Oncocytic neoplasms; rare adrenocortical tumours - a report of eleven patients
Nowotwory onkocytarne, rzadkie guzy kory nadnerczy - prezentacja jedenastu chorych
Hande Peynirci1, Bengür Taskıran2, Nagehan Dik3, Özlem Saraydaroğlu4, Canan Ersoy5
1Department of Internal Medicine, Division of Endocrinology and Metabolism, Kastamonu State Hospital, Kastamonu, Turkey 2Department of Internal Medicine, Division of Endocrinology and Metabolism, Yunus Emre State Hospital, Eskisehir, Turkey
3Department of Internal Medicine, Bursa State Hospital, Bursa, Turkey
4Department of Pathology, Uludag University Faculty of Medicine, Bursa, Turkey
5Department of Internal Medicine, Division of Endocrinology and Metabolism, Uludag University Faculty of Medicine, Bursa, Turkey
Abstract
Introduction: Oncocytomas of adrenal glands are extremely rare and usually present as incidentally detected masses. We aimed to present a series of patients with adrenal oncocytomas and review the literature.
Material and methods: Electronic database of patients with adrenal tumours, who were admitted to the internal medicine and endo- crinology and metabolism outpatient clinics of Uludag University Medical Faculty between January 2005 and November 2016, were assessed retrospectively. Those who underwent surgery and pathological diagnosis of oncocytoma (n = 11) were included to the study. The demographic, clinical, pathological, radiological, and laboratory features were evaluated.
Results: Of these 11 patients, 54.5% (n = 6) were female and 45.5% (n = 5) were male. They aged between 31 and 76 years (45.36 ± 13.68). Five (45.5%) of the masses showed endocrinological activity and were more frequent in women. The masses were 25-130 (57.63 + 34.04) mm in width and 20-100 (47.82 ± 28.95) mm in length. Seven (63.6%) oncocytomas were classified as benign and the remainder as hav- ing uncertain malignant potential according to Lin-Weiss-Bisceglia criteria. Mean duration of follow-up were 24.8 (6-60) months and 38.2 (15-82) months, respectively.
Conclusions: Because there are no unique clinical and imaging characteristics differentiating adrenal oncocytomas from other types of adrenal masses, it should be kept in mind in differential diagnosis of adrenal masses, especially large ones and those suspicious for adrenocortical carcinoma. (Endokrynol Pol 2018; 69 (6): 682-687)
Key words: adrenal incidentaloma; adrenal oncocytoma; Cushing syndrome; Conn syndrome; undetermined malignant
Streszczenie
Wstęp: Onkocytoma nadnerczy to niezwykle rzadki nowotwór, zwykle wykrywany przypadkowo. Autorzy przedstawiają serię 11 przy- padków chorych z guzem onkocytarnym nadnerczy oraz przegląd piśmiennictwa.
Materiał i metody: Oceniono retrospektywnie elektroniczną bazę danych pacjentów z guzami nadnerczy przyjętych do Kliniki Chorób Wewnętrznych oraz Kliniki Endokrynologicznej i Zaburzeń Metabolicznych Wydziału Medycznego Uniwersytetu w Uludag w okresie od stycznia 2005 do listopada 2016 roku. Do badania włączono osoby, u których wykonano zabieg chirurgiczny i na podstawie badania histopa- tologicznego rozpoznano onkocytoma (n = 11). Przeanalizowano dane demograficzne, kliniczne, patologiczne, radiologiczne i laboratoryjne. Wyniki: Spośród tych 11 chorych kobiety stanowiły 54,5% (n = 6), a mężczyźni 45,5% (n = 5). Badani byli w wieku 31-76 lat (45,36 ± 13,68). Aktywność hormonalną stwierdzono w przypadku 5 guzów (45,5%), hormonalnie czynne guzy występowały częściej u kobiet. Wymiary guzów wynosiły: szerokość - 25-130 mm (57,63 ± 34,04 mm) i długość - 20-100 mm (47,82 ± 28,95 mm). Siedem guzów onkocytarnych (63,6%) sklasyfikowano jako łagodne, a pozostałe jako guzy o niepewnym potencjale złośliwości na podstawie kryteriów klasyfikacji Lin-Weiss-Bisceglia. Średni czas obserwacji wynosił odpowiednio 24,8 miesiąca (6-60 mies.) i 38,2 miesiąca (15-82 mies.).
Wnioski: Z uwagi na to, że nie ma szczególnych objawów klinicznych ani cech w badaniach obrazowych odróżniających nowotwory onkocytarne od innych guzów nadnerczy, należy pamiętać o tych guzach podczas diagnozy różnicowej masy wykrytej w nadnerczach, zwłaszcza jeśli jest ona duża i budzi podejrzenie raka kory nadnerczy. (Endokrynol Pol 2018; 69 (6): 682-687)
Słowa kluczowe: incidentaloma nadnerczy; onkocytoma nadnerczy; zespół Cushinga; zespół Conna; niepewny stopień złośliwości
Introduction
An adrenal mass that is detected incidentally on radiological evaluation of a patient without signs or symptoms attributable to adrenal disease is defined
as an “adrenal incidentaloma”. Most of the cases are non-functional adrenocortical adenomas. Adrenocorti- cal carcinomas, cysts, ganglioneuromas, myelolipomas, haematomas, pheochromocytomas, and adrenal me- tastases are the other possible causes [1]. Oncocytoma
☒
is a rare aetiology of adrenal incidentaloma. The term “oncocyte” was first used by Hamperl to describe large granular cells with eosinophilic cytoplasm observed in Hurthle cell tumours of the thyroid gland [2]. In 1986, Kakimoto et al. reported a mass in the adrenal gland with a similar appearance to oncocytoma; however, the tumour was termed as adrenocortical adenoma due to lack of clear definition of adrenal oncocytoma (AO) [3]. In the same year, after confirmation by electron mi- croscopy by Smirnova et al. [4], the term AO emerged. Oncocytomas are defined as neoplasms consisting of cells with an abundant amount of eosinophilic granu- lar cytoplasm packed with swollen mitochondria and composed solely or mostly of oncocytes [5].
They are mostly localised in the adrenal cortex; rarely they have been detected in adrenal medulla or heterotopic adrenal tissue [6, 7]. Neither environmental nor genetic risk factors were found so far for oncocyto- mas and they are usually incidentally detected [8]. Al- though the exact incidence is unknown, approximately 159 cases have been reported in the literature up to now [7]. Most of the literature on adrenal oncocytomas (AOs) focus on the clinical and pathologic features, and a limited number of them reveal the radiological findings. In this study, we aimed to present clinical, radiological, pathological, and immunohistochemical staining features of 11 AOs and review the literature.
Material and methods
Study population
The study was approved by the Clinical Investiga- tions Ethics Committee of Uludag University, Faculty of Medicine (Reference no: 2013-13/22). The patients who were followed up due to adrenal masses in in- ternal medicine and endocrinology and metabolism outpatient clinics of Uludag University Medical Faculty between January 2005 and November 2016 were evalu- ated retrospectively. The inclusion criteria were age over 18 years, histopathological diagnosis of AOs after surgical resection, available data regarding hormonal assessment, and absence of any other malignancy.
Study parameters
Demographic and clinical data such as age, gender, signs and symptoms suggesting hormonal activity, and accompanying diseases including diabetes mel- litus (DM), hypertension (HT), coronary artery disease (CAD), osteoporosis (OP), thyroid nodule, or hyper- parathyroidism were recorded. Imaging characteristics such as localisation, size, adenomatoid component, presence of calcification, and hyperplasia were assessed using computerised tomography (CT) or magnetic reso- nance imaging (MRI). Lin-Weiss-Bisceglia criteria were
used for histological subtype (9). Duration of follow-up was also noted.
Biochemical and hormonal assessment Biochemical and endocrinological assessment included the following:
- serum fasting blood glucose, urea, creatinine, so- dium, alanine aminotransferase, aspartate amino- transferase, complete blood count;
- serum adrenocorticotropic hormone (ACTH) and cortisol levels were measured at 08:00 a.m .;
- measurements of adrenaline, noradrenaline, meta- nephrine, normetanephrine, dopamine, and vanil- lylmandelic acid in 24-hour collected urine (one or more of them);
- plasma renin activity (PRA) and serum aldosterone level only in patients with hypertension;
- serum cortisol level after 1 mg dexamethasone suppression test (DST) (1 mg dexamethasone was administered via oral route at 23:00 p.m., and fasting serum samples were collected at 08:00 a.m.);
- 2 mg DST for two days in patients with serum corti- sol levels not suppressed below 1.8 ug/dl after 1 mg DST (dexamethasone 0.5 mg tablet was given orally every six hours for two consecutive days and serum samples were collected at 08:00 a.m.);
- midnight serum cortisol level at 23:00 p.m .;
- cortisol measurement in 24-hour collected urine.
The patients with cortisol levels not suppressed below 1.8 µg/dL (50 nmol/L) during 1 and 2 mg DST, impaired di- urnal rhythm, and low morning ACTH level without clin- ical manifestations of Cushing syndrome (CS) were con- sidered to have subclinical CS. Patients with PRA less than 1 ng/ml/hour, plasma aldosterone level over 15 ng/dL, and renin activity/aldosterone ratio (RAO) over 20 were further tested for hyperaldosteronism.
Statistical analysis
Statistical analysis was made using computer soft- ware SPSS version 16.0 (SPSS Inc. Chicago, IL, USA). Categorical variables were expressed as number and percentage (%) and continuous variables were ex- pressed as mean (± standard deviation) and median (minimum-maximum).
Results
Out of 11 patients, 54.5% (n:6) were female and 45.5% (n: 5) were male. The patients were aged between 31 and 76 (45.36 ± 13.68) years. The mean ages of the female and male patients were 48.50 ± 16.86 and 41.60 ± 8.96 years, respectively. The masses were mostly detected during radiological investigation for vague abdominal pain, urological problems, or pulmonary
| Case | Age | Sex | Reason for applying | Accompanying illnesses | Diagnosis based on hormonal activity |
|---|---|---|---|---|---|
| Case 1 | 31 | Female | Weight gain, hirsutism, purple striae, buffalo hump, moon face | HT + MNG | Cushing |
| Case 2 | 32 | Male | Secondary HT workup | HT | Conn |
| Case 3 | 35 | Male | Abdominal pain | None | Non-functional |
| Case 4 | 35 | Female | Abdominal pain | None | Subclinical Cushing |
| Case 5 | 39 | Male | Shortness of breath | Chronic bronchitis | Non-functional |
| Case 6 | 39 | Female | Palpable mass | None | Non-functional |
| Case 7 | 50 | Male | Intermittent urination | None | Non-functional |
| Case 8 | 52 | Male | Side pain | None | Non-functional |
| Case 9 | 54 | Female | Weight gain | DM2, HT, OP | Cushing |
| Case 10 | 56 | Female | Abdominal pain | HT | Non-functional |
| Case 11 | 76 | Female | Secondary HT workup | HT | Conn |
HT - hypertension; MNG - multinodular goitre; DM2 - diabetes mellitus type 2; OP - osteoporosis
| Case | Imaging method | Side | Mass size | Radiological characteristics |
|---|---|---|---|---|
| Case 1 | CT | Left | 30 × 25 mm ☒ | Densely stained, ovoid, homogeneous solid lesion with regular margins (HU: 7) |
| Case 2 | MRI | Left | 62 × 56 mm ☒ | Lesion with regular margins, isointense to liver, significant signal drop-off on out-of- phase images due to the high lipid content |
| Case 3 | MRI | Right | 72 × 69 mm ☒ | Lesion containing cystic foci with the biggest one being approximately 1 cm, absence of signal drop-off on out-of-phase images due to the poor lipid content |
| Case 4 | CT | Right | 35 × 35 mm ☒ | Solid lesion containing millimetric calcification |
| Case 5 | MRI | Left | 108 × 96 mm ☒ | Lesion with solid appearance, containing small cystic components from place to place, heterogeneous enhancement after contrast administration, absence of signal drop-off on out-of-phase images due to the poor lipid content |
| Case 6 | CT | Left | 130 × 100 mm ☒ | Lesion containing necrotic areas (HU: 43) |
| Case 7 | MRI | Left | 50 x 30 mm ☒ | Ovoid non-adenomatous lesion containing cystic and necrotic areas, absence of signal drop-off on out-of-phase images due to the poor lipid content |
| Case 8 | CT | Bilateral | 46 × 43 mm ☒ | Two lesions compatible with non-adenoma (HU: 29) |
| Case 9 | MRI | Right | 50 × 32 mm ☒ | Non-adenomatous lesion, absence of signal drop-off on out-of-phase images due to the poor lipid content |
| Case 10 | MRI | Right | 25 × 20 mm ☒ | Non-adenomatous lesion, absence of signal drop-off on out-of-phase images due to the poor lipid content |
| Case 11 | CT | Right | 26 × 20 mm ☒ | Round lesion with regular contours with a relative contrast wash-out 56% |
CT - computed tomography; MRI - magnetic resonance, HU - Hounsfield units
diseases. However, one patient underwent imaging due to left-sided abdominal palpable mass, and one patient was evaluated due to characteristic features of Cushing syndrome. Five (45.5%) of the masses proved to be functional tumours and were more common in women. Clinical characteristics and hormonal evalua- tion of the patients are shown in Table I.
Five patients had CT and six had MR imaging of the abdomen. The masses were 25-130 (57.63 + 34.04) mm in width and 20-100 (47.82 ± 28.95) mm in length. One patient had undergone right adrenalectomy in another health facility and benign AO had been diagnosed in 2009. He was admitted to our institution with recurrent mass on the left side. Therefore, this mass was consid-
| Case | Pathological diagnosis | Immunohistochemical examination | Follow-up period |
|---|---|---|---|
| Case 1 | Benign | Not examined | 19 months |
| Case 2 | Uncertain malignant potential | Synaptophysin (negative) Inhibin (weakly positive) | 15 months |
| Case 3 | Benign | Not examined | 27 months |
| Case 4 | Benign | Synaptophysin (weakly positive) Inhibin (positive) | 19 months |
| Case 5 | Uncertain malignant potential | Synaptophysin (negative) Inhibin (negative) | 32 months |
| Case 6 | Uncertain malignant potential | Synaptophysin (negative) Inhibin (positive) | 24 months |
| Case 7 | Benign | Not examined | 6 months |
| Case 8 | Uncertain malignant potential | Synaptophysin (positive) Inhibin (positive) | 82 months |
| Case 9 | Benign | Not examined | 60 months |
| Case 10 | Benign | Not examined | 25 months |
| Case 11 | Benign | Not examined | 18 months |
ered to be bilateral. The radiological characteristics of the masses are shown in Table II.
The pathological and immuno-histochemical fea- tures are shown in Table 3. Immuno-histochemical profile was studied in five cases. Chromogranin A was negative and Melan-A was positive in all cases. The duration of follow-up was 6-82 months after surgery (mean 29.7 months) (Table III).
Discussion
Oncocytomas commonly occur in kidney, thyroid, parathyroid, salivary, and pituitary gland. They rarely originate from respiratory system, larynx, and cho- roid plexus [8]. Oncocytomas of adrenal glands are extremely rare.
It has been reported to occur at any age without a cer- tain age distribution (mean age at diagnosis is 47 years, ranging from 27 to 72 years) [8]. Also, there are case reports in childhood [10]. Our patients were aged between 31 and 76 years (45.36 ± 13.68), compatible with the literature. AOs have a female preponderance with a ratio of 2.5:1 in the literature [8]. We did not observe a prominent gender preponderance (1.19:1) in concordance with the report (1.8:1) by Wong et al. [11]. Nearly half of our patients had HT (n = 5). Two had hyperaldosteronism and two had Cushing syndrome, which may contribute to HT. Only one had non-functional AO. The patient with subclinical Cushing syndrome also did not have HT. These findings suggest a close relation between overt hormone secretion and HT in cases with AOs. On the other hand, another comorbidity accompanying functional adrenal tumours is DM, which was rarely encountered in our series (only one patient with Cushing syndrome).
AOs are mostly detected incidentally and 17% of them have been reported to be hormonally active [8]. Since the first description of AOs by Kakimoto et al., 49 hormone-secreting cases were published in the literature [12]. AOs secreting androgen, cortisol, and aldosterone together or individually have been reported. Also, there are case reports regarding inter- leukin-6 producing AOs [13]. It has been shown that patients may present with pseudo-precocious puberty and virilisation due to the androgen hypersecretion [8, 14]. Another clinical presentation is Cushing syndrome, and approximately 6 cases were published in the litera- ture [12]. In our study, two patients were diagnosed with Cushing syndrome, and only one of them had typical Cushing stigmata. To the best of our knowl- edge, there is only one case report presenting with subclinical Cushing syndrome associated with AO. One of our patients had subclinical Cushing syndrome [15]. Although very rare, aldosterone-secreting AOs have also been reported [16]. Two of our patients were diagnosed with hyperaldosteronism during workup for secondary hypertension. Five masses (45.5%) were found to be functional, similarly to past studies but in line with the data from a study done by Wong et al., which reported the hormonal activity as 54% [11]. These findings suggest that AOs exert endocrinological activity more than previously thought.
AOs have a predilection for the left side, with a ratio of 2-3.5:1 [3, 17]. We did not detect a predilection for localisation. AOs were generally large in size. The size of the masses ranged from 30 to 150 mm with a mean of 80 mm [18, 19]. In our study the dimensions for width and length were (25-130 mm, 57.63 ± 34.04 mm and 20-100 mm, 47.82 + 28.95 mm, respectively)
similar to previous reports. In one of the largest stud- ies regarding the imaging characteristics of AOs, the mean diameter of benign oncocytic tumours was 76 mm, and the authors suggested that size criteria used for adrenal adenomas are not reliable for benign AOs [20]. While radiological characteristics for renal oncocytomas are well defined, there is no imaging characteristic for AOs. Central scarring at varying rates can be observed on CT or MR images; however, it is not a reliable indicator of differentiating benign AOs from malignant ones and oncocytomas from other adrenal masses [7, 8, 20]. We observed some imaging characteristics compatible with pheochromocytomas and adrenocortical carcinomas.
AOs and other adrenal masses are treated in the same way, taking functional status and radiological characteristics into consideration for surgery. All of the AO cases in the literature have been diagnosed retrospectively because there are no definite clinical or radiological features to discriminate preoperatively.
According to the current classification system, AOs are divided into three histological categories: benign, uncertain malignant potential, and malignant. The histological scoring system for adrenocortical tumours was first introduced by Weiss [21]. Recently, Bisceglia et al. recommended a scoring system consisting of major and minor criteria, especially to determine the histological extent of the AOs [9]. Three major criteria are high mitotic rate (> 5 mitosis in 50x magnification), atypical mitosis, and venous invasion. Four minor crite- ria include tumour measuring over 10 cm in diameter or weighing over 200 g, tumour necrosis, and capsular and sinusoidal invasion. The presence of one major criteria confirms malignancy, 1-4 minor criteria indicate uncertain malignant potential, and absence of major and minor criteria suggest benignity [9]. Seven of 11 patients were classified as benign and the remaining as uncertain malignant potential (63.6% and 36.4%, re- spectively), according to the Lin-Weiss-Bisceglia criteria in our study. In a review of the pathologic features of 147 cases, approximately 80% of cases were reported to have benign or low malignancy potential [8]. To the best of our knowledge, there were 47 cases with uncertain malignant potential in the literature [11].
Determining the immunohistochemical profile of AOs is difficult because immunohistochemical exami- nation was not performed and same staining pattern was not used in all cases. In challenging situations, im- munohistochemical examinations aid in differentiating adrenocortical tumours from the medullary ones. They are generally negative for S100 and chromogranin and positive for melan-A [8, 22, 23]. Inhibin is generally positive [8, 11, 23, 24]. Low positivity rate has been reported for synaptophysin [8, 11, 22]. Although im-
munoreactivity for vimentin is variable, diffuse posi- tivity is evident in most cases [8, 11, 14, 22, 24]. Sangoi and McKenney compared 63 adrenocortical lesions with 35 pheochromocytomas using the usual stains (chromogranin, calretinin, inhibin, melan A, and syn- aptophysin) and novel (steroidogenic factor-1 [SF-1], microtubule-associated protein 2, and mammalian achaete-scute homolog-1) antibodies. The adrenocor- tical tumours were 100% negative for chromogranin, 89% positive for calretinin, 86% positive for inhibin and melan-A, and 59% positive for synaptophysin. The authors concluded that chromogranin plus SF-1, cal- retinin, or inhibin improves diagnostic sensitivity and specificity [25]. In our study chromogranin-negative and melan-A-positive staining in all specimens support the previous reports.
Prognosis of AOs varies according to the histological subtype. Currently, there are no recommendations for follow-up of benign AOs. The follow-up duration rang- es from six months to 37 months without any recurrence in current literature [17, 26]. There was only one case which was initially reported as benign but diagnosed to be malignant AO after recurrence and re-examination of the original specimen [9]. We did not observe recurrence of disease during 6-60 (mean 24.8) months of follow-up in seven patients with benign AOs. Recurrence rates for AOs with uncertain malignant potential are variable. It was reported as 6% in a series of 47 patients during a mean follow-up of 96 months [11]. Bisceglia et al. reported no recurrence in four patients during a mean follow-up time of 38.7 (10-61) months [9]. Lin et al. also did not observe recurrence in two patients followed up for 12-19 (mean 15.5) months [22]. We followed up four patients with uncertain malignant potential for 15-82 (mean 38.25) months, similarly to the study by Bisceglia et al. [9]. Wong et al. showed that estimated total median survival period of malignant AOs was 58 months (95% confidence interval 27.5-88.5 months), which was better than that of adrenocortical carcinomas [11]. We have no experience with malignant AOs.
Conclusions
AOs pose challenges during radiological and histologi- cal examinations. They usually occur in adults. They are frequently non-functional; however, half of them may present as hormone active tumours, as we have shown. CT or MRI features cannot conclusively dif- ferentiate AOs from other adrenal masses or benign AOS from malignant ones. We observed that AOs may reveal imaging features common with pheo- chromocytomas and adrenocortical carcinomas. They are usually benign, although those with uncertain malignant potential or malignancy may be evident.
Therefore, because there is no clear evidence regarding the true potential of this tumour, long-term follow-up is recommended.
Conflict of interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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