | CO | 5,5 | NI |
| Hsiao HL [21] | 2008 | 1 | M | 49 | A | US, CT | S | R | NS | LP | CE | 5 | 5 |
| Onoda N [9] | 2008 | 1 | M | 62 | A | CT,MRI | S | L | NS | LP | NI | 4,5 | 36 |
| Târcoveanu E [49] | 2009 | 1 | M | 59 | A | US, CT | S | L | NS | LP | CE | 4,5 | 18 |
| Yang CY [73] | 2009 | 1 | F | 30 | AP | CT,MRI | SC | L | NS | LP | CO | NI | 18 |
| Xiao C [32] | 2011 | 6 | F | 38 | A | US, CT | S | L | NS | OL | CO | 3,5 | 48 |
| Xiao C [32] | 2011 | F | 46 | A | US, CT | S | L | NS | OL | CO | 4,5 | 48 | |
| Xiao C [32] | 2011 | M | 39 | AP | US, CT | S | R | NS | OL | CO | 3,5 | 48 | |
| Xiao C [32] | 2011 | F | 43 | AP | US, CT | S | L | NS | OL | CO | 5,1 | 48 | |
| Xiao C [32] | 2011 | M | 47 | A | US, CT | S | L | NS | OL | CO | 6 | 48 | |
| Xiao C [32] | 2011 | F | 30 | A | US, CT | S | L | NS | OL | CO | 3 | 48 | |
| Richter KK [35] | 2011 | 1 | F | 30 | AP | US, CT | S | L | NS | LP | CO | 15 | NI |
| Toutouzas KG | 2012 | 1 | F | 71 | A | US, CT | SC | L | NS | LP | CO | 5,5 | NI |
| [67] | |||||||||||||
| Adas M [74] | 2013 | 1 | F | 32 | AP | US, CT, FDGPET | SC | L | NS | OL | CE | 10 | NI |
| Mohiuddin Y [43] | 2013 | 1 | M | 79 | NI | NI | NI | NI | NI | TR | NI | NI | NI |
| Hernández | 2014 | 1 | F | 42 | AH | CT, MRI | SC | R | NS | LP | NI | 3,7 | NI |
| Domínguez S [75] | |||||||||||||
| Jeshtadi A [76] | 2014 | 1 | F | 55 | AP | US, CT | S | R | NS | OL | CE | 8 | NI |
| Li SQ [44] | 2015 | 19 | F | 38 | AP | US, CT, OCS, PETGA | S | R | NS | LP | CE | 6,9 | NI |
| Li SQ [44] | 2015 | F | 31 | A | US, CT, OCS, PETGA | S | R | NS | LP | CE | 4 | NI | |
| Li SQ [44] | 2015 | F | 50 | A | US, CT, OCS | S | R | NS | LP | CE | 4 | NI | |
| Li SQ [44] | 2015 | F | 55 | A | US, CT, OCS | S | L | NS | LP | CE | 5,8 | NI | |
| Li SQ [44] | 2015 | F | 50 | AP | US, CT, OCS | SC | R | NS | LP | AN | 8,8 | NI | |
| Li SQ [44] | 2015 | M | 23 | A | US, CT, OCS | S | L | NS | LP | CE | 6,2 | NI | |
| Li SQ [44] | 2015 | F | 54 | A | US, CT, OCS | S | R | NS | LP | CE | 7 | NI | |
| Li SQ [44] | 2015 | F | 66 | A | US, CT, OCS | S | R | NS | LP | CE | 6,4 | NI | |
| Li SQ [44] | 2015 | F | 56 | A | US, CT, OCS | S | R | NS | LP | CO | 5,6 | NI | |
| Li SQ [44] | 2015 | M | 61 | AP | US, CT, OCS | S | L | NS | LP | CE | 6,2 | NI |
| Author | Year | N. of pati- ents | Sex | Age | Clinical presenta- tion | Diagnostic modalities | Solid/ Cystic | Side | Hormon secretion | Treat- ment | Histo- logy | Size (cm) | Follow-up (months) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Li SQ [44] | 2015 | F | 65 | AP | US, CT, OCS | SC | R | NS | LP | AN | 8,3 | NI | |
| Li SQ [44] | 2015 | M | 34 | A | US, CT, OCS | S | L | NS | LP | CE | 4,9 | NI | |
| Li SQ [44] | 2015 | F | 64 | A | US, CT, OCS | S | L | NS | LP | CE | 6 | NI | |
| Li SQ [44] | 2015 | F | 44 | A | US, CT, OCS | S | R | NS | LP | CE | 5,8 | NI | |
| Li SQ [44] | 2015 | F | 46 | A | US, CT, OCS | S | R | NS | LP | CE | 6,4 | NI | |
| Li SQ [44] | 2015 | F | 50 | A | US, CT, OCS | SC | R | NS | LP | CE | 7,2 | NI | |
| Li SQ [44] | 2015 | F | 40 | A | US, CT, OCS | S | R | NS | LP | CE | 5,3 | NI | |
| Li SQ [44] | 2015 | F | 32 | A | US, CT, OCS | S | R | NS | LP | CE | 6,1 | NI | |
| Li SQ [44] | 2015 | F | 58 | A | US, CT, OCS | S | R | NS | LP | CE | 6,8 | NI | |
| Zhou J [12] | 2015 | 1 | F | 31 | A | NI | S | R | NS | TR | MC/R | 4,2 | 52 |
| Yang KF [25] | 2015 | 1 | F | 47 | AP | CT | S | L | NS | LP | AN + | 7 | 24 |
| MY | |||||||||||||
| Blanco Fernandez R [77] | 2016 | 1 | F | 56 | AP | CT | SC | R | NS | LP | CO | 11 | NI |
| Yun HJ [78] | 2016 | 2 | F | 39 | NI | CT | S | L | NI | LP | NI | 1,4 | NI |
| Yun HJ [78] | 2017 | F | 45 | NI | CT | S | L | NI | LP | CE | 4 | NI | |
| Zhang YM [38] | 2016 | 8 | M | 51 | A | CT | SC | L | NS | TR | NI | 7 | NI |
| Zhang YM [38] | 2016 | M | 43 | AP | CT | SC | R | NS | TR | NI | 9 | NI | |
| Zhang YM [38] | 2016 | F | 28 | AP | CT | SC | R | NS | TR | NI | 12 | NI | |
| Zhang YM [38] | 2016 | M | 46 | A | CT | SC | R | NS | TR | NI | 6,7 | NI | |
| Zhang YM [38] | 2016 | F | 49 | A | CT | SC | R | NS | TR | NI | 4 | NI | |
| Zhang YM [38] | 2016 | M | 37 | A | CT | SC | L | NS | TR | NI | 4,3 | NI | |
| Zhang YM [38] | 2016 | M | 52 | AP | CT | SC | L | NS | TR | NI | 14 | NI | |
| Zhang YM [38] | 2016 | M | 25 | AP | CT | SC | R | NS | TR | NI | 11 | NI | |
| Kumar S [79] | 2016 | 1 | M | 42 | AP | US, CT | S | R | NS | OL | CE | 8 | NI |
| Hou J [40] | 2016 | 1 | F | 41 | AP | CT | SC | L | NS | TR | NI | 7,7 | NI |
| Said S [80] | 2017 | 1 | M | 64 | A | CT | SC | R | NS | OL | AN | 9 | NI |
| Babaya N [29] | 2017 | 1 | M | 69 | AP | CT, MRI | S | L | IPAC | TR | CO | 5,8 | 6 |
| Shivalingaiah PH [39] | 2018 | 1 | M | 68 | UTD | US, CT | S | L | NS | OL | CE | 14 | NI |
| Tang W [36] | 2018 | 17 | F | 47 | A | CT | C | L | NS | LP | CO | 5,5 | 44 |
| Tang W [36] | 2018 | F | 65 | A | CT | C | L | NS | LP | CO | 5 | 44 | |
| Tang W [36] | 2018 | F | 64 | A | CT | C | R | NS | LP | CO | 3,8 | 44 | |
| Tang W [36] | 2018 | F | 50 | AP | CT | C | R | NS | LP | CO | 8,2 | 44 | |
| Tang W [36] | 2018 | F | 31 | A | CT | S | L | NS | LP | CO | 3,5 | 44 | |
| Tang W [36] | 2018 | F | 49 | A | CT | C | R | NS | LP | CO | 3,5 | 44 | |
| Tang W [36] | 2018 | F | 34 | A | CT | S | R | NS | LP | CO | 3 | 44 | |
| Tang W [36] | 2018 | F | 58 | AP | CT | C | R | NS | LP | CO | 8 | 44 | |
| Tang W [36] | 2018 | F | 56 | AP | CT | C | L | NS | LP | CO | 8,8 | 44 | |
| Tang W [36] | 2018 | F | 35 | A | MRI | C | L | NS | LP | CO | 4,5 | 44 | |
| Tang W [36] | 2018 | F | 48 | A | MRI | C | R | NS | LP | CO | 3,5 | 44 | |
| Tang W [36] | 2018 | F | 46 | A | MRI | C | R | NS | LP | CO | 5,5 | 44 | |
| Tang W [36] | 2018 | F | 31 | A | MRI | S | R | NS | LP | CO | 3 | 44 | |
| Tang W [36] | 2018 | M | 30 | A | CT | C | L | NS | LP | CO | 6,5 | 44 | |
| Tang W [36] | 2018 | M | 35 | A | CT | C | R | NS | LP | CO | 4,3 | 44 | |
| Tang W [36] | 2018 | M | 28 | A | CT | C | R | NS | LP | CO | 2,5 | 44 |
| Author | Year | N. of pati- ents | Sex | Age | Clinical presenta- tion | Diagnostic modalities | Solid/ Cystic | Side | Hormon secretion | Treat- ment | Histo- logy | Size (cm) | Follow-up (months) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Tang W [36] | 2018 | M | 39 | A | MRI | C | R | NS | LP | CO | 5,5 | 44 | |
| Thomas MB [81] | 2018 | 1 | F | 56 | AP | US, CT | C | L | NS | OL | CO | 5,5 | NI |
| Oberoi A [66] | 2019 | 1 | F | 50 | A | US, CT, MIBGSPECT | S | L | NS | OL | CO | 14 | 18 |
| Maciel JM [11] | 2019 | 1 | F | 69 | AH | CT, MRI, PETFDG | S | L | NS | OL | MC/R | 7 | 12 |
| Salhi H [31] | 2019 | 1 | NI | 41 | AP | US, CT, MRI | S | L | NS | TR | NI | 3,4 | NI |
| Shabana W [82] | 2019 | 1 | M | 32 | AP | CT | S | R | NS | LP | AN | 4,7 | NI |
| Zhou J [10] | 2019 | 30 | F | 45 | A | CT | S | R | NS | LP | P | 3,2 | 54 |
| Zhou J [10] | 2019 | M | 53 | A | CT | C | R | NS | LP | CO | 8,3 | 52 | |
| Zhou J [10] | 2019 | M | 66 | AH | CT | SC | R | CSB | LP | AN | 5,3 | 51 | |
| Zhou J [10] | 2019 | M | 43 | A | CT | S | R | NS | LP | CE | 6,5 | 56 | |
| Zhou J [10] | 2019 | F | 62 | IF | CT | S | L | NS | LP | CO | 5 | 56 | |
| Zhou J [10] | 2019 | F | 32 | A | CT | S | L | NS | LP | CO | 6 | 64 | |
| Zhou J [10] | 2019 | F | 42 | A | CT | S | L | NS | LP | CO | 6 | 63 | |
| Zhou J [10] | 2019 | F | 44 | AP | CT | S | L | CSB | LP | CO | 5 | 66 | |
| Zhou J [10] | 2019 | F | 26 | A | CT | S | R | NS | LP | CO | 3 | 70 | |
| Zhou J [10] | 2019 | M | 50 | AP | CT | S | R | IPAC | LP | CO | 4,2 | 70 | |
| Zhou J [10] | 2019 | M | 58 | A | CT | S | L | IPAC | LP | CO | 2,5 | 71 | |
| Zhou J [10] | 2019 | F | 56 | A | CT | S | L | IPAC | LP | CO | 1 | 74 | |
| Zhou J [10] | 2019 | M | 38 | A | CT | S | R | NS | LP | CE | 3,5 | 76 | |
| Zhou J [10] | 2019 | F | 61 | A | CT | S | R | NS | LP | CE | 12 | 78 | |
| Zhou J [10] | 2019 | F | 57 | WL | CT | S | L | CSB | LP | CE | 6,2 | 90 | |
| Zhou J [10] | 2019 | F | 47 | A | CT | S | R | NS | LP | CE | 12 | 95 | |
| Zhou J [10] | 2019 | F | 48 | A | CT | S | L | NS | LP | CE | 8 | 102 | |
| Zhou J [10] | 2019 | M | 40 | A | CT | S | L | NS | LP | CO | 3 | 112 | |
| Zhou J [10] | 2019 | M | 42 | A | CT | S | L | NS | LP | CO | 3 | 115 | |
| Zhou J [10] | 2019 | F | 42 | A | CT | S | L | NS | LP | CO | 4 | 23 | |
| Zhou J [10] | 2019 | F | 52 | A | CT | S | L | NS | LP | P | 4,5 | 21 | |
| Zhou J [10] | 2019 | M | 31 | A | CT | C | R | NS | LP | CO | 7 | 20 | |
| Zhou J [10] | 2019 | M | 69 | A | CT | SC | R | NS | LP | CE | 2,5 | 20 | |
| Zhou J [10] | 2019 | M | 67 | A | CT | C | R | NS | LP | CO | 6 | 13 | |
| Zhou J [10] | 2019 | F | 46 | A | CT | S | L | NS | LP | CO | 12 | 7 | |
| Zhou J [10] | 2019 | F | 29 | AP | CT | S | L | NS | LP | CO | 2 | 32 | |
| Zhou J [10] | 2019 | M | 54 | A | CT | S | L | NS | LP | CO | 8,5 | 13 | |
| Zhou J [10] | 2019 | F | 67 | A | CT | SC | R | NS | LP | CO | 7 | 14 | |
| Zhou J [10] | 2019 | M | 71 | A | CT | SC | L | NS | LP | CO | 10 | 20 | |
| Zhou J [10] | 2019 | F | 33 | A | CT | S | R | NS | LP | E | 4 | 13 | |
| Zhou W [33] | 2019 | 15 | F | 55 | AP | US | SC | R | NS | TR | CO | 5 | NI |
| Zhou W [33] | 2019 | F | 37 | A | US | SC | R | NS | TR | CO | 7 | NI | |
| Zhou W [33] | 2019 | F | 70 | A | US | S | R | NS | TR | CO | 5 | NI | |
| Zhou W [33] | 2019 | M | 43 | A | US | S | R | NS | TR | CO | 5 | NI | |
| Zhou W [33] | 2019 | F | 56 | A | US | SC | R | NS | TR | CO | 5 | NI | |
| Zhou W [33] | 2019 | M | 54 | A | US | SC | L | NS | TR | CO | 8 | NI | |
| Zhou W [33] | 2019 | F | 45 | AP | US | SC | R | NS | TR | CO | 8 | NI | |
| Zhou W [33] | 2019 | M | 54 | AP | US | SC | L | NS | TR | CO | 9 | NI |
| Author | Year | N. of pati- ents | Sex | Age | Clinical presenta- tion | Diagnostic modalities | Solid/ Cystic | Side | Hormon secretion | Treat- ment | Histo- logy | Size (cm) | Follow-up (months) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Zhou W [33] | 2019 | F | 63 | A | US | SC | L | NS | TR | CO | 5 | NI | |
| Zhou W [33] | 2019 | F | 61 | AP | US | SC | L | NS | TR | CO | 4 | NI | |
| Zhou W [33] | 2019 | F | 61 | A | US | SC | L | NS | TR | CO | 3 | NI | |
| Zhou W [33] | 2019 | M | 84 | A | US | S | R | NS | TR | CO | 5 | NI | |
| Zhou W [33] | 2019 | F | 22 | AP | US | SC | L | NS | TR | CO | 7 | NI | |
| Zhou W [33] | 2019 | F | 55 | A | US | SC | L | NS | TR | CO | 5 | NI | |
| Zhou W [33] | 2019 | F | 42 | A | US | S | L | NS | TR | CO | 4 | NI | |
| Ma T [83] | 2020 | 9 | NI | NI | NI | NI | NI | NI | NI | LP | NI | NI | NI |
| Gomez [26] | 2020 | 1 | M | 65 | A | CT | S | L | NI | LP | NI + | 13 | NI |
| MY | |||||||||||||
| Dell'Aversano | 2020 | 1 | F | 61 | A | US, MRI, | SC | L | NS | TR | AN | 8 | NI |
| Orabona G [64] | CT, PETFDG | ||||||||||||
| Almalki MH [51] | 2020 | 1 | F | 62 | AP | CT | S | R | NS | LP | CO | 4,5 | 5 |
| Yi Y [84] | 2020 | 1 | F | 56 | AP | CT | S | R | NS | LP | CE | 6 | NI |
| Cojab MJ [85] | 2020 | 1 | F | 44 | AP | CT | S | L | NI | LP | CO | 6 | NI |
| Wilson MP [41] | 2020 | 1 | M | 81 | A | CT | SC | L | NS | NT | AN | 10 | 6 |
| Venkataramana | 2020 | 1 | F | 55 | AP | US, CT | SC | R | NS | OL | AN | 6 | 10 |
| CG [48] | |||||||||||||
| Timilsina S [86] | 2021 | 1 | M | 55 | AP | US, CT | SC | L | NS | LP | CO | 8,3 | NI |
| Yorita K [65] | 2021 | 1 | M | 90 | A | CT, | S | L | NS | TR | CO | 3,4 | NI |
| MRI, PETFDG | |||||||||||||
| Janjua A [87] | 2021 | 1 | F | 50 | AP | US, CT | SC | L | NS | OL | CO | 14 | 12 |
| Fuentes C [88] | 2021 | 1 | F | 55 | A | MRI | SC | L | NS | LP | CO | 3,5 | NI |
| Huang H [89] | 2021 | 13 | F | 44 | A | US, CT | S | R | NS | TR | CO | 9,9 | 61 |
| Huang H [89] | 2021 | F | 19 | A | US, CT | S | R | NS | TR | CO | 3,9 | 61 | |
| Huang H [89] | 2021 | M | 40 | A | US, CT | SC | L | NS | TR | CO | 5,9 | 61 | |
| Huang H [89] | 2021 | F | 59 | A | US, CT | S | R | NS | TR | CO | 4,5 | 61 | |
| Huang H [89] | 2021 | F | 27 | AP | US, CT | SC | L | NS | TR | CO | 8 | 61 | |
| Huang H [89] | 2021 | M | 24 | A | US, CT | SC | R | NS | TR | CO | 6,1 | 61 | |
| Huang H [89] | 2021 | M | 51 | A | US, CT | S | L | NS | TR | CO | 4,5 | 61 | |
| Huang H [89] | 2021 | M | 62 | D | US, CT | SC | R | NS | TR | CO | 13 | 61 | |
| Huang H [89] | 2021 | F | 57 | A | US, CT | S | R | NS | TR | CO | 10 | 61 | |
| Huang H [89] | 2021 | M | 47 | A | US, CT | S | L | NS | TR | CO | 1,6 | 61 | |
| Huang H [89] | 2021 | F | 46 | AP | US, CT | S | L | NS | TR | CO | 6 | 61 | |
| Huang H [89] | 2021 | F | 53 | A | US, CT | SC | R | NS | TR | CO | 7,4 | 61 | |
| Huang H [89] | 2021 | M | 52 | A | US, CT | SC | L | NS | TR | CO | 12 | 61 | |
| Bayramoglu Z | 2021 | 1 | M | 13 | AP | US, MRI | SC | R | NS | LP | CO | 3 | NI |
| [28] | |||||||||||||
| Incampo (Case 1) | 2022 | 2 | F | 76 | A | CT, MRI | SC | L | NS | LP | CO | 5 | 30 |
| Incampo (Case 2) | 2022 | F | 61 | AP | US, CT, | S | L | NS | LP | AN | 9 | 24 | |
| MRI, PETFDG |
F female, M male, A asymptomatic, AP abdominal pain, AP arterial hypertension, UTD urinary tract disturbances, IF intermittent flushing, WL weight loss, D dizziness, RX plain abdominal radiography, US ultrasound scan, CT computer tomography, MR/ Magnetic resonance imaging, PETFDG fluorodexossiglucose positron emission tomography, PETGA 68Ga PET, OCS Octreoscan, MIBG metaiodobenzylguanidine scintigraphy, COLSCIN 131I-6beta-iodomethyl-nor-cholesterol scintigraphy, S solid, C cystic, SC solid and cystic, R right, L left, NS no secretion, ICLU increased 24 h urinary cortisol, IPAC increased plasma aldosteron concentration, TR tumour resection, LP laparoscopy, OL open laparotomy, NT no treatment, CO conventional, CE cellular, AN ancient, MY myelolipoma, TBC tuberculosis, P plexiform, E epitheliod, R reticular, NI not indicated
[4]. An association with previous radiation exposure, mostly for head or neck schwannomas, has been reported [5]. According to the current literature, no patients with AS have been associated with genetic syndromes.
The aetiology of schwannomas is not completely understood, but NF2 gene mutation has a pivotal role in the tumorigenesis, even in sporadic cases. NF2 gene is located at 22q12.2 and encodes for NF2, also called merlin, a tumour suppressor protein [6]. The biallelic inactivation of NF2, with the loss of the NF2 protein, is responsible for the transformation of Schwann cells into NF2-associated schwannomas. The genetic events involved are usually frameshift and nonsense mutations. Mutations of additional tumour suppressor genes, such as SMARCB1 [7] or the LZTR1 [8], both located on chromosome 22, are also involved in schwannomas pathogenesis.
Pathology
AS are thought to originate from Schwann cells associated with the nerves that innervate the adrenal medulla, in par- ticular the phrenic nerve, the vagal nerve and the sympathetic trunk.
At a macroscopic examination, AS present as solitary, well-circumscribed and encapsulated masses; the cut sur- face usually consists in glistening firm white-greyish to tan- yellow tissue. Although most of the AS are solid and homogenous throughout, large AS may present secondary changes, including cysts, haemorrhage and calcifications, which are typical features of the ‘ancient degeneration’. Sometimes, the mass might compress the surrounding cor- tical and medullary tissues [9].
Microscopically, schwannomas are classified in several variants: conventional, cellular, ancient, plexiform, epithe- lioid and microcystic/reticular. The recently published WHO classification has recognised the melanotic schwan- noma, which is mostly seen in patients with Carney com- plex, as a specific class of peripheral nerve sheath tumour with a prominent malignant behaviour [3].
Most of AS are either conventional (57%, 91/160) or cellular (21%, 33/160); few cases of ancient (8%, 12/160), plexiform (1%, 2/160), microcystic/reticular (1%, 2/160) and epithelioid (1%, 1/160) pattern have been described [10-12]. To the best of our knowledge, melanotic schwannomas have never been found in the adrenal gland.
The conventional pattern consists in hypercellular areas (Antoni A) alternating with a loosely textured hypocellular areas (Antoni B). Further histological findings are Verocay bodies (nuclear-free zones within the regions of nuclear palisading) and thick-walled hyalinized blood vessels. The cellular variant is characterised by the predominance of Antoni A growth pattern and the absence of Verocay
bodies. Infiltrates of inflammatory cells, mostly macro- phages and lymphocytes, might be present, character- istically disposed as a peripheral lymphoid cuff [13-15], as we observed in case 2 of the present series. Moreover, areas of necrosis are usually not present. Nuclear atypia, which is typical of the ancient degeneration, should not be mis- interpreted as a sign of malignancy.
On immunohistochemical examination, schwannomas present with prominent nuclear and cytoplasmic staining for S100 protein [16]; SOX10 expression is also very frequent [17]. Auxiliary diagnostic stains are also reported [18-22]. Mitotic figures are common, but the mitotic count is <5 mitosis/mm2 in most cases [23].
AS have been characterised on electron microscopy, but ultrastructural evaluation is not mandatory at the moment for the diagnosis. This specific evaluation might be helpful for differential diagnosis with the ‘sustentaculoma’ [22], that shows similar immunohistochemical features, but dif- fers from the AS mainly for lacking a well-defined basal lamina. Nevertheless, the most recent edition of WHO Classification did not include this tumour, yet [3].
A report of an AS reported positively staining for immunoglobulins, mostly IgG, both in the tumour cell cytoplasm and in the extracellular space. This finding has been interpreted as an interaction between host and tumour [23].
Interestingly, in 2% of cases (3/160) AS presented as a collision tumour together with a myelolipoma [24-26].
Clinical characteristics of patients
Between 1986 and 2021, 167 patients with a pathological diagnosis of AS have been reported in the literature and we considered two more patients we observed in our Institu- tions, with a comprehensive amount of 169 cases included in the analysis (Table 2).
The median age at diagnosis of AS is 49 years (IQR 39.3-58.8) and the male:female ratio 1:1.7.
Only 13% of patients are older than 65 years (21/160) at diagnosis and less than 3% (5/160) are older than 75. Only two paediatric cases have been reported so far [27, 28].
The median lesion size is 6 cm (IQR 4.3-8), compre- hensively ranging from 1 to 15 cm; less than 20% (31/158) are smaller than 4 cm and 16% (25/158) are equal or greater than 10 cm.
AS usually are solitary and one-sided, and equally dis- tributed in the left and right adrenal gland. One exception is represented by two cases reported by Zhou et al. who pre- sented multiple tumours, two and three respectively, on the same side [10].
Clinical presentation of AS is fairly constant: 62% (97/ 157) of patients are asymptomatic, whereas 32% (51/157)
| Patients (n. 169) | Value (interquartile range) |
|---|---|
| Sex (n. 159) | |
| Female | 101 |
| Male | 58 |
| Median age, years (n. 160) | 49 (39.3-59.8) |
| Clinical presentation (n. 157) | |
| No symptoms | 97 |
| Abdominal pain/discomfort | 51 |
| Arterial hypertension | 3 |
| Haematuria/urinary disorders | 2 |
| Intermittent flushing | 1 |
| Weight loss | 1 |
| Dizziness | 1 |
| Size (n. 158) | |
| Median, cm | 6 (4.3-8) |
| Diameter ≥ 4 cm | 127 |
| Diameter < 4 cm | 31 |
| Diameter ≥ 10 cm | 25 |
| Side (n. 159) | |
| Left | 83 |
| Right | 76 |
| Solid/Cystic (n. 160) | |
| Solid | 98 |
| Solid and Cystic | 10 |
| Cystic | 20 |
| Hormone Secretion (n. 153) | |
| No hormone secretion | 146 |
| Increased aldosteron concentration | |
| Increased urinary free cortisol 24 h | 3 |
| Treatment (n. 169) | |
| Surgery | 168 |
| Laparoscopy | 98 |
| Open Laparotomy | 20 |
| Not Specified | 50 |
| No surgery | 1 |
| Histology (n. 160) | |
| Conventional | 91 |
| Cellular | 33 |
| Ancient | 12 |
| Microcystic/reticular | 2 |
| Plexiform | 2 |
| Epithelioid | 1 |
| Not specified | 20 |
| Mean follow-up, months (n. 85) | 45 |
complain of abdominal pain possibly due to the mass effect. Other non-specific symptoms are described, but without an evident causality relation with the AS.
We found that the lesions mean size of symptomatic patients is significantly larger than that of asymptomatic patients (7.9 cm vs 5.8 cm, p<0.01).
AS are non-secreting adrenal tumours: in 95% (146/153) of cases, hormone hypersecretion was excluded. Four cases showed an increase in plasma aldosterone concentration and three cases an increase in 24 h-urinary excretion of cortisol [10]. In most of the cases, the hypersecretion was not confirmed and in one case the aldosteronism, confirmed by adrenal vein sampling, was actually due to co-occurrence of an adrenal schwannoma with aldosterone-producing adrenal micronodules [29].
Radiological imaging
Plain film X-ray plays no role in detecting AS with very few exceptions [27, 30].
Ultrasonography (US) scan, albeit not accurate, fre- quently is the first exam that displays AS, as found in the 48% (75/158) of cases (we consider a possible under- estimation due to the lack of the entire diagnostic process in many reports); just in one case the US failed to describe a 3 cm adrenal mass, otherwise displayed at a subsequent CT- scan [31]. On US, AS appear as solid, oval, well- circumscribed hypoechoic masses [31, 32] and the capsule usually appears as a hyperechoic thin layer surrounding the mass. The US structure of AS is mostly heterogeneous; cystic changes can be identified, and internal septa might be present. Calcifications frequently are detected and can be punctate or mottled, without or with a posterior acoustic shadow respectively. Colour Doppler study may reveal no or minimal vascularity [33].
Consistent with the ESE-ENSAT guidelines recommen- dation [34], a CT scan was performed in 94% (133/141) of cases (excluding one case found at autopsy, 14 cases not specified and 2 cases described before the widespread availability of the imaging procedure). On unenhanced CT, AS typically present as solid, encapsulated, oval or round masses. Albeit tumour margins are typically smooth and sharp, they can look misleadingly irregular [35]. AS have usually homogeneous texture, with an average CT attenuation of 30.2 Hounsfield Units (HU) (range 18-43) [36], but inhomogeneous appearance with low-density areas is reported for larger tumours. Therefore, AS are quite easily differentiated from typical adrenal adenomas and myelolipomas, as the latter usually present a homogenous structure with an attenuation lower or equal to 10 HU [37]; less simple is the differential diagnosis with lipid-poor adenomas, which amount to almost 30% of all adrenal adenomas and demonstrate a higher attenuation. AS fre- quently present cystic or haemorrhagic changes with inter- nal septa, previously reported in 66-100% of cases [30, 38].
We found specifically reported cystic and/or necrotic changes only in the 43% (69/159) of cases retrieved. Cal- cifications can be described as punctate, curvilinear or nodular, mostly related to the tumour wall [38-41]. AS show an early mild heterogeneous contrast enhancement in the hepatic arterial phase, and progressive enhancement during the portal vein and equilibrium phases, with an average CT attenuation of 60 HU (range 51-69) [36, 42]. This enhancement pattern shows a heterogeneous pre- sentation, most likely due to the alternation of Antoni A and Antoni B areas and to the cystic or haemorrhagic degen- eration [43].
Based on these concepts, adrenocortical carcinoma is not rarely a mistaken preoperative diagnosis of AS [35, 39, 44]; indeed, the radiological suspicion of a adrenocortical carcinoma is higher for lesions with a size greater than 4 cm, central tumoral haemorrhages, heterogeneous enhancement and calci- fications; but, unlike the AS, carcinomas typically have irre- gular shape and margins, enhance rapidly in the hepatic arterial phase on enhanced CT, due to the high vascularity, and present a local or distant tumour invasion [45, 46]. Pheochromocyto- mas as well can be mistaken on CT scan [47, 48], as they enhance avidly after medium contrast, with regions of no enhancement due to cystic or haemorrhagic changes. In addi- tion, AS can mimic adrenal metastases, in particular when a history of a primary malignancy is already known [49]. CT scan is also important for detecting local or distant invasion of tumours, which has never been reported for AS. Nevertheless, abdominal lymphadenopathies might be present, as it was for our Case 1 (see Table 1).
Magnetic Resonance Imaging (MRI) is performed for additional characterisation of adrenal lesions with atypical features at other imaging examination and it was carried out in 14% (22/159) of cases. Just in one case, MRI was first undertaken after the US detection of an adrenal lesion [50].
At MRI, AS displays a low signal intensity on T1-WI and heterogeneous high signal intensity on T2-WI [30, 43, 51]. AS usually depict no significant drop of sig- nal intensity in the out-phase image, indicating no intra- cellular lipids or fat tissue within the tumour [31, 52]. Due to this behaviour, AS could be mistaken for cysts, pheo- chromocytomas or adrenocortical carcinomas at MRI. Cysts present typically a low signal on T1-WI and an extensive high T2-WI signal, whereas haemorrhages can be differ- entiated from the liquid/liquid levels [36]. Moreover, AS show a mild and progressive gadolinium enhancement on the dynamic scans. Interestingly, pheochromocytomas have a similar MRI pattern, albeit with a more evident contrast between the low signal intensity at T1-WI and the higher at T2-WI [53]. Schwannomas, as other benign peripheral nerve sheath tumours, might present with some typical radiological signs, described in detail by Zhang et al. [38] and De Vos et al. [54].
Furthermore, ganglioneuromas show more similar radi- ological features to schwannomas, both presenting a low signal intensity on T1-WI and heterogeneously increased T2 signal intensity at MRI; however, the former seldom have cystic changes. However, a very specific feature of ganglioneuroma is the ‘whorled’ appearance, characterised by curvilinear bands of signal intensity on T2-WI [55].
Overall sensitivity and specificity of US, CT and MRI in the diagnosis of adrenal schwannoma cannot be determined due to the design of the available studies that are mainly case reports. Imaging modalities are not specific enough to distinguish between schwannomas and some other adrenal masses. For this reason, in almost all reports the diagnosis of schwannoma is set postoperatively at pathology. An exception is represented by 4 cases in a Chinese series of 19 patients with adrenal masses, where the diagnosis of schwannoma was established preoperatively based on the evaluation of US and CT. This finding sets the sensitivity of these combined imaging procedures to 21% [44].
Functional imaging
Fluorodeoxyglucose positron emission tomography (FDG- PET) is considered a sensible functional study for distin- guishing benign from malignant tumours, even in the con- text of adrenal masses [56-59]. Two meta-analyses have shown that FDG-PET, in combination with CT scan, has high sensitivity and specificity (91% and 91%, respectively) for the characterisation of the adrenal masses [60, 61]; besides, Metser et al. found accurate a cut-off of 3.1 Stan- dard Uptake Value (SUV) for this distinction [57].
Despite their benign biological behaviour, AS can show uptake of the tracer when tested with FDG-PET.
Schwannomas usually show a wide variation of SUV, for maximum values ranging from 1.9 to 7.2, likely due to the alternating hypocellular and hypercellular areas [62]. Miyake et al. found a significant positive correlation between FDG uptake and the histological presence of a dense peritumoral lymphoid cuff, resulting in positive images in all the five cases characterised by this finding [63].
In only six AS case reports and in our Case 2, reported in Table 1, (presenting a SUV max of 10.3, Fig. 2), FDG-PET was carried out, showing a heterogenous increased meta- bolic activity [64]; indeed, Maciel et al. described a case of a microcystic reticular AS presenting a SUV max of 71.7, extremely suggestive of malignancy [11]. An increased, even though less intense, FDG uptake was reported in the two cases in a Chinese study, reporting a SUV max of 2.8 and 3.2 [44] and in a 90-year-old patient with a 3.4 cm lesion with a SUV max 4.4 [65]. According to the hypothesis of Miyake [63], FDG uptake in our patient was
A
B
C
D
consistent with the histological presence of chronic inflammation areas with lympho-follicular organisation, in the context of degenerative components (‘ancient schwan- noma’) found at pathology.
As to radioiodinated metaiodobenzylguanidine (MIBG) scintigraphy, we found only two cases where MIBG scin- tigraphy was performed, showing no increased uptake of the radioactive tracer [30, 66].
Other functional studies have been used in the pre- operative evaluation of AS, such as somatostatin receptor scintigraphy [44] and 131I-6beta-iodomethyl-nor-choles- terol scintigraphy [29], reporting no significant uptake.
Treatment and follow-up
AS undergo surgery, as it is mandatory for the diagnosis, but also for the treatment. Open or laparoscopic adrena- lectomy is performed and the choice of the technique depends on the characteristic of the patient, tumour size and surgeon preference [67].
Based on our review of the literature, only a 81-year-old patient underwent surveillance due to his age and general condition and the diagnosis was set by core biopsy of the lesion; at control imaging after 6 months the lesion was unchanged [41].
According to our revision, 85 patients were followed-up for 5-115 months. So far, neither recurrence nor distant metastases have been reported.
Of particular interest is the report of a 90-year-old patient who underwent surgery for a growing adrenal mass that turned out to be a schwannoma. His previous CT scans were retrospectively evaluated, showing a suspected right adrenal gland tumour 10 years earlier, a lesion measuring 1.3 cm 7 years earlier and a progressive increase in size to 2.2 cm and 3.4 cm after 4 and 9 years, respectively [65].
Conclusions
Primary AS are extremely rare tumours and, according to the Chinese reports, the estimated prevalence is 0.48% up to 2.7% of the adrenal lesions [10, 44, 65]. This estimation is far higher than that reported by Authors in experienced high-volume centres. There is no clear explanation for this difference: it might be due to casualty, depending on the small numbers of patients involved, even if an ethnic dif- ference in the prevalence of the disease cannot be ruled out. In this context, it is worth noticing that large part of the literature on AS comes from hospitals and Academies in China.
AS are always benign lesions, differently from other visceral schwannoma arising in other sites, such as liver, lung or peripheral nerve sheaths. However, due to their slow growth and absence of specific symptoms, AS often appear as large lesions at the time of diagnosis. This occurrence, as well as its radiological features, almost invariably raise the suspicion of being faced with a malignant tumour or a pheochromocytoma. It is noteworthy that pheochromocy- tomas and adrenocortical carcinomas or metastases are actually more frequent among incidentalomas than AS (~7% and 4%, respectively) and that adrenocortical carci- nomas can be found in more than 6% of all adrenal inci- dentalomas with a diameter of 4-6 cm and in 25% of those larger than 6 cm [45], which is the range of size typical of AS.
According to its origin, AS is not a hormone-secreting mass; this finding should be taken into consideration in the diagnostic process since, on the contrary, about 50-60% of patients with adrenocortical carcinoma have biochemical and clinical evidence of hormone excess.
Recently, FDG-PET has been proposed as the second- line best test to diagnose adrenal lesions with indeterminate characteristics at CT, although it is recognised that sensi- tivity and negative predictive value are much better than
specificity or positive predictive value [34]. Our review shows that even this diagnostic functional imaging may be misleading in the case of AS, presenting with an intense uptake of the tracer similarly to a malignant tumour.
Based on the relatively long follow-up of the patients of our review, who show neither recurrence nor metastasis overtime, it could be suggested to withdraw the radiological follow-up after diagnosis; however, we want to underline that for more than half of the patients details on follow-up were lacking and we highlight the need of further pro- spective studies to reach definitive results.
In conclusion, AS preoperative diagnosis is more than challenging and pathologic examination is so far the only way to make a certain diagnosis. Therefore, it is important to consider also AS in the list of possible differential diagnoses when faced with a large non-secreting adrenal tumour, with suspicious radiological features.
Author contributions Study conception and design (Paola Loli), lit- erature search, data analysis and interpretation of data (Giuseppina Incampo, Luigi Di Filippo, Erika Grossrubatscher, Paolo Dalino Ciaramella), first draft of the manuscript (Giuseppina Incampo, Paola Loli), critical revision of the work (Paola Loli, Stefano Frara, Andrea Giustina). All Authors approved the version to be published.
Compliance with ethical standards
Conflict of interest The authors have no relevant financial or non- financial interests to disclose. The authors have no competing interests to declare that are relevant to the content of this article. All authors certify that they have no affiliations with or involvement in any organisation or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. The authors have no financial or proprietary interests in any material discussed in this article.
Ethical approval Ethics Committee of Ospedale Niguarda and Ospe- dale San Raffaele waived the requirement to sign the consent.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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