Adrenal ganglioneuromas: Incidentalomas with misleading clinical and imaging features

Adrenal ganglioneuromas: Incidentalomas with misleading clinical and imaging features Dimitrios Linos, MD,a Theodoros Tsirlis, MD,a Athina Kapralou, MD,a Andreas Kiriakopoulos, MD,a Dimitrios Tsakayannis, MD,a and Dimitrios Papaioannou, MD,b Athens, Greece

Background. Ganglioneuromas are benign neoplasms of the neural crest, occurring rarely in the adrenal glands. This study presents our experience regarding diagnostic and therapeutic management of these neoplasms and a review of the relevant literature. Methods. Among 150 patients with of incidentalomas, we had 7 primary ganglioneuromas. Their clinical, imaging, and operative data were collected retrospectively, and the literature was reviewed using MEDLINE. There were 4 females and 3 males, with mean age of 50 years (range, 39--64). All neoplasms were discovered incidentally with ultrasonography and were evaluated subsequently with computed tomography (CT). One patient was studied further with 131I-MIBG due to asymptomatic increased in urine vanillylmandelic acid, and 1 patient with history of breast cancer underwent additional FDG-PET/CT. Results. All but 2 patients were asymptomatic. Two patients complained of epigastric pain and hypertension, respectively. The preoperative mean size on CT was 6.8 cm, whereas the postoperative true mean histologic size was 7.7 cm. Both patients who were evaluated with radionuclide studies had false positive results, suggestive of pheochromocytoma and adrenal metastasis, respectively. Three patients underwent open adrenalectomy due to preoperative suspicion of carcinoma, and the remaining 4 underwent laparoscopic anterior adrenalectomy. Histologically, all 7 neoplasms were completely differentiated, mature ganglioneuromas. We had no mortality or significant morbidity. No recurrence occurred during a mean follow-up of 6 years (range, 1--18). Conclusion. Adrenal ganglioneuromas are rare incidentalomas that can mimic primary or secondary adrenal malignancies as well as pheochromocytomas. Despite their usually large size, resection via laparoscopic approach is safe and effective. (Surgery 2011;149:99-105.) From the 1st Surgical Clinic,a and Histopathology Department,b Diagnostic and Therapeutic Center of Athens ‘‘Hygeia,’’ Athens, Greece

NEOPLASMS OF GANGLION CELL ORIGIN include neuroblastomas, ganglioneuroblastomas, and ganglioneuromas, with descending degree of immaturity and malignant behavior. Ganglioneuromas arise most commonly from mediastinal and aortocaval sympathetic ganglia, and less frequently in the adrenals, and affect primarily pediatric patients and young adults.1-3 They may present de novo as primary neoplasms, but can also evolve from neuroblastomas either spontaneously or after response to treatment.3-6 Their reported incidence is less than 5% in series of adrenalectomies.7-13 The aim of

Accepted for publication March 24, 2010. Reprint requests: Dimitrios Linos, MD, Erythrou Stavrou 4, Kifissias Av 151 23, 145 61 Athens, Greece. E-mail: dlinos@ hms.harvard.edu. 0039-6060/$ - see front matter Ó 2011 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2010.03.016

this study is to delineate the clinical course, diagnostic imaging, and operative treatment of primary adrenal ganglioneuromas in adults. MATERIALS AND METHODS From 1991 to 2008, we operated on 150 adrenal incidentalomas. Seven patients (4.6%) were proven histologically to have primary adrenal ganglioneuromas (Table). They were 4 females and 3 males, with a mean age of 50 years (range, 39--64) and no medical history of neuroblastoma. Their clinical, diagnostic, and operative data were collected retrospectively. All 7 neoplasms were incidental, ultrasonographic findings during investigation of abdominal pain, blunt abdominal trauma, and breast cancer follow-up in 1 patient each, and routine check-up in the remaining 4. Except for the patient with abdominal pain and suspected gallstones, all ultrasonographies included upper and lower abdominal examination. Abdominal SURGERY 99

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Table. Clinical and imaging features of the series CT size (cm)

Pre contrast HU

Post contrast HU

4 10

<30 30

<30 30

None None

5

<30

<30

13

<30

<30

" Plasma Dopamine None

None

6

30

30

+

43

None

5

30

60

+ FDG-PET

64

None

4,5

<30

<30

Patient #

Gender

Age

Symptoms

1 2

F M

35 47

3

M

56

4

F

63

None Abdominal pain Hypertensive crises None

5

M

39

6

F

7

F

computer tomography (CT) was done subsequently in all patients. Biochemical and hormonal screening was carried out in all patients to exclude functional cortical adenomas and pheochromocytomas. One patient had 131I-MIBG scanning due to a marginal increase in urinary levels of vanillylmandelic acid (VMA), and the patient with a history of breast cancer underwent an FDG-PET scan to differentiate an adrenal mass 5 cm in size. Indications for adrenalectomy included increased size in 4 patients, suspected metastasis in 1 patient, and pheochromocytoma in 2 patients. MEDLINE was used to review papers regarding ‘‘primary adrenal ganglioneuromas in adults.’’ RESULTS Clinical and hormonal findings. All but 2 patients were asymptomatic. As seen in the Table, patient 2 had complaints of atypical upper abdominal pain and a 10-cm adrenal mass was found during ultrasonographic investigation for suspected cholelithiasis. Patient 3 presented with hypertensive episodes (systolic pressure, 200--220 mmHg) on grounds of poorly controlled arterial hypertension. Hormonal evaluation disclosed 2 patients with mildly increased plasma concentrations of dopamine (134.9 pg/ml with normal upper limit <85 pg/ml, patient 3) and urine VMA (14.1 mg/24 hr with normal upper limit 12.6 mg/24, patient 5) respectively. The increased urinary VMA was found several days after the mild, blunt abdominal trauma in patient 3. Imaging findings. Computed tomography: All neoplasms were reported as unilateral adrenal lesions and six of seven were right sided. Mean size was 6.8 cm (range, 4--13), while 4 were larger than 5 cm (Table). All cases had a solid appearance and low unenhanced attenuation value, up to 30

Functional status

131

MIBG

None

Preliminary diagnosis

Surgical technique

None Suspected malignancy Pheochromo cytoma Suspected malignancy Pheochromo cytoma Suspected metastatic tumor None

Open posterior Open anterior Laparoscopic Open anterior

Histological size (cm) 4 10 6.7 13

Weight (g) 49 360 65 990

Laparoscopic

6.5

80

Laparoscopic

6.7

48

Laparoscopic

5.4

65

Hounsfield units (HU). Contrast enhanced CT showed increased attenuation of 60 HU in 1 (patient 6; Fig 1, A and B). Calcifications were evident in 2 neoplasms of 13 cm (patient 4; Fig 2) and 6 cm (patient 5). The remaining neoplasms were homogeneous. Neither CT showed evidence of surrounding tissue infiltration or regional lymph node enlargement. Functional imaging: A 39-year-old male (patient 5) presented with a right-sided incidentaloma of 6 cm, which was discovered during imaging work up for blunt abdominal trauma. The patient was otherwise asymptomatic, and his 24-hr urine levels of VMA exceeded marginally the upper normal limit. Further evaluation with 131I-MIBG scintigraphy was undertaken, showing radioactive concentration corresponding to the right adrenal. Patient 6 was a 43-year-old female with a history of bilateral lobular breast cancer. On follow-up 2 years postoperatively, a 5-cm right adrenal mass was discovered. The lesion was attributed to a metastasis and a PET-CT was done to verify diagnosis. 9.9 mCi 18F-FDG were administered, and 60 minutes later a double helical CT and PET were carried out. The tomography showed a right adrenal neoplasm with increased metabolic activity (SUVmax 4; Fig 3). Treatment. All patients underwent uneventful complete resections, 3 open and 4 laparoscopic adrenalectomies. An open retroperitoneal approach was used in patient 1, while patients 2 and 4 underwent open, transabdominal adrenalectomy due to size (10 and 13 cm, respectively) and radiologic suspicion of malignancy. Mean operative time of open procedures was 102 min (range, 75--150). Patients 3 and 5--7 underwent anterior laparoscopic adrenalectomy. All procedures were completed

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Fig 2. Ganglioneuroma 13 cm in size with multiple calcifications, suspicious of adrenal carcinoma.

Fig 1. CT showing a right adrenal ganglioneuroma with (A) low unenhanced attenuation of 30 HU and (B) postcontrast enhancement of 60 HU.

without conversion. Mean laparoscopic operative time was 136 min (range, 75--270). We had no mortality and minor morbidity. Patient 3 developed pulmonary atelectasis of the right base. No patient required blood transfusion. Mean duration of hospitalization was 2.8 days (range, 2--5). There was no recurrence, during a mean follow-up of 6.4 years (range, 1--18). The abdominal pain of patient 2 and the hypertensive episodes of patient 3 were relieved after the adrenalectomy, although patient 3 is on antihypertensive medications to remain normotensive. Histopathology. Mean tumor size on pathologic examination was 7.7 cm (range, 4--13) on maximum diameter, despite the mean radiologic preoperative size of 6.8 cm. The mean specimen weight was 268 g (range, 48--990). All neoplasms consisted of fascicles of Schwann-like cells and dispersed mature ganglion cells. No neoplasm showed immature neuroblastic cells or areas of pheochromocytoma. Two neoplasms showed calcifications. Although 6/7 neoplasms seemed

macroscopically to compress adjacent yellow adrenal tissue, close microscopic observation of multiple sections revealed areas of entrapment of normal elements of the adrenal cortex within the neoplasm in all seven ganglioneuromas (Fig 4). In 1 patient, the neoplasm macroscopically seemed to arise within in the adrenal with destruction of the surrounding gland (Fig 5). These findings are strong indications that all neoplasms were primary adrenal ganglioneuromas. Immunohistochemistry was employed in patients 4--6, showing positive staining of ganglion cells for neuron-specific enolase (NSE; Fig 6), Synaptophysin, and positive staining of Schwann cells for S100 and CD57. Entrapped adrenal cortical cells were negative for the above mentioned markers and positive for Inhibin A. DISCUSSION Primary adrenal ganglioneuromas in adults are reported sporadically as case reports or in small series.14-25 We identified approximately 230 cases in the literature. Their most relevant clinical characteristics are those of hormonally inactive, slow growing, and incidentally discovered neoplasms, findings consistent with most of our patients (Table). Occasionally they may produce nonspecific, mass-related symptoms, as in patient 2. Less common manifestations include catecholamine secretion,14,16,17,19-21 as was the case in our patient 3, VIP-related diarrhea,20 and virilization.22-25 Clinical, biochemical, and scintigraphic adrenergic activity mimicking pheochromocytomas is not uncommon in pediatric ganglioneuromas and neuroblastomas,2,26,27 but is found rarely to be evident in mature ganglioneuromas. Erem

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Fig 3. 18F-FDG PET-CT shows increased tracer uptake of right adrenal lesion with a standardized uptake value (SUVmax) of 4, suggestive of metastatic adrenal neoplasm (arrows).

Fig 4. Macroscopic appearance of adrenal ganglioneuroma (white) destroying the normal adrenal tissue (yellow).

et al19 reported a patient with a 4-cm, dopaminesecretive adrenal ganglioneuroma in a 46-year-old woman with hypertensive crises, whereas Koch et al20 described symptomatic, fractionated metanephrines excess in a 63-year-old woman with concomitant VIP immunostaining of a 5-cm adrenalganglioneuroma. Interestingly, a case of sudden death has been attributed to catecholamine hypersecretion of a 1-cm ganglioneuroma.21 Our patient with hypertensive episodes (patient 3) had a 5-cm ganglioneuroma, whereas larger neoplasms were metabolically inactive. Two of our

Fig 5. Mixture of large ganglion cells (center and right, short arrows) and spindle-shaped Schwann like cells (center, long arrow). Entrapment of adrenal cortical cells (left, arrowhead) suggests primary adrenal ganglioneuroma. H&E 3 400, original magnification.

patients (3 and 5) had borderline increases in blood and urine metanephrines, and were operated for a suspected pheochromocytoma (PCC). A less than 2-fold increase in blood and/or urine metanephrines is of low specificity regarding biochemical diagnosis of PCC,28 especially in patients with potential drug interactions.29 Both our patients were free of medications by the time their neoplasms were discovered. None of our patients exhibited any histologic components of a

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Fig 6. NSE-positive ganglion cells, stained brown (arrows). Schwann-like cells are also weakly positive, while adrenal cortical cells are negative.

pheochromocytoma. Less than 30 cases of a mixture of ganglioneuroma/pheochromocytoma have been reported; all were benign and, in addition to secreting catecholamines, several of these neoplasms also secreted neuropeptides of pancreatic islet cells.30-33 Occasionally, a mixture of histology of adrenal ganglioneuromas with cortical adenoma34 and myelolipoma35 has been described. Imaging characteristics of adrenal ganglioneuromas on CT have been described as well circumscribed, low attenuated, homogeneous masses which demonstrate slight to moderate enhancement.14,15,18,36,37 Calcifications appear in about 50% of ganglioneuromas. The mean radiologic size in our patients was 6.8 cm, whereas the mean histologic size was 7.7 cm, underscoring again the radiologic underestimation of adrenal tumor size.38-41 Tumor size >5 cm, heterogeneity, and calcifications are considered radiologic signs suggestive of adrenal cancer.42 Because adrenal ganglioneuromas generally present as tumors >5 cm and frequently lack hormonal activity, they are usually treated as adrenal carcinomas. The largest neoplasms of our series measured 10 and 13 cm, respectively, the latter with discrete calcifications, and were treated by open, transabdominal adrenalectomy due to the suspicion of cancer. One interesting finding of our study was the positive PET-CT in patient 6, who presented with a right adrenal mass proven to be a primary ganglioneuroma; the medical history, radiologic features, and macroscopic appearance were suggestive of an adrenal metastasis. A previously described incident of positive 18FDG uptake43 pertained to a patient with a history of treated neuroblastoma in childhood and a recurrence of

retroperitoneal tumor in adulthood. Whole body PET using 18FDG integrated with CT has been shown to be highly accurate in differentiating malignant adrenal masses.44-46 Nevertheless, although the negative predictive value approaches 100%, the specificity of the method was reported to be 90% in the largest study evaluating 94 adrenal masses in patients with lung cancer.47 PCCs in particular are found to accumulate FDG.48,49 Common neurogenic origin of PCCs and ganglioneuromas may have a pathophysiologic implication regarding FDG uptake in our patient. Data regarding positive 131MIBG uptake of adrenal ganglioneuromas in adults, as was the case in patient 5, are scarce and controversial regarding secretive profile. The few published reports have not shown any consistent correlation between positive scanning and functional status.20,50,51 Prognosis of completely resected mature adrenal ganglioneuromas is excellent. We encountered no recurrence, and all adrenalectomies were carried out with no mortality and minimal morbidity despite the large size of the neoplasms. Complete resection of ganglioneuromas is not only feasible but also necessary, because malignant transformation has been reported.52-54 We believe that a laparoscopic approach should be used in almost all adrenal masses irrespective of the size, with the exception of the adrenal carcinoma infiltrating the surrounding tissues as seen on preoperative imaging.55 There is always the possibility to convert the laparoscopic procedure to an open adrenalectomy if needed. Similar ‘‘liberal’’ surgical attitudes are shared recently by most experienced endocrine surgeons.56,57 REFERENCES 1. Enzinger FM, Weiss SW. Ganglioneuroma. In: Soft Tissue Tumors. 3rd ed. St Louis: Mosby-Year Book; 1995. p. 929-64. 2. Geoerger B, Hero B, Harms D, Grebe J, Scheidhauer K, Berthold F. Metabolic activity and clinical features of primary ganglioneuromas. Cancer 2001;91:1905-13. 3. Lonergan GJ, Schwab CM, Suarez ES, Carlson CL. Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma: radiologicpathologic correlation. Radiographics 2002;22:911-34. 4. Iwanaka T, Yamamoto K, Ogawa Y, Arai M, Ito M, Kishimoto H, et al. Maturation of mass-screened localized adrenal neuroblastoma. J Pediatr Surg 2001;36:1633-6. 5. Ambros IM, Zellner A, Roald B, Amann G, Ladenstein R, Printz D, et al. Role of ploidy, chromosome 1p, and Schwann cells in the maturation of neuroblastoma. N Engl J Med 1996;334:1505-11. 6. Berthold F, Hero B. Neuroblastoma: current drug therapy recommendations as part of the total treatment approach. Drugs 2000;59:1261-77. 7. Walz MK, Alesina PF, Wenger FA, Deligiannis A, Szuczik E, Petersenn S, et al. Posterior retroperitoneoscopic adrenalectomy--results of 560 procedures in 520 patients. Surgery 2006;140:943-8.

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52. Hayashi Y, Iwato M, Hasegawa M, Tachibana O, von Deimling A, Yamashita J. Malignant transformation of a gangliocytoma/ganglioglioma into a glioblastoma multiforme: a molecular genetic analysis. Case report. J Neurosurg 2001; 95:138-42. 53. Kulkarni AV, Bilbao JM, Cusimano MD, Muller PJ. Malignant transformation of ganglioneuroma into spinal neuroblastoma in an adult. Case report. J Neurosurg 1998;88: 324-7. 54. Ghali VS, Gold JE, Vincent RA, Cosgrove JM. Malignant peripheral nerve sheath tumor arising spontaneously from retroperitoneal ganglioneuroma: a case report, review of the literature, and immunohistochemical study. Hum Pathol 1992;23:72-5. 55. Linos D. Clinically inapparent adrenal mass (incidentaloma or adrenaloma). In: Linos D, Van Heerden J, editors. Adrenal glands. New York: Springer; 2005. p. 241-50. 56. Ippolito G, Palazzo FF, Sebag F, Thakur A, Cherenko M, Henry JF. Safety of laparoscopic adrenalectomy in patients with large pheochromocytomas: a single institution review. World J Surg 2008;32:840-4. 57. Soon PS, Yeh MW, Delbridge LW, Bambach CP, Sywak MS, Robinson BG, et al. Laparoscopic surgery is safe for large adrenal lesions. Eur J Surg Oncol 2008;34:67-70.