Urologia Internationalis
Luigi Meariniª Rachele Del Sordob Elisabetta Costantiniª Elisabetta Nunzia Massimo Porenaª
aUrology Department and bPathological Anatomy and Histology Department, University of Perugia, Perugia, Italy
Urol Int DOI: 10.1159/000345141
Adrenal Oncocytic Neoplasm: A Systematic Review
Key Words
Oncocytoma . Adrenal gland . Adrenal oncocytic neoplasm
Abstract
Introduction: Oncocytic neoplasms as tumors arising in the adrenal glands are rare, usually considered as nonfunctional and benign. In the current literature, there are extremely limited reports of adrenal oncocytic neoplasms; as to date, only 147 cases have been described. The rarity of the event prompted this study which reviews and presents the inci- dence, histology, diagnosis and therapy of adrenal oncocyt- ic neoplasms. Materials and Methods: A review by system- atic literature search was done using the MEDLINE®/Cochrane libraries from 1950 to date using the medical subject head- ings ‘oncocytoma’, ‘adrenal gland’, ‘adrenal oncocytoma’, ‘adrenal oncocytic neoplasm’ and ‘adrenal oncocytic carci- noma’. Results: Adrenal oncocytic neoplasm is a rare dis- ease, usually incidentally detected because only 17% are functional adrenal masses. The typical oncocyte displays abundant granular eosinophilic cytoplasm, due to the ac- cumulation of mitochondria. Computed tomography and magnetic resonance imaging are not able to identify or dif- ferentiate benign and malignant oncocytic neoplasms. The mainstay of therapy is adrenalectomy, recently performed by laparoscopy. The prognosis is good for benign tumors, while adrenocortical oncocytic carcinoma has a poor surviv- al rate of only 5 years. Conclusions: Adrenal oncocytic neo-
plasm, a rare and mostly benign tumor, usually presents as an incidental, large adrenal mass; surgery is the mainstay of therapy, by means of laparoscopy which is now the most dif- fuse approach to adrenalectomy.
Copyright @ 2012 S. Karger AG, Basel
Introduction
Oncocytic neoplasms or oncocytomas are in most cas- es benign tumors, usually arising in the kidneys or thy- roid, parathyroid, salivary or pituitary glands [1, 2]; rare- ly, they have also been reported at other sites including the respiratory tract (as oncocytic neuroendocrine carci- noma [3]), larynx [4] and choroid plexus [5].
Oncocytic neoplasms arising in the adrenal glands are extremely rare, and are usually discovered to be nonfunc- tional and mostly benign tumors. Since the first descrip- tion [6] confirmed by electron microscopy in 1986 [7], approximately 147 cases have been reported in the litera- ture, most frequently described as incidental findings. Despite the fact that they have mostly been traditionally considered to be nonfunctional and benign tumors, re- cent data indicate that about 20% of the adrenocortical oncocytomas demonstrate some elements of malignancy [8] and 10-20% of them appear to affect hormone pro- duction in the adrenal glands.
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In a decision-making process, a general imaging fea- ture that usually differentiates a benign from a malignant adrenal mass is tumor size: a diameter <4-5 cm usually suggests a benign form. In case of oncocytic neoplasm, however, the size of the mass and imaging findings [com- puted tomography (CT) or magnetic resonance imaging (MRI)] cannot be used to identify such a lesion or to dif- ferentiate benign and malignant oncocytic neoplasms [9]. In such cases, the oncocytic adrenal mass should be con- sidered in the differential diagnosis of indeterminate, in- cidentally detected, adrenal tumors. As adrenal oncocyt- ic neoplasm usually presented as a large adrenal mass, surgical excision is often considered inevitable, tradition- ally by open adrenalectomy. Recent advances in laparo- scopic techniques, even in the presence of a large adrenal mass, have made possible the application of minimally invasive procedures.
The rarity of the disease prompted this study, which reviews and discusses incidence, histology, diagnosis and current trends in the therapy of adrenal oncocytic neo- plasms.
Materials and Methods
Review of the Literature: Search Strategy
A literature search was done using the MEDLINE®/Cochrane libraries from 1950 to date using the medical subject headings ‘oncocytoma’, ‘adrenal gland’, ‘adrenal oncocytoma’, ‘adrenal on- cocytic neoplasm’ and ‘adrenal oncocytic carcinoma’. No lan- guage restrictions were imposed. Where information was missing from published papers, we contacted authors to obtain relevant information. Original articles, review articles and editorials were included and reviewed in order to select relevant articles.
In August 2012, the search for oncocytoma, adrenal gland, ad- renal oncocytoma, adrenal oncocytic neoplasm, adrenal oncocyt- ic carcinoma produced 93 references, 19 of which were reviews.
Results
Incidence
The term ‘adrenal mass’ refers to neoplasms of the ad- renal gland, most of which are identified during a endo- crine evaluation for their tendency to overproduce endo- crine hormones: adrenal pheochromocytomas (up to 11% of incidentally detected adrenal masses) and all adreno- cortical adenomas are benign tumors which may never- theless cause significant health problems by giving rise to hormonal hyperproduction.
In general, however, most of these adrenal masses are called ‘incidentalomas’ since they are tumors found by coincidence and in the absence of clinical symptoms: they are one of the more common unexpected findings re- vealed on ultrasound scan, CT or MRI.
According to the definition, an adrenal incidentaloma is a mass greater than 1 cm in diameter, serendipitously discovered by radiological examination [10]. Numerous autopsy studies have examined the frequency of inciden- tal adrenal nodules, and have shown an overall frequency of adrenal adenomas of about 6%. A review on abdominal CT yields similar findings, with a prevalence of adrenal incidentaloma of 4%, mostly represented by adrenal ad- enoma (75%) and metastasis in up to 21% of cases.
Malignant adrenal tumors, which include neuroblas- toma, adrenocortical carcinoma [11] with its oncocytic variant [12] and a minority of adrenal pheochromocyto- mas, are extremely rare, with an incidence of 1-2 per mil- lion population annually.
Adrenal incidentalomas show different distribution in the population with regard to the age and sex of the pa- tient and the size and nature of the mass and on which side it occurs. Peak incidence is in 50- to 70-year-olds and more frequently found in females (which could be due to a higher rate of abdominal diagnostic procedures being performed in women than in men).
Adrenal oncocytic neoplasm is a more rare disease; to date, it has been described in only 147 cases. Most of them are incidentally detected [13-18], since only 17% are func- tional adrenal masses [19]. Their occurrence in all ages has been described, without a precise age distribution (mean age at diagnosis 47 years, range 27-72 years), and have been observed to occur more frequently in females (2.5:1) and in the left gland (3.5:1).
In most cases, adrenal oncocytic neoplasm is located in the adrenal cortex, with only 1 case having been de- scribed of an oncocytic tumor of the adrenal medulla or in heterotopic adrenal tissue [20, 21]. Adrenocortical on- cocytic neoplasm, although extremely rare, should be in- cluded in the differential diagnosis of solid, nonfunction- ing, adrenal tumors in pregnancy [22].
To date, there are no identified specific risk factors (environmental or genetic), and there is a minimum of knowledge available on the mechanisms that lead to on- cocytosis in general and in the adrenal glands in particu- lar. Experimental studies in rats have demonstrated that N-nitrosomorpholine, an airborne contaminant, induces renal oncocytosis and is followed by the formation of re- nal oncocytoma [23], suggesting that the excessive mito- chondrial proliferation is a compensatory mechanism in
the presence of toxic substances. Another hypothesis is that oncocytic neoplasms are tumors of the mitochondria because these have their own DNA that codes their own characteristic proteins [24], and that the tumor arises via mutations in the mitochondrial genome [25]. A peculiar differentiation towards cells of high-energy output or a physiological response to a defect in the energy produc- tion machinery of the cell is another possible explanation [26].
Histology
The term ‘oncocyte’, derived from the Greek root ‘onco-’, which means mass or bulk and first used by Ham- perl in 1950 [27], usually describes a large, highly eosino- philic, granular cell, typically associated with a Hurthle cell tumor of the thyroid gland. It is also known as an oxyphilic cell (typically found in the parathyroid glands) or an Askanazy cell (in the thyroid).
The oncocyte is 1-2 times the size of normal acinar cells which compose original tissue, and typically dis- plays an abundant and granular eosinophilic cytoplasm with a central pyknotic nucleus. The cytoplasmatic gran- ularity is due to the accumulation of mitochondria that may occupy up to 60% of the cytoplasm. The increased concentration of mitochondria is accompanied by a gradual compression and sometimes disappearance of other cytoplasmic membrane systems. Electron micros- copy is an invaluable tool for the demonstration of mito- chondria in the cytoplasm of oncocytes. The character- istic acidophilia should be distinguished from acidophil- ia that is secondary to the accumulation of keratin, collagen, lysosomes, neurosecretory granules and cyto- filaments, smooth endoplasmic reticulum or a combina- tion of these.
The adrenal oncocytic neoplasms have their own structural characteristics. Macroscopically, most of them are a large, rounded, encapsulated and well-circum- scribed mass, with an average diameter of 8 cm (2-20 cm). The mass tends to be brown, yellow or mahogany on cut-section. Some tumors display areas of hemorrhage and necrosis. The classic central radiating scar that has been described in most renal oncocytomas is not always present in adrenocortical oncocytic neoplasms.
The microscopic appearance of oncocytic neoplasm includes cells arranged in solid, trabecular, tubular or papillary patterns. The tumor cells are highly eosinophil- ic and granular; rarely, the oncocyte has pleomorphic nu- clei or a mitotic figure.
Upon observation by electron microscope, the tumor cells contain abundant mitochondria, typical of adreno- cortical cells [28].
The immunophenotypic profile of adrenal oncocytic neoplasm [29] is difficult to evaluate because immuno- histochemical studies were only performed in approxi- mately half of the reported cases, and no single immuno- staining was performed in any of them. Nevertheless, the cases were generally negative for S100 and chromogranin. Bégin [17] and Lin et al. [30] reported immunoreactivity to cytokeratins 8 and 18 (or CAM 5.2), in contrast to the findings of other authors.
Vimentin immunoreactivity was also variable, with most cases being strongly positive, while others showed only weak or absent immunoreactivity. In some cases, through immunocytochemical study, vimentin was dif- fusely expressed, whereas AE1/AE3 cytokeratin was de- tected only in some cells.
Some authors used immunopositivity with an antimi- tochondrial antibody to prove that such a tumor was tru- ly oncocytic [19, 31, 32].
A variant of adrenal oncocytic neoplasm is a disease of adrenal medulla [33]: in such a case, the morphologic distinction between adrenocortical and medullary tu- mors can be difficult [17]. Sangoi and McKenney [34] characterized the immune profile of adrenal cortical lesions and pheochromocytomas with a panel of anti- bodies. From the adrenal cortical lesions analyzed, 89% were calretinin-positive, 86% alpha-inhibin-positive and melan-A-positive and 59% were synaptophysin-positive. All the adrenal cortical lesions were chromogranin-neg- ative. Of the pheochromocytomas analyzed, 100% were positive for synaptophysin and chromogranin and all of them were negative for calretinin, inhibin and melan-A. Calretinin has been proven to be sensitive and specific in differentiating tumors of the adrenal cortex from those of the adrenal medulla. Chromogranin was proven to be the sole pheochromocytoma marker, given its high sensi- tivity and specificity.
In general, the immune profile of an oncocytic tumor is: diffuse positivity for vimentin, melan-A, synaptophy- sin (fig. 1) and alpha-inhibin [35].
According to the currently used classification, there are three histological categories: pure and benign onco- cytoma, oncocytic neoplasm of uncertain malignant po- tential [36-38] and oncocytic carcinoma [39-42].
A tumor is defined as an adrenocortical carcinoma when three or more of the following criteria are met: (1) a high nuclear grade, (2) a mitotic rate of ≥6 per 50 high power fields, (3) atypical mitosis, (4) <25% clear
a
b
cells, (5) a diffuse architecture pattern in more than one third of the tumor, (6) confluent necrosis, (7) venous invasion, (8) sinusoidal invasion and (9) capsular inva- sion. The criteria, also known as Weiss criteria [43], are considered the standard tools for the diagnosis of adre- nocortical malignancy. However, great care should be taken in applying these criteria to histological evalua- tion of the relatively rare and peculiar adrenocortical oncocytic neoplasm. Some other markers, such MIB1 or Ki-67, are of some practical value in terms of achieving a differential diagnosis between benign mass and carci- noma [44].
Bisceglia et al. [8] proposed a review of the common Weiss criteria. The morphologic parameters of the Weiss system were reviewed in the context of their possible ap- plication to the oncocytic tumor variant. Proposed major (high mitotic rate, atypical mitoses and venous invasion) and minor (large size and huge weight, necrosis, capsular invasion and sinusoidal invasion) criteria in distinguish- ing malignant tumors have been analyzed by the authors. Defining criteria (predominantly cells with eosinophilic and granular cytoplasm, a high nuclear grade and a dif- fuse architectural pattern) in common with all types of oncocytic tumors have been outlined. The presence of
1 major criterion indicating malignancy, 1-4 minor cri- teria indicating uncertain malignant potential (border- line) and the absence of all major and minor criteria in- dicative of benign mass.
Diagnosis
The two most important factors in the diagnostic work-up of adrenal mass, also valid for adrenal oncocyt- ic neoplasm, are: the lesion’s size and/or function. The size of an adrenal incidentaloma does not affect recom- mendations regarding biochemical testing.
The size of an adrenal mass is very important in the decision-making process. In a report involving 887 pa- tients who had adrenal incidentalomas, a diameter great- er than 4 cm was shown to have a 90% sensitivity for the detection of adrenocortical carcinoma, but a low specific- ity; only 24% of the lesions were malignant [45]. Decisions regarding surgery should also take into account the imag- ing phenotype of the mass as well as the patient’s age and any coexisting conditions. Increase in size over time is another indication for surgery. In general, however, re- section is recommended for all adrenal masses of >6 cm. The size is a problem in adrenal oncocytic neoplasms be- cause most oncocytic adrenal tumors, although benign,
display a large volume [46]. A preoperative percutaneous biopsy [47], by means of CT or ultrasound scan guidance, provides an accurate diagnosis in some cases of indeter- minate mass, with a sensitivity of 73.3%.
Careful biochemical analyses should be undertaken to rule out the presence of a primary functioning mass which requires surgical resection despite the size: some cases of adrenal oncocytic neoplasm have presented as functioning tumors. It is extremely rare to find a case of adrenal oncocytic neoplasm with a clinical presentation mimicking pheochromocytoma, a finding which poses a considerable preoperative diagnostic dilemma [48-51], as the pheochromocytoma itself can be confused with the oncocytic neoplasm. The distinction is possible in most cases, based on clinical, biochemical and immunohisto- chemical study. In rare cases, a Cushing’s syndrome is caused by benign adrenocortical oncocytic neoplasm [18, 52-55] or an oncocytic subtype of malignant adrenocor- tical carcinoma [56].
An adrenocortical oncocytic neoplasm occurring with an aldosteronoma has been described [57, 58] as well as very rare cases of virilizing adrenocortical oncocytic neoplasm in a female child [59-61] or old woman [62], an adrenocortical oncocytic carcinoma producing testoster- one [63] or presenting with pseudoprecocious puberty in- duced by adrenocortical oncocytoma [64] and an adrenal oncocytic neoplasm producing cortisol and testosterone [65] or cortisol and aldosterone [66]. A case of an adreno- cortical oncocytic neoplasm producing interleukin (IL)-6 has been reported [67].
In the imaging of oncocytic neoplasms, as of any mass of the adrenal glands, it is important to differentiate the lesion from adrenal adenoma. The majority of malignant and benign adrenal lesions can be differentiated based on fat concentration: almost all malignant lesions are lipid- poor, whereas the majority of benign lesions (usually cor- tical adenomas) are lipid-rich, and present lower attenu- ation on CT scan. The CT criterion used for the diagnosis of benign lipid-rich adenoma was unenhanced attenua- tion of 10 HU or less [68], avoiding measurement of ne- crotic or cystic areas, which can be seen in some malig- nant lesions and adrenal cysts [69]. More recently, it has been noted that injected contrast material tends to wash out of benign adrenal lesions faster than malignant ones. However, the CT imaging findings are, unfortunately, in general nonspecific [70-72], and there is no characteristic imaging of adrenal oncocytic neoplasm. The central scar is variably present.
MRI with chemical shift subtraction [73] provides a high confidence level in distinguishing adrenal adeno-
mas from other disease [74, 75]. However, MRI is not able to detect adrenal oncocytic tumor [76]. Moreover, a re- port of fat within an oncocytic adrenocortical neoplasm demonstrated on CT and MRI has been described. De- spite being uncommon, this diagnosis must at least be considered in the presence of a large adrenal mass dem- onstrating predominantly soft tissue with only scattered areas of fat [77].
In conclusion, CT and MRI findings cannot be used to detect an adrenal oncocytic neoplasm or to differenti- ate between benign and malignant oncocytic neoplasms.
No typical pattern has been described on ultrasound scan. The use of contrast-enhanced ultrasound has shown an excellent sensitivity and specificity in the differential diagnosis between benign and malignant adrenal mass [78]; however, no experiences of adrenal oncocytic neo- plasm has been described.
18F-FDG whole-body positron emulsion tomography is utilized to differentiate benign from malignant non- functioning adrenal masses; in the literature there are only a few published reports about findings in adrenocor- tical oncocytoma by this method [79], and the findings are contradictory [80, 81]. Paradoxical positive results have emerged on the use of radiotracers such as meta- iodobenzylguanidine - labeled with various iodine iso- topes, proven to be the most reliable tracer for human studies of adrenal medulla - in adrenal oncocytic neo- plasm [82].
The diagnosis of oncocytic neoplasm can be secured preoperatively by fine-needle aspiration cytology [83]; this alone [84, 85], however, and even an open biopsy, would not be able to characterize and define the disease as adrenal oncocytic neoplasm [86].
Therapy
The approach to an adrenal mass depends upon size and function. The surgical management of oncocytic ad- renal tumors has been traditionally involving open surgi- cal approach [87, 88]. Adrenalectomy is the standard, since adrenal oncocytic neoplasm usually presented as large adrenal mass. Recent advances in endoscopic tech- niques have allowed the performance of an increasing number of laparoscopic adrenalectomies [89-92].
Retrospective comparative studies have consistently shown that the laparoscopic approach to an adrenal mass carries less morbidity, quicker patient recovery and short- er hospital stay in comparison with open adrenalectomy. Nevertheless, safe laparoscopic resection of large or po- tentially malignant adrenal tumors still remains a matter of scientific debate. Safety includes the ability to obtain a
| Authors | Year | Type of paper | Number of cases | Key message | |
|---|---|---|---|---|---|
| Incidence | Kakimoto [6] - de Krijger [11] | 1986 - to date | case report, reviews | 147 | Low incidence, rare disease More than 80% benign or with low malignant potential More frequent in females and in the left gland Usually with large size (mean 8 cm) |
| Incidentaloma | Angeli [45] | 1997 | epidemiology | 83% incidentally detected | |
| Lee [13] | 2006 | epidemiology | |||
| Young [10] | 2007 | case repot | 1 | 17% functional adrenal mass | |
| Functional mass | Wong [19] | 2011 | consecutive cases | 7 | (Cushing, pheochromocytoma, virilizing syndrome) |
| Kiriakopoulos [48] | 2011 | case report | 1 | ||
| Li [51] | 2000 | case report | 1 | ||
| Geramizadeh [53] | 2008 | review | 1+ | ||
| Risk factors | Unknown | ||||
| Histology | Seo [28] | 2002 | case report | 2 | Abundant mitochondria at electron microscopy |
| Immunoprofiling | Hoang [29] | 2002 | consecutive case | 4 | Positivity for vimentin, melan-A, synaptophysin and |
| Schittenhelm [35] | 2009 | case report | 1 | alpha-inhibin | |
| Duregon [25] | 2011 | consecutive case | 27 | Reticuline framework, mitochondrial DNA profiling | |
| Criteria (benign/malignant) | Medeiros [43] | 1992 | review | Weiss criteria | |
| Bisceglia [8] | 2004 | consecutive cases | 10 | Lin-Weiss-Bisceglia criteria | |
| Lin [30] | 1998 | consecutive cases | 7 | ||
| Imaging | Shah [70] | 2004 | case report | 1 | No definitive pattern on CT scan or MRI |
| Park [72] | 2006 | consecutive cases | 91 (1 oncocytoma) | ||
| Kekis [76] | 2012 | case report and review | 1 | ||
| Surgical therapy | Eldahshan [91] | 2008 | case report | 1 | Laparoscopic adrenalectomy if feasible |
complete resection without disrupting the capsule. Con- tra-indications are the presence of capsular or vascular invasion or the diffusion to the surrounding structures, or the presence of a lymphadenopathy.
In general, the laparoscopic approach to adrenal tu- mors can be safely performed in well-experienced hand, when the preoperative CT and MRI findings reveal a well-encapsulated tumor, with no evidence of invasion into surrounding tissue and no regional adenopathy. More recently, a surgical resection of adrenal oncocytic neoplasm with the assistance of the da Vinci robotic sys- tem has been described [93].
Partial adrenalectomy is proposed in some case, how- ever it is an incomplete approach to incidentally detected adrenal mass [94].
Prognosis
Accurate classification of adrenal oncocytic neoplasm is important. The prognosis is based upon the cited crite- ria for the classification of oncocytic adrenocortical tu- mors. These criteria (Lin-Weiss-Bisceglia system) in- clude: (1) major criteria (a mitotic rate of more than 5
mitoses per 50 high power fields, any atypical mitoses or venous invasion), (2) minor criteria [large size (>10 cm and/or >200 g), necrosis, capsular invasion or sinusoidal invasion] and (3) definitional criteria (predominantly cells with eosinophilic-granular cytoplasm, high nuclear grade and diffuse architectural pattern). The presence of any one of the major criteria indicates malignancy, the presence of one to four minor criteria is indicative of un- certain potential while the absence of all major and minor criteria indicates benign behavior.
Adrenal oncocytic neoplasms are predominately be- nign [29]. After surgery, adrenal oncocytic neoplasm can be assessed conservatively in the absence of mitotic activ- ity, necrosis, or invasion. The limited literature available supports this recommendation.
A safer approach, utilized until objective criteria are devised, would be judicious regular follow-up for a mini- mum of 5 years. On the other side, adrenocortical carci- noma and its oncocytic variant is an aggressive cancer, and often invaded nearby tissues or metastasized [95] to distant organs at the time of diagnosis, with a poor 5-year survival rate (20-35%) [96]. The 5-year survival rate after
successful surgery is 50-60%, but unfortunately, a large percentage of patients are not surgical candidates, and will present local relapse [97]. Radiation therapy and ra- diofrequency ablation may be used for palliation, while chemotherapy includes mitotane [98] as well as standard cytotoxic drugs.
Discussion and Conclusion
Adrenal oncocytic neoplasm is one of the histological subtypes of incidentally detected adrenal masses. It is usually a large, benign, nonfunctional adrenal tumor, with prevalence in women and on the left side.
As it usually presents as an incidental, large adrenal mass, CT and MRI findings cannot be used to differenti- ate benign and malignant oncocytic neoplasms and only microscopic criteria are able to identify precise histology characterization and clinical behavior, so adrenalectomy is the mainstay of therapy and laparoscopy is now the most diffuse approach.
It is difficult to trace a guideline with a high level of evidence on adrenal oncocytic neoplasms, since most of the current literature is based upon singular experience, with very few papers reporting on extensive experience, although these are of a high scientific level. In conclusion, table 1 reports the key points with the most important studies as references.
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