Continuous and progressive ‘wash-in’ without ‘wash-out’ of contrast in adrenal mass: a useful feature of ganglioneuroma
Neeti Agrawal, Avivar Awasthi, Rahin Mahata, Partha Pratim Chakraborty İD
Endocrinology and Metabolism, Medical College and Hospital Kolkata, Kolkata, West Bengal, India
Correspondence to Dr Partha Pratim Chakraborty; docparthapc@yahoo.co.in
Accepted 10 May 2021
Check for updates
C BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
To cite: Agrawal N, Awasthi A, Mahata R, et al. BMJ Case Rep 2021;14:e241661. doi:10.1136/bcr-2021- 241661
SUMMARY
Computed tomography (CT) scan is a useful and widely performed diagnostic modality to evaluate adrenal masses. Nature of the mass determines the degree of attenuation both in unenhanced and in different phases of contrast enhancement. Benign neurogenic tumours like ganglioneuroma mimicks pheochromocytoma and adrenocortical carcinoma in non-contrast CT scan. The ‘adrenal protocol’ routinely calculates the wash- out pattern at delayed venous phase (DVP) (15 min) following contrast administration to differentiate majority of benign masses from the malignant ones. Ganglioneuromas typically exhibit continuous wash-in of contrast where enhancement gradually increases to attain its peak in DVP. Such wash-in pattern is different from the wash-out pattern observed in pheochromocytomas or adrenocortical adenomas or carcinomas. Presence of this wash-in pattern provides a useful clue to the clinician for underlying ganglioneuroma in hormonally inactive adrenal masses with suspicious morphological appearances. This wash-in pattern also effectively rules out any malignant potential of ganglioneuroma, and thus helps in preoperative decision-making.
BACKGROUND
With widespread uses of computed tomography (CT) and magnetic resonance imaging (MRI) scans, ‘adrenal incidentalomas’ are increasingly being diag- nosed in routine practice. The prevalence of these incidentally detected adrenal masses varies between 0.2%-7%, depending on the mean age of the study population, with an overall prevalence of ~5%.1 The main purpose of evaluating any such unilat- eral adrenal incidentaloma is to rule out functional adrenocortical adenoma (ACA), pheochromocy- toma (PCC) or adrenocortical carcinoma (ACC). Characterisation of radiological patterns along with assessment of functional status are routinely performed to identify the nature of any adrenal mass before contemplating surgical removal. Plasma free metanephrines or urinary deconju- gated metanephrines, measured by liquid chroma- tography with tandem mass spectrometry have a very high sensitivity (~97%) for detection of PCC. PCCs and ACCs at times are clinically silent and might also be biochemically inactive, and in such scenarios, imaging characteristics and ‘wash-out’ patterns on contrast-enhanced CT (CECT) scan are often helpful to identify these sinister conditions.2 3 PCCs typically are heterogeneous, but may often
be homogeneous and the Hounsfield units (HU) on unenhanced CT is characteristically more than 10.4 Large diameter (more than 4-6cm), irreg- ular border, heterogeneous appearance, high pre- contrast attenuation and low wash-out of contrast at 15 min (absolute value: less than 60% and rela- tive value: less than 40%) suggest malignancy.5 Assessment of contrast wash-out, however, is unre- liable for ruling out those rare clinically silent, biochemical marker negative PCCs. Though focus has long been given on wash-out of contrast on CECT, continuous ‘wash-in’ pattern of contrast is also useful to rule out underlying ominous lesions.
Ganglioneuromas are uncommon benign tumours derived from neural crest tissues; a vast majority of them originate from posterior medias- tinum, while others are located in retroperitoneum. Ganglioneuromas arising from adrenal medulla are relatively rare.6 Though most ganglioneuromas are hormonally silent, very few of them produce symp- toms suggestive of catecholamine excess.7 Gangli- oneuromas share many features with PCC and ACC on unenhanced CT scan; hence often are evaluated extensively.
CASE PRESENTATION Case 1
A 10-year-old boy was referred for right adrenal incidentaloma, detected during work-up for left iliac fossa pain. He had no symptoms suggestive of catecholamine or cortisol excess. The boy had no significant medical history, and his family history was unremarkable.
Clinical examination revealed the follow- ing:Height: 140cm (75th-97th percentile); weight: 38 kg (75th-97th percentile); body mass index (BMI): 19.4kg/m2 (85th-95th percentile, over- weight category); blood pressure: 100/70 mm Hg (systolic: 50th percentile, diastolic: 50th-90th percentile). There was no postural drop in blood pressure. He had age appropriate testicular volume (5 mL (left) and 6 mL (right)), with Tanner stage 2 pubic hairs without axillary hairs. Systemic exam- ination was normal. He had no signs of cortisol excess (easy bruising, proximal myopathy, wide purple striae, thin skin, moon face, facial plethora).
Case 2
Right adrenal incidentaloma was discovered in a 65-year-old normotensive male patient, who under- went ultrasonography of whole abdomen for vague abdominal discomfort. He had been diagnosed with
BMJ
Case report
Table 1 Summary of investigations
Hormonal parameters
| Case 1 | Case 2 | Sex-specific reference range | |
|---|---|---|---|
| 08:00 cortisol | 28.27 | 5-23 mcg/dL | |
| 08:00 cortisol (after 1 mg ONDST) | <0.5 | 1.72 | <1.8 mcg/dL |
| 17-hydroxyprogesterone | 1.04 | <2 ng/ml | |
| DHEAS | 117.9 | 136 | 80-560 mcg/dL |
| 24 hours urinary creatinine | 18.4 | 16 | >15 mg/kg/day |
| 24 hours urinary metanephrine | 33.46 | 56.5 | <400 mcg/day |
| 24 hours urinary normetanephrine | 124 | 255 | <900 mcg/day |
Imaging
| Case 1 | Case 2 | |
|---|---|---|
| USG | 3.6×2.1 cm Hypoechoic SOL with thin capsule in right adrenal gland | 9.4×7.4×4.9cm SOL with varying echogenicity in right adrenal gland with calcified foci |
| CT adrenals (figures 1-3) | 3.8×3.5×4.8cm | 5.9×7.6×6.1 cm |
| Homogeneous SOL | Heterogeneous SOL with areas of cystic degeneration and punctate calcification | |
| Pre-contrast attenuation | 26 HU | 26 HU |
| Post-contrast attenuation (at 1 min) | 40 HU | 47 HU |
| Post-contrast attenuation (at 15 min) | 46 HU | 54 HU |
| Histopathology | ||
| Macroscopical features | Mass measuring 5.5×4.5x3.6 cm, external surface has thin capsule | Mass measuring 9×7×5 cm, firm in consistency |
| Microscopical features | Tumour is composed of proliferating Schwann cells with clusters as well as scattered mature ganglion cells. There are foci of lymphocytic cell collection. No neuroblastomatous foci are seen. | Tumour comprised of groups of mature ganglion cells surrounded by Schwann cell rich stroma together with variable amount of collagen (figure 4). Schwannian stroma is more prominent at the periphery of the tumour. A few multinucleated ganglion cells were seen. No neuroblasts seen. |
DHEAS, dehydroepiandrosterone sulfate; HU, Hounsfield unit; ONDST, overnight dexamethasone suppression test; SOL, space occupying lesion; USG, ultrasonography.
type 2 diabetes mellitus 5 years ago and his glycaemic control was maintained (fasting plasma glucose: 98 mg/dl, post-meal plasma glucose: 125 mg/dL, glycated haemoglobin: 6.5%) with metformin (2 g/day) monotherapy. He denied symptoms sugges- tive of catecholamine or cortisol excess. His medical history and family history was unremarkable.
His weight, height and BMI were 55 kg, 168 cm and 19.5 kg/ m2, respectively. Blood pressure: 120/70mm Hg without postural drop. Systemic examination was unremarkable without signs of cortisol excess.
(A
07 Jul
(B)
1
AH
INVESTIGATIONS
Relevant investigations have been summarised in table 1.
DIFFERENTIAL DIAGNOSIS
The incidentally detected adrenal masses in both these patients were hormonally inactive, and had pre-contrast HU of more than 10. In case 1, the mass was homogeneous, while in case 2, it was heterogeneous with areas of necrosis and calcification suggesting ACC or PCC. About 30% of ACCs demonstrate either microcal- cification or coarse calcification.8 PCCs may also contain areas of calcification within the tumour. The differential diagnoses, considered in both these cases, were hormonally silent ACC and non-secreting/dopamine secreting PCC. In addition lipid- poor ACA was also considered in case 1. However, there was
(A)
Wr:2.
(B)
MT:2.
(C)
w:2.
A)
18 00t (B)
18 00t
C
no wash-out of contrast at 15 min in either of them, and delayed progressive enhancement patterns were observed instead, which were inconsistent with the above possibilities.
TREATMENT
Both of them underwent unilateral adrenalectomy following laparotomy. The perioperative and postoperative periods were uneventful, and none of them required perioperative hydrocor- tisone coverage. Histopathological examination was consistent with ganglioneuroma. No visible neuroblast was seen ruling out neuroblastoma.
OUTCOME AND FOLLOW-UP
Both the patients were followed-up at endocrinology and surgery clinics post surgery with clinical examination and adrenal imaging at 6 months. Both of them are doing well at 1-year post surgery without any recurrence.
DISCUSSION
The contrast enhancement and time-related distribution patterns are determined by the vascularity of the tumours and capillary permeability; early enhancement occurs in presence of increased vascularity and capillary permeability. Recently a study looked into the patterns of contrast enhancement in malignant adrenal masses, and concluded that peak enhancement (>5 HU from other phases) at 20s post-contrast (ie, early arterial phase (EAP)), EAP attenuation value ≥100HU and percentage arte- rial enhancement (((EAP-HU - unenhanced HU)/unenhanced HU)×100) value ≥100% differentiate PCC from other malig- nant adrenal masses with high specificity.9 Normetanephrine secreting PCCs demonstrated peak enhancement in EAP, while metanephrine secreting ones showed peak enhancement in early venous phase (EVP) at 1 min post contrast. However, norme- tanephrine secreting PCCs demonstrated higher attenuation
A
B
compared with metanephrine secreting ones in EVP as well. None of the PCCs, nonetheless, demonstrated maximum atten- uation in delayed venous phase (DVP) at 15 min post contrast. Enhancement of an adrenal mass during EAP is not measured in routine clinical practice.
ACCs are associated with absolute wash-out of less than 60% (((EVP-HU - DVP-HU)/(EVP-HU - unenhanced HU))×100) and relative wash-out of less than 40% (((EVP-HU - DVP-HU)/EVP- HU)×100). The wash-in patterns, which we came across in these patients are not seen in ACC. Unlike ACAs, ACCs exhibit peak enhancement in EVP and slow wash-out of contrast material. This behaviour is attributed to presence of disturbed capillary permeability in ACC causing prolonged retention of contrast material in effective extracellular space.10
Both these masses exhibited moderate attenuation (26 HU) on pre-contrast scans, minimal enhancement in EVP (1 min), that reached its maximum in DVP (15 min). There were no wash-out of contrast as DVP-HUs were higher than EVP-HUs. This charac- teristic wash-in pattern has been described in neurogenic tumours like ganglioneuroma. Having a neurogenic origin, ganglioneu- romas on CT and/or dynamic MRI demonstrate continuous wash-in of contrast with gradual progressive enhancement and peak enhancement in DVP. Enlarged extracellular spaces with abundant fibrous or myxoid stroma results in greater accumu- lation of contrast leading to late peak enhancement in delayed phase.11 Thus, presence of gradual and persistent contrast wash-in with maximum enhancement in DVP is an useful clue to underlying ganglioneuroma, and not PCC or ACC, though they share similar radiological features on unenhanced CT scan.
Ganglioneuromas are the most differentiated and benign form, while neuroblastomas are the most undifferentiated and malig- nant variety; ganglioneuroblastoma is the intermediate form of the disease spectrum with low-grade malignant potential. Ganglioneuromas exhibit low-to-moderate attenuation on unen- hanced CT scan and demonstrate mild-to-moderate contrast enhancement, which can either be homogeneous or hetero- geneous.12 13 Unlike ganglioneuromas, neuroblastomas and ganglioneuroblastomas show marked early enhancement, and no delayed progressive enhancement pattern, mimicking PCCs. Moreover, detection of the typical wash-in pattern also excludes the possibility of coexistent malignant foci like neuroblastoma and ganglioneuroblastoma within ganglioneuroma. Discrete intratumoral punctate calcification also favours ganglioneuroma, while amorphous or coarse calcifications suggest neuroblastoma or ganglioneuroblastoma.11 12 14 Punctate calcification in case 2 was also suggestive of ganglioneuroma. This differentiation is important for formulating management protocol and prog- nostication, as ganglioneuromas with foci of ganglioneuroblas- toma or neuroblastoma should always be treated with surgical removal and adjuvant chemotherapy. Surgical removal is also the preferred treatment for ganglioneuroma; however, frequent surveillance without surgery is also justified in some of these cases.15 Patients, who undergoes surgical removal of ganglioneu- roma should also be under regular long-term follow-up, as local recurrence is not uncommon in those with residual tumour.16
In addition to ganglioneuroma, adrenal schwannoma, a benign peripheral nerve sheath tumour also demonstrates similar contrast enhancement pattern. Punctate calcification is also common in schwannomas, and it is difficult to discriminate these two conditions based on radiological appearance alone.17 Visceral schwannomas (including adrenal schwannomas) are extremely rare with very few cases, reported so far. They also share similar histological features like spindle-shaped schwann cells, abundant myxoid matrix and well-formed capsule;
Case report
however, ganglion cells are characteristically absent in schwan- noma, and thus is an important discriminatory feature.18
Other than these neurogenic tumours, benign adrenal masses like angiomyolipoma with minimal macroscopic fat and myelo- lipoma with infarction may also demonstrate such wash-in pattern.19 However, diagnosis of myelolipoma is often straight- forward in non-contrast CT scan. Most advocate resection of any hormonally inactive unilateral adrenal mass larger than 4 cm, unless there is a clearly benign cause like myelolipoma.1 Gangli- oneuroma may also be included in that list, if the typical wash-in pattern with maximum attenuation in DVP, along with punctate calcification is encountered while evaluating a biochemically silent adrenal incidentaloma, which is otherwise asymptomatic.
Learning points
Pheochromocytoma and adrenocortical carcinoma at times are clinically silent and biochemically inactive. Pheochromocytoma, adrenocortical carcinoma and adrenal ganglioneuroma share similar morphological characteristics on unenhanced CT scan, contrast enhancement patterns are useful to differentiate ganglioneuroma from the other two.
Being highly vascular tumour, pheochromocytomas show rapid contrast enhancement with maximum attenuation in the early arterial phase (20s), minimum attenuation in delayed venous phase (DVP) (15 min) and variable wash- out pattern, while adrenocortical carcinomas demonstrate maximum attenuation in early venous phase (1 min) and delayed wash-out of contrast. Ganglioneuroma typically is associated with slow and continuous wash-in of contrast with maximum attenuation in DVP (15 min).
Presence of punctate calcification along with this characteristic wash-in pattern suggests typical benign ganglioneuroma. Moreover, such features effectively eliminate the coexistence of malignant foci within ganglioneuroma like neuroblastoma or ganglioneuroblastoma helping in decision-making as far as management protocol is concerned.
Similar wash-in characteristics are also encountered in other benign conditions like adrenal schwannoma and rarely in myelolipomas or angiomyelolipomas with paucity of macroscopic fat.
Contributors All the authors (NA, AA, RM, PPC) were involved in evaluation and management of the patients. NA and AA did the literature search. NA and RM wrote the manuscript. PPC provided intellectual inputs and finalised the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Disclaimer Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Patient consent for publication Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
ORCID İD Partha Pratim Chakraborty http://orcid.org/0000-0002-3316-4525
REFERENCES
1 Nieman LK. Approach to the patient with an adrenal incidentaloma. J Clin Endocrinol Metab 2010;95:4106-13.
2 Spiro A, Usman A, Ajmal A, et al. Asymptomatic and biochemically silent pheochromocytoma with characteristic findings on imaging. Case Rep Endocrinol 2020;2020:8847261-4.
3 Curfman KR, Di Como JA, Chung TR, et al. Functionally silent, giant pheochromocytoma presenting with varicocele. Am Surg 2021;87:97-100.
4 Canu L, Van Hemert JAW, Kerstens MN, et al. Ct characteristics of pheochromocytoma: relevance for the evaluation of adrenal incidentaloma. J Clin Endocrinol Metab 2019;104:312-8.
5 Szolar DH, Korobkin M, Reittner P, et al. Adrenocortical carcinomas and adrenal pheochromocytomas: mass and enhancement loss evaluation at delayed contrast- enhanced CT. Radiology 2005;234:479-85.
6 Jasinski RW, Samuels BI, Silver TM. Sonographic features of retroperitoneal ganglioneuroma. J Ultrasound Med 1984;3:413-5.
7 Geoerger B, Hero B, Harms D, et al. Metabolic activity and clinical features of primary ganglioneuromas. Cancer 2001;91:1905-13.
8 Bharwani N, Rockall AG, Sahdev A, et al. Adrenocortical carcinoma: the range of appearances on CT and MRI. AJR Am J Roentgenol 2011;196:W706-14.
9 Goroshi M, Jadhav SS, Sarathi V, et al. Radiological differentiation of phaeochromocytoma from other malignant adrenal masses: importance of wash-in characteristics on multiphase CECT. Endocr Connect 2019;8:898-905.
10 Korobkin M, Brodeur FJ, Francis IR, et al. Delayed enhanced CT for differentiation of benign from malignant adrenal masses. Radiology 1996;200:737-42.
11 Ichikawa T, Ohtomo K, Araki T, et al. Ganglioneuroma: computed tomography and magnetic resonance features. Br J Radiol 1996;69:114-21.
12 Johnson GL, Hruban RH, Marshall FF, et al. Primary adrenal ganglioneuroma: CT findings in four patients. AJR Am J Roentgenol 1997;169:169-71.
13 Radin R, David CL, Goldfarb H, et al. Adrenal and extra-adrenal retroperitoneal ganglioneuroma: imaging findings in 13 adults. Radiology 1997;202:703-7.
14 David R, Lamki N, Fan S, et al. The many faces of neuroblastoma. Radiographics 1989;9:859-82.
15 Sánchez-Galán A, Barrena S, Vilanova-Sánchez A, et al. Ganglioneuroma: to operate or not to operate. Eur J Pediatr Surg 2014;24:025-30.
16 Decarolis B, Simon T, Krug B, et al. Treatment and outcome of ganglioneuroma and ganglioneuroblastoma intermixed. BMC Cancer 2016; 16:542.
17 Zhang Y-M, Lei P-F, Chen M-N, et al. Ct findings of adrenal schwannoma. Clin Radiol 2016;71:464-70.
18 Lau SK, Spagnolo DV, Weiss LM. Schwannoma of the adrenal gland. Am J Surg Patho 2006;30:630-4.
19 Park BK, Kim CK, Kim B, et al. Adrenal tumors with late enhancement on CT and MRI. Abdom Imaging 2007;32:515-8.
Copyright 2021 BMJ Publishing Group. All rights reserved. For permission to reuse any of this content visit https://www.bmj.com/company/products-services/rights-and-licensing/permissions/ BMJ Case Report Fellows may re-use this article for personal use and teaching without any further permission.
Become a Fellow of BMJ Case Reports today and you can:
Submit as many cases as you like
Enjoy fast sympathetic peer review and rapid publication of accepted articles
Access all the published articles
Re-use any of the published material for personal use and teaching without further permission
Customer Service
If you have any further queries about your subscription, please contact our customer services team on +44 (0) 207111 1105 or via email at support@bmj.com.
Visit casereports.bmj.com for more articles like this and to become a Fellow