ELSEVIER
Available online at www.sciencedirect.com ScienceDirect
journal homepage: www.elsevier.com/locate/radcr
RCR RADIOLOGY CASE REPORTS
Case Report
Neuroendocrine carcinoma of the adrenal gland: A rare case report and literature review*
Achmad Romy Syahrial Rozidi, MDª, Wahjoe Djatisoesanto, PhD, MDª,*, Ridholia, MDb
a Department of Urology, Dr. Soetomo Academic General Hospital, Faculty of Medicine, Airlangga University, Surabaya, Indonesia
b Department of Pathological Anatomy, Faculty of Medicine, Universitas Airlangga, Soetomo General Academic Hospital, Surabaya, Indonesia
ARTICLE INFO
Article history: Received 20 March 2024 Revised 18 June 2024 Accepted 30 June 2024
Keywords: Neuroendocrine carcinoma Adrenal gland Chemotherapy Case report
ABSTRACT
Neuroendocrine carcinoma (NEC) presence in the adrenal glands is rare. Neuroendocrine carcinoma manifests across a wide range of clinical presentations, from asymptomatic cases to those characterized by hormone overproduction or the tumor’s mass effect. We report a 48-year-old male referred by a urology specialist with a chief complaint of right- sided back pain for the past 6 months accompanied by nausea, vomiting, and sharp stabbing headaches. The patient had a history of right adrenalectomy surgery. Elevated blood pres- sure of 150/110 mmHg, and no abnormalities found. The radiologist found a solid lesion and cyst at the lower pole of the right kidney and observed multiple recurrent tumors in the right adrenal on the MRI examination. The biopsy revealed poorly differentiated carci- noma and adrenocortical carcinoma tissue on the second biopsy 2 months later. The patient was diagnosed with neuroendocrine carcinoma; the patient underwent a biopsy guided by CT, followed by a pathological assessment (PA). The surgeon carried out the tumor removal surgery and performed an immunohistochemical (IHC) analysis. A 3-month follow-up is planned to evaluate the potential need for adjuvant chemotherapy. The case underscores the importance of accurate pathological diagnosis and multimodal management in recur- rent adrenal tumors, particularly when considering NEC as a differential diagnosis.
@ 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Introduction
Neuroendocrine carcinoma (NEC) originates from neuroen- docrine cells and spreads throughout the body. Although tu-
mors can appear in almost any organ, their presence in the adrenal glands is rare. Neuroendocrine carcinoma presents a broad clinical spectrum, ranging from asymptomatic cases to symptoms caused by excessive hormone production or the tu- mor’s mass effect. The pathophysiology of NEC is complex and
* Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
* Corresponding author.
E-mail address: wahjoe.djatisoesanto@fk.unair.ac.id (W. Djatisoesanto). https://doi.org/10.1016/j.radcr.2024.06.079
1930-0433/ 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
A
multifaceted [1]. The molecular mechanisms underlying NEC’s development are not fully understood, but various genetic and epigenetic changes have been identified [1-4].
Management recommendations suggest conducting radio- logical examinations like CT scans, MRIs of the pelvis or ab- domen, and FDG-PET CT scans. Help differentiate whether NEC can be resected, is unresectable, or represents metastasis [5-7]. Treatment options include chemotherapy, tumor resec- tion, and regular evaluations are essential, with CT scans ev- ery 12 weeks for the first year and every 6 months afterwards [8]. This case report presents a rare occurrence of neuroen- docrine carcinoma of the adrenal gland treated at a tertiary referral center hospital in Surabaya, Indonesia.
Cases description
A 48-year-old male was referred by a urologist from the re- gional government hospital with a diagnosis of right adrenal tumor recurrence. The patient presented to a urology clinic with complaints of intermittent right-sided back pain for the past six months, which worsens when fatigued, along with nausea, vomiting, and sharp stabbing headaches. He had a history of right adrenalectomy surgery in November 2011. However, he did not have the pathological anatomy exami- nation results from the previous hospital. He did not smoke but had hypertension and was taking Candesartan 16 mg and Herbeser 200 mg.
General examination revealed elevated blood pressure of 150/100 mmHg while other vital signs were within normal lim- its. A physical examination showed a postoperative scar in the right subcostal region region, but no other abnormalities were found. Laboratory investigations yielded normal results (BUN of 14 mg/dL, serum creatinine of 1.1 mg/dL). The cortisol hor- mone test was normal at 3.8 ug/dL.
A single chest X-ray (AP/lateral) showed no signs of metas- tasis before the operation. The abdominal CT scan with con- trast detected a solid lesion measuring 2.77 x 2.65 x 2.3 cm in the right suprarenal area and another lesion measuring 2.41 x 2.74 × 2.12 cm in the anterior side of the right middle
pole. Additionally, another cyst measuring 1.7 cm was seen in the lower right renal pole (Fig. 1). Advanced imaging with MRI showed multiple solid masses, the largest being approxi- mately 2.9 x 2.7 x 2.9 cm, 1.8x 3.5×2.4cm, and 4.3×1.7×4.0 cm, indicating multiple recurrent tumors in the right adrenal gland (Fig. 2).
Histopathological examinations revealed poorly- differentiated carcinoma in the recurrent suprarenal area biopsy; b) microscopic findings suggestive of adrenocor- tical carcinoma from a post-operation tumor tissue; c) immunohistochemical test show negative results for inhibin, calretinin, and CK, which are markers commonly used in the diagnosis of adrenocortical carcinomas, but positive for vi- mentin, synaptophysin, chromogranin, and CD56 confirming neuroendocrine carcinoma diagnosis (Fig. 3).
The patient underwent a CT-guided biopsy, and the patho- logical examination (PA) revealed characteristics of poorly dif- ferentiated carcinoma. Subsequently, an excision surgery was performed on the tumor (Fig. 4), and the PA results indicated adrenocortical carcinoma. Based on these findings, there were suspicions of NEC (neuroendocrine carcinoma). An Immuno- histochemical (IHC) examination was conducted to differen- tiate between adrenocortical carcinoma and NEC. The IHC re- sults indicated that the type of tumor in the patient was in- deed NEC. The patient is scheduled for a follow-up 3 months later to evaluate the prognosis and tumor progression using contrast-enhanced abdominal CT scans. At 3-month follow- up, the patient had no complaints and started receiving adju- vant therapy.
Discussion
Neuroendocrine tumors are most commonly found in the di- gestive tract, followed by the respiratory system. The appear- ance of neuroendocrine tumors in other locations is infre- quent. Although neuroendocrine tumors can be found in the retroperitoneum, they usually result from metastasis. A pri- mary neuroendocrine tumor in the retroperitoneum itself is infrequent. In the adrenal glands, primary malignant tumors
A
M. 4BY
N
C
C
48Y
4
R
R
MF 1.25
10cm
10cm
MF 1.25
TP FIS
TR 110020
TR 1100 0
PRU
TE 97.0
TE 97.0
3.88
TA 00 908
TA 00.509
201/ 898-85
BW 7
480p-3C81
BW 7
4688-998 1
BO1
C
B
L 48Y
D
MMMMMMMMMM
:
ER
R
10cm
EMF 1.17
10cm
MF 1.45
TP H20
TP F24
TR 4.0
SP H69.7
TR 4.2
SP P94.7
TE 1.3
SL 3.0
TE 1.3
SL 3.0
TA 13.01
FoV 309 380
TA 05.34
FOV 366 450
BW 1040.0
196 320
BW 745.0
2340-320
BO1-3:SP5-8
with contrast
BO1-3:SP6-8
“#3d2/9
with contrast
W 956
BOA
C 467
A
B
C
D
that are often found include adrenal cortex carcinoma, ma- lignant pheochromocytoma, malignant lymphoma, and neu- roblastoma [9,2]. Neuroendocrine tumors (NETs) represent a heterogeneous group of tumors that arise from the endocrine cell system distributed throughout the body, especially from the gastro-entero-pancreatic organs. Neuroendocrine tumors are classified based on morphological indices and cell prolif- eration observed through the Ki67 marker. Well-differentiated NETs are categorized into Group 1 if Ki67 ≤2, Group 2 if Ki67 is between 3% and 20%, and Group 3 if Ki67 > 20%. Poorly differ- entiated NETs are classified as NEC. Patients with NEC often also have pheochromocytoma. Although most pheochromo-
cytomas are benign, there is a possibility of malignancy. How- ever, NEC originating directly from the adrenal gland is an in- frequent condition and not fully understood [2].
This case study reports a patient diagnosed with recurrent neuroendocrine carcinoma in the adrenal gland. The patient had a previous history of right adrenal tumors and had un- dergone an adrenalectomy. In the exact location, based on radiological and histopathological examinations, a recurrent malignancy was found, leading to the excision of the recur- rent tumor in the patient. Local resection involving surround- ing structures, including vascular and lymph nodes, was per- formed [8]. Most extrapulmonary NECs are aggressive, requir-
5
6
7
8
9
110
1 1
4
5
6
7
8
9.
110
ing multimodal management. Moreover, NEC in the adrenal gland is rarely found and often does not involve symptoms of hormonal disorders, indicating a nonspecific clinical picture. Upon radiological evaluation, no metastasis was found in this patient; hence, no adjuvant therapy was administered post- resection.
According to consensus [10] for patient with clini- cally/biochemically suspected NEC (not pathologically veri- fied), MRI abdomen or contrast-enhanced triple phase CT and PET/CT with [68Ga]Ga-DOTA-SSA (including [68Ga]Ga-DOTA- TOC, [68Ga]Ga-DOTATATE, and [68Ga]Ga-DOTA-NOC) were cho- sen. [68Ga]Ga-DOTA-SSA PET/CT was preferred for SSTR imag- ing to stage all NEC, complementing conventional imaging. SSTR imaging, CT, and/or MRI were required for all patients at initial or subsequent staging. [68Ga]Ga-DOTA-SSA PET/CT was recommended for NEC patients with metastatic disease but uncertain primary tumour location. SSTR imaging was considered necessary at re-staging after potentially curative surgery in patients with clinically significant risk of residual or metastatic disease as a supplement to conventional imag- ing, even if no SSTR imaging was done before surgery to con- firm SSTR expression. All patients required SSTR imaging for re-staging after noncurative surgery as a supplement to con- ventional imaging. In this case, [68Ga]Ga-DOTA-SSA not per- formed due to resources limitation. PET imaging is quite valu- able in differentiating between benign NETs and NECs. Al- though not all centres have access to PET, there are situations where clinicians must differentiate lesions only using an alter- native imaging modality. Generally, neuroendocrine tumours (NETs) are characterised by a strong blood supply and a dis- tinct boundary, often causing displacement of nearby tissues without entering them. This is usually determined by the ra- diographic features. In contrast, carcinomas often exhibit a more aggressive and uneven morphology. Computed tomog- raphy (CT) and magnetic resonance imaging (MRI) are 2 imag- ing techniques that can be useful for distinguishing between the 2 in this specific scenario. NETs frequently display uni- form enhancement on CT scans and seem hypointense on T1-weighted MRI images. However, carcinomas might exhibit varied amplification and increased brightness on T1-weighted
MRI scans. Although ultrasonography (USG) can be used to de- tect neuroendocrine tumours (NETs), particularly in the liver, it is less effective in differentiating them from carcinomas [11]. In a study by Ogawa et al. [12], a 79-year-old male patient with a history of diabetes mellitus presented with abdominal pain. An abdominal CT scan revealed a 51 × 36 mm heterogeneous mass in the left adrenal gland with normal hormonal tests. Two months later, an evaluation CT scan showed the mass in- creased to 68 × 52 mm without tumor metastasis. A laparo- scopic adrenalectomy was performed, revealing a whitish tu- mor tissue with necrosis. Immunohistochemical examination showed tumor cells positive for CD56 and synaptophysin, in- dicating small-cell neuroendocrine carcinoma. Postoperative CT scan evaluation revealed metastases in lymphatic tissues, the right adrenal gland, the liver, and lymph nodes at the left kidney hilum. Eleven months post-operation, the patient’s condition deteriorated, leading to death due to cancer, pre- sented in Table 1 [12].
In another case report, a 62-year-old male with a history of hypertension presented with back pain, a 25 kg weight loss, decreased appetite, and night sweats for a month. The abdominal CT scan showed a retroperitoneal mass measur- ing 18.3 × 12.2 cm in the left adrenal gland. Biopsy results indicated NEC with tumor cells positive on immunohisto- chemical examination. The patient underwent neoadjuvant chemotherapy, resulting in a significant reduction in mass size. Subsequently, the patient underwent tumor resection in the spleen, left kidney, adrenal gland, and distal pancreas. Upon evaluation, no recurrence was observed, presented in Table 1 [13].
In another study, Chang et al. [14] conducted a retrospec- tive review of patients diagnosed with small cell carcinoma in the genitourinary organ, finding only 1 patient with a primary tumor from the adrenal gland. However, the tumor in this pa- tient had metastasized. Currently, there are no standard treat- ment guidelines for neuroendocrine carcinoma in the adrenal gland, partly due to the rarity of the disease. NCCN provides guidelines for resectable extrapulmonary operations, but for poorly differentiated neuroendocrine carcinoma, the thera- peutic options are numerous and depend on the disease’s
| Author | Cases | CT-Scan | IHC Examination | Management |
|---|---|---|---|---|
| Ogawa et al. [12] | a 79-year-old male patient with a history of diabetes mellitus presented with abdominal pain | Heterogeneous mass measuring 51 × 36 mm in the left adrenal gland. | Small-cell NEC with tumor cells positive for CD56 and synaptophysin. | Laparoscopic adrenalectomy. |
| Limonnik et al. [13] | a 62-year-old male with a history of hypertension presented with back pain, a 25 kg weight loss, decreased appetite, and night sweats for a month. | Retroperitoneal mass measuring 18.3×12.2 cm in the left adrenal gland. | NEC with tumor cells positive. | Tumor resection in the spleen, left kidney, adrenal gland, and distal pancreas with neoadjuvant chemotherapy. |
location. Treatment options include different combinations such as tumor resection, neoadjuvant or adjuvant chemother- apy with cisplatin/etoposide, carboplatin/etoposide, FOLFOX, FOLFIRI, and radiation therapy [8].
Conclusions
Neuroendocrine carcinoma in the adrenal gland poses a rare and challenging clinical scenario, often lacking specific symp- toms and showing aggressive behavior. The cases discussed underscore the importance of timely diagnosis and multi- modal management approaches due to the high propensity for recurrence and metastasis. Surgical resection remains key, but standardized treatment guidelines are lacking due to its rarity. Multimodal management with adjuvant therapies such as chemotherapy and radiation therapy should be considered, emphasizing the need for individualized approaches. Further research and collaborative efforts are warranted to elucidate optimal therapeutic strategies and improve outcomes for pa- tients with neuroendocrine carcinoma originating from the adrenal gland.
Patient consent
Informed consent for patient information to be published in this article was obtained. Appropriate informed consent was obtained for the publication of this case report and accompa- nying images.
Ethical approval
This report has been approved by the ethical committee of Dr. Soetomo General-Academic Hospital.
REFERENCES
[1] Libé R. Adrenocortical carcinoma (ACC): diagnosis, prognosis, and treatment. Front Cell Dev Biol 2015;3:45. doi:10.3389/fcell.2015.00045.
[2] Antunes E, Lopes J, Silva I, Fernandes V. Pheochromocytoma: a case report. Cureus 2022;14:e31409. doi:10.7759/cureus.31409.
[3] Strosberg JR. Update on the management of unusual neuroendocrine tumors: pheochromocytoma and paraganglioma, medullary thyroid cancer and adrenocortical carcinoma. Semin Oncol 2013;40:120-33. doi:10.1053/j.seminoncol.2012.11.009.
[4] Jimenez C, Armaiz-Pena G, Dahia PLM, Lu Y, Toledo RA, Varghese J, et al. Endocrine and neuroendocrine tumors special issue-checkpoint inhibitors for adrenocortical carcinoma and metastatic pheochromocytoma and paraganglioma: do they work? Cancers (Basel) 2022;14:467. doi:10.3390/cancers14030467.
[5] Arlt W, Biehl M, Taylor AE, Hahner S, Libé R, Hughes BA, et al. Urine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal tumors. J Clin Endocrinol Metab 2011;96:3775-84. doi:10.1210/jc.2011-1565.
[6] Kebebew E, Reiff E, Duh Q, Clark OH, McMillan A. Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress? World J Surg 2006;30:872-8. doi:10.1007/s00268-005-0329-x.
[7] Rindi G, Mete O, Uccella S, Basturk O, La Rosa S, Brosens LAA, et al. Overview of the 2022 WHO classification of neuroendocrine neoplasms. Endocr Pathol 2022;33:115-54. doi:10.1007/s12022-022-09708-2.
[8] Shah MH, Goldner WS, Benson AB, Bergsland E, Blaszkowsky LS, Brock P, et al. Neuroendocrine and adrenal tumors, Version 2.2021, NCCN Clinical Practice Guidelines in oncology. J Nat Comprehens Canc Netw 2021;19:839-68. doi:10.6004/jnccn.2021.0032.
[9] Alicja H-D, Małgorzata T, Anna S-S, Aleksandra G-J, Ewelina B, Piotr S, et al. Neuroendocrine tumours of rare location. Endokrynol Pol 2010;61:322-7.
[10] Ambrosini V, Kunikowska J, Baudin E, Bodei L, Bouvier C, Capdevila J, et al. Consensus on molecular imaging and theranostics in neuroendocrine neoplasms. Eur J Cancer 2021;146:56-73. doi:10.1016/j.ejca.2021.01.008.
[11] Maxwell JE, Howe JR. Imaging in neuroendocrine tumors: an update for the clinician. Int J Endocr Oncol 2015;2:159-68. doi:10.2217/ije.14.40.
[12] Ogawa K, Shimizu Y, Uketa S, Utsunomiya N, Kida K, Ishihara M, et al. Primary small cell neuroendocrine carcinoma of adrenal gland. Int Cancer Conf J 2019;8:122-5. doi:10.1007/s13691-019-00368-4.
[13] Limonnik V, Shah D, Sandhu A, Monga DK. A rare case of locally advanced primary small cell neuroendocrine carcinoma of the adrenal gland. Anticancer Res 2020;40:5933-8. doi:10.21873/anticanres.14614.
[14] Chang K, Dai B, Kong Y-Y, Qu Y-Y, Gan H-L, Gu W-J, et al. Genitourinary small-cell carcinoma: 11-year treatment experience. Asian J Androl 2014;16:705. doi:10.4103/1008-682X.127811.