The level of accordance between preoperative and postoperative diagnosis in patients undergoing adrenalectomy - a study of 230 consecutive cases
Michał Aporowicz1, Paweł Domosławski2, Krzysztof Kaliszewski2, Krzysztof Sutkowski2, Eliza Kubicka3, Marek Bolanowski3
1Department and Division of Surgical Didactics, Wroclaw Medical University, Wroclaw, Poland
2Department of General, Minimally Invasive and Endocrine Surgery, Wroclaw Medical University, Wroclaw, Poland
3Department and Clinic of Endocrinology, Diabetology and Isotope Therapy, Wroclaw Medical University, Wroclaw, Poland
Submitted: 12 September 2019; Accepted: 14 November 2019 Online publication: 19 January 2020
Arch Med Sci 2024; 20 (2): 485-493
DOI: https://doi.org/10.5114/aoms.2020.92343
Copyright @ 2020 Termedia & Banach
Corresponding author: Michał Aporowicz MD Department and Division of Surgical Didactics Wroclaw Medical University 66 Marii Skłodowskiej-Curie St 50-369 Wroclaw, Poland Phone: +48 505 349 825 E-mail: micapo@interia.pl
Abstract
Introduction: Patients are qualified for an adrenalectomy due to endocrine or oncologic reasons. Final histopathological diagnoses include a wide spec- trum of more than a dozen entities. The aim of this study was to compare preoperative and postoperative diagnoses of patients undergoing adrenal- ectomy to determine the level of diagnostic accuracy, as well as sex and age of patients.
Material and methods: A group of 214 patients (230 specimens in total) op- erated on in a single center was studied and their demographic and patho- logical data were investigated.
Results: The majority of diagnoses were characterized by both high positive predictive value and sensitivity, excluding pheochromocytoma (60.0% and 67.7%, respectively) and adrenal cyst (100% and 37.5%, respectively). Pa- tients operated on due to Cushing’s syndrome were statistically significantly more often females (p = 0.009), while those with metastases (diagnosed both pre- and postoperatively) were more often males (both p = 0.001). Pa- tients qualified due to non-functioning tumors were older than those with Cushing’s or Conn’s syndrome (p = 0.044 and p = 0.002, respectively).
Conclusions: The lowest diagnostic accuracy is observed in cases of pheo- chromocytoma and adrenal cyst. Meticulous preparation of the patient for hormonal tests, including discontinuation of certain medications, is essen- tial for obtaining accurate results. The diagnosis of Cushing’s syndrome is more prevalent in females, while metastasis syndrome is more prevalent in males. Adrenocortical carcinoma may initially be diagnosed as a non-func- tioning tumor (1.6% of such cases) or a recurrence of a previously resected tumor, which should always raise a suspicion of a malignant neoplasm.
Key words: adrenal gland neoplasms, adrenocortical tumors, pheochromocytoma, adrenalectomy, histopathology,
Introduction
An adrenalectomy is a surgical resection of an adrenal gland. Patients are most commonly qualified for adrenalectomy due to a diagnosis of an
AMS
adrenal tumor, either symptomatic or incidentally detected during imaging studies (so-called inci- dentaloma). Symptoms of an adrenal tumor may be associated with its size (a mass effect) or an excessive secretion of hormones [1]. Indications for adrenalectomy may therefore be divided into two large groups, namely endocrine and oncolog- ic ones. Endocrine indications include basically all hypersecretion syndromes: Cushing’s syndrome (ACTH-independent or ACTH-dependent, but with contraindications or refractory to transsphenoi- dal surgery), primary hyperaldosteronism (Conn’s syndrome), hyperandrogenic syndrome of adre- nal origin (very rare) and a pheochromocytoma (PHEO; or even a suspicion of one). Oncologic indications appear when an adrenal tumor is of high risk of being malignant, either metastatic or primary. Adrenal glands are common sites of metastases, while primary adrenal malignancies (adrenocortical carcinoma (ACC) and malignant PHEO)) are less common. Oncologic recommenda- tions for adrenalectomy include certain radiologic features of a tumor (high density in unenhanced CT (> 30 Hounsfield units (HU)), slow contrast me- dium washout (< 50% in the 10th minute) and low lipid content in MR) as well as tumor size greater than 5 cm and/or its fast growth assessed during consecutive imaging studies [2-5].
Preoperative preparations for adrenalectomy depend on the initial diagnosis. Patients diag- nosed with hypersecretion syndromes require specific management, which consists of normal- ization of blood pressure and heart rate using a- and (sometimes) ß-blockers (PHEO), control of hypercortisolemia with steroidogenesis inhib- itors, e.g. ketoconazole (Cushing’s syndrome), or normalization of blood pressure and hypokalemia using spironolactone and potassium (Conn’s syn- drome) [2, 6].
Following the operation, the histopathological examination of the excised specimen ultimately determines the tumor’s character and verifies the preoperative diagnosis. The scope of pathologi- cal diagnoses varies widely, including more than a dozen entities, with benign adrenocortical ade- noma (ACA) being the most common one [1, 6, 7]. Various pathologic techniques can be used, rang- ing from classic staining with hematoxylin and eosin (H-E), through different scales designed to assist in the diagnostic process (e.g. the Weiss system), to immunohistochemistry (IHC), which allows one to stain the specimen with antibodies in order to look for a specific protein (antigen). In the case of an adrenal tumor, the most commonly investigated proteins include melan-A (MART-1), inhibin a, chromogranin A (CgA), synaptophysin, neurofilament, protein S-100, calretinin, vimentin, cytokeratins, D2-40, steroidogenic factor-1 (SF-1,
Ad4BP), epithelial membrane antigen (EMA) and glycoprotein HMFG-2.
The aim of our study was to compare the initial and final diagnoses of patients undergoing adre- nalectomy to determine the level of coherence be- tween them. Based on these data, we estimated the accuracy (sensitivity and positive predictive value (PPV)) for each diagnosis. We also compared the sex and age of patients in every group.
Material and methods
The data of all patients undergoing adrenal- ectomy, regardless of operation technique, in the 1 st Department and Clinic of General, Gastroenter- ological and Endocrine Surgery, Wroclaw Medical University (WMU), from 2004 to 2018, were inves- tigated. Patients’ demographic data, the results of preoperative laboratory and imaging studies, as well as postoperative histopathological reports, were gathered in a database.
Prior to admittance to the surgical department, patients were diagnosed in an endocrine depart- ment for comprehensive evaluation of their hor- monal status and establishing or confirming an indication for surgical treatment. The vast majori- ty of patients were referred to our clinic by the De- partment and Clinic of Endocrinology, Diabetology and Isotope Therapy, WMU. The standard preop- erative evaluation included at least one imaging study (computed tomography was preferred) and the following laboratory parameters: complete blood count (CBC), electrolytes (Na+ and K+), serum cortisol profile, free cortisol excretion in 24-hour urine collection, aldosterone and plasma renin ac- tivity (PRA) - both in resting and supine position, aldosterone excretion in 24-hour urine collection, metanephrines in 24-hour urine collection. In se- lected patients, additional tests were performed, including androgen metabolism markers (dehy- droepiandrosterone sulfate (DHEA-S), testos- terone, androstenedione, sex hormone-binding globulin (SHBG)), dexamethasone test (with small (2 mg) or large (8 mg) dose), adrenocorticotropic hormone (ACTH), catecholamines in plasma and excretion in 24-hour urine collection, vanillylman- delic acid (VMA), chromogranin A (CgA). Based on clinical presentation, imaging studies and lab- oratory test, patients were qualified for surgical treatment in 8 categories: 1) tumor without hor- monal hypersecretion, 2) adrenal cyst, 3) pheo- chromocytoma or suspicion of one, 4) Cushing’s syndrome, 5) primary hyperaldosteronism (Conn’s syndrome), 6) Conn’s syndrome coexisting with hypercortisolemia, 7) metastatic tumor or sus- picion of one and 8) recurrence of previously re- moved adrenal tumor.
After adrenalectomy, the postoperative speci- mens were fixed with 10% formalin, transferred to
the Department and Division of Pathomorpholo- gy, WMU, then processed into paraffin-embedded blocks. Slices from blocks were evaluated using classic H-E staining, as well as IHC techniques, depending on the pathologist’s choice. Definitive pathological diagnoses included 14 positions, namely: (benign) ACA, nodular hyperplasia (NH), ACA/NH (distinction impossible), PHEO, adrenal gland without any detected pathology, myelolipo- ma, hematoma, adrenal cyst, hemangioma, gan- glioneuroma; and (malignant) metastasis, ACC, lymphoma and schwannoma.
When evaluating the PPV and sensitivity for specific preoperative diagnoses, the following as- sumptions were made: 1) a non-functioning tu- mor can turn out to be anything on postoperative pathology, apart from an adrenal gland with no pathology or a cyst; 2) a cyst, a pheochromocyto- ma and a metastasis can only be a cyst, a pheo- chromocytoma or a metastasis, respectively; 3) Cushing’s or Conn’s syndrome or both com- bined can be an ACA, NH, ACA/NH or ACC; 4) a re- current tumor can be any type of malignancy. The assessment of sensitivity was possible only for those preoperative diagnoses that had the same postoperative equivalent, that is: a cyst, PHEO and metastasis (as only then could a false negative (FN)) value be calculated).
Statistical analysis
For statistical comparisons of patients’ sex, the x2 test was used. The Shapiro-Wilk test was used to check the normality of distribution of the age of patients. For further comparisons of the age of patients between groups, the Kruskal-Wallis test with post-hoc Conover test was used.
Results
There were 214 patients undergoing adrenal- ectomy from January 2004 to December 2018 in the studied department and clinic. There were 150 (70.1%) females and 64 (29.9%) males, from 21 to 81 years old (mean age: 56.0 ±11.3). The majority of patients underwent a single resection, but 6 of them were operated on twice and one was oper- ated on three times (222 operations in total). The laparoscopy was the preferred surgical approach (141 procedures, 63.5%), followed by laparotomy (55, 24.8%), laparoscopy with conversion to lapa- rotomy (15, 6.8%), retroperitoneoscopic (9, 4.1%) and open extraperitoneal method (2, 0.9%). The left adrenalectomy was slightly more common than the right one (109 (49.1%) vs. 105 (47.3%)); 8 (3.6%) procedures were a simultaneous bilateral adrenalectomy. Therefore 230 postoperative spec- imens were evaluated in total. Among this group there were no cases of a malignant PHEO or an
androgen-producing tumor. Perioperative compli- cations that accompanied some of these proce- dures were described in the previous paper [8].
The comparison between preoperative and postoperative diagnoses is summarized in Table I. Specimens indicated as non-functioning tumors had a variety of pathological diagnoses, both be- nign and malignant. The ACA was the most com- mon one (62, 48.8%), followed by NH (14, 11.0%) and - interestingly - myelolipoma (13, 10.2%). Only 8 cases did not match the assumed scope of diagnoses - 3 adrenal glands without any patholo- gy and 5 cysts; therefore the PPV was 93.7%. Three specimens diagnosed as adrenal cysts had their diagnosis confirmed (PPV 100%). However, for 8 cysts recognized in total, only 3 were described as one before an operation (sensitivity 37.5%). Out of 35 cases indicated as PHEO, only 21 were con- firmed by pathology (PPV 60.0%). At the same time, for 31 PHEOs diagnosed in total, only 21 had the same preoperative diagnosis (sensitivity 67.7%); the remaining 10 were marked as non-functioning tumors. In the Cushing’s syndrome group, there was only 1 mismatch per 26 (1 adrenal gland with- out pathology; PPV 96.2%). Similarly in the Conn’s syndrome group, there were 2 mismatches per 20 (1 adrenal gland without pathology and 1 hema- toma; PPV 90.0%). One single case of Conn’s syn- drome with coexisting hypercortisolemia turned out to be an adrenal gland without pathology. Out of 17 cases of suspected metastases 14 were con- firmed (PPV 82.4%), yet 3 actual metastases were initially classified simply as non-functioning tu- mors (sensitivity 82.4%). The origin of metastases was: lung cancer (7 cases, 41.2%), renal cancer (4, 23.5%), adenocarcinoma (site unknown; 2, 11.8%) digestive tract neoplasm (suspicion; 2, 11.8%), skin melanoma (1, 5.9%) and neoplasm of unknown or- igin (1, 5.9%). One single case of a recurrence of a tumor in a lodge of a previously removed adre- nal gland was an ACC; the pathological report from the first procedure was “borderline adenoma” and a close clinical follow-up was indicated. Out of 3 recognized ACCs, 2 were initially diagnosed as non-functioning tumors.
A high PPV signifies a high chance of confir- mation of preoperative diagnosis. Most of them were characterized by a high PPV: adrenal cyst and recurrent tumor - both 100%, Cushing’s syn- drome - 96.2%, non-functioning tumor - 93.7%, Conn’s syndrome - 90.0%, suspected metastases - 82.4%. Only pheochromocytoma had consider- ably lower PPV (only 60.0%), indicating that the remainder (40.0%) were over-diagnosed.
The lower the sensitivity, the greater was the fraction of patients with said condition that was not properly diagnosed (under-diagnosed). Sus- pected metastases had the highest value (82.4%),
| TU | Cyst | PHEO | Cushing | Conn | C + C | Meta | REC SUM | |
|---|---|---|---|---|---|---|---|---|
| ACA | 62 | 9 | 13+3s | 16 | 1 | 104 | ||
| NH | 14 | 4 | 6 | 2 | 2 | 28 | ||
| ACA/NH | 3 | 3 | ||||||
| PHEO | 10 | 21 | 31 | |||||
| AG w/o pathol. | 3 | 1 | 1 | 1 | 1 | 7 | ||
| Myelolipoma | 13 | 13 | ||||||
| Hematoma | 5 | 1 | 6 | |||||
| Cyst | 5 | 3 | 8 | |||||
| Hemangioma | 2 | 2 | ||||||
| Ganglioneuroma | 2 | 2 | ||||||
| Meta | 3 | 14 | 17 | |||||
| ACC | 2 | 1 3 | ||||||
| Lymphoma | 1 | 1 | ||||||
| Schwannoma | 1 | 1 | ||||||
| Non-diagnostic | 4 | 4 | ||||||
| SUM | 127 | 3 | 35 | 26 | 20 | 1 | 17 | 1 230 |
| TP | 119 | 3 | 21 | 25 | 18 | 0 | 14 | 1 |
| FP | 8 | 0 | 14 | 1 | 2 | 1 | 3 | 0 |
| FN | 5 | 10 | 3 | 2 | ||||
| Sensitivity | 37.5 | 67.7 | 82.4 | |||||
| PPV | 93.7 | 100 | 60.0 | 96.2 | 90.0 | 0 | 82.4 | 100 |
TU - non-functioning tumor, PHEO - pheochromocytoma, C + C - Conn’s and Cushing’s syndrome, META - metastasis, REC - recurrence of a removed tumor, AG w/o pathol. - adrenal gland without any detected pathology, TP - true positive, FP - false positive, FN - false negative, PPV - positive predictive value; diagnostic mismatches are marked by filled (grey) boxes.
followed by pheochromocytoma (67.7%), and ad- renal cyst (37.5%).
Regarding the initial (preoperative) diagnosis, there was a statistically significant difference in terms of patients’ sex (p = 0.001) - Table II. Fur- ther analysis showed that the diagnosis of Cush- ing’s syndrome was more common in females (p = 0.009) and, in turn, the diagnosis of metas- tases to adrenal glands was more common in males (p = 0.001). There was also a statistically significant difference in terms of patients’ age (p = 0.008). Patients diagnosed with Conn’s syndrome were significantly younger than those diagnosed with PHEO (p = 0.005), non-functioning tumor (p = 0.002) and recurrent tumor (p = 0.043). Pa- tients diagnosed with a recurrent tumor were also older than those diagnosed with an adrenal cyst (p = 0.045) and simultaneous Cushing’s and Conn’s syndrome (p = 0.028). Patients diagnosed with non-functioning tumor were older than those with Cushing’s syndrome (p = 0.044).
Regarding the final (postoperative) diagnosis, there was a statistically significant difference in terms of patients’ sex (p = 0.016). Metastases to adrenal glands were more common in males (p = 0.001). There was no statistically significant differ- ence in terms of patients’ age (p = 0.112).
Discussion
The majority of patients in our study were qualified for an adrenalectomy due to a non-func- tioning adrenal tumor (127/230; 55.2%). Specific indications for surgical resection included: suffi- ciently large tumor size (≥ 4 cm, associated with an increased risk of malignancy), its fast growth in consecutive imaging studies, high density in CT (not typical for a benign adenoma) or other suspi- cious CT features, such as calcifications or necro- sis - Figures 1 A and B [5, 9]. Most of the tumor in this group (116/127; 91.3%) turned out to be benign in postoperative histopathological eval-
| Parameter | Female | Male | SUM | P-value (sex) | Age | P-value (age) |
|---|---|---|---|---|---|---|
| Initial diagnosis: | 0.001 | 0.008 | ||||
| TU | 95 (74.8%) | 32 (25.2%) | 127 | n/s | 57.7 ±11.1 | |
| Cyst | 1 (33.3%) | 2 (66.7%) | 3 | n/s | 42.7 ±10.8 | |
| PHEO | 24 (68.6%) | 11 (31.4%) | 35 | n/s | 57.8 ±11.0 | |
| Cushing | 24 (92.3%) | 2 (7.7%) | 26 | 0.009 | 52.7 ±10.7 | |
| Conn | 11 (55.0%) | 9 (45.0%) | 20 | n/s | 49.7 ±11.1 | |
| Cushing and Conn | 1 (100.0%) | 0 (0.0%) | 1 | n/s | 31.0 | |
| Meta | 5 (29.4%) | 12 (70.6%) | 17 | 0.001 | 55.3 ±10.9 | |
| REC | 1 (100.0%) | 0 (0.0%) | 1 | n/s | 70.0 | |
| Final diagnosis: | 0.016 | 0.112 | ||||
| ACA | 80 (76.9%) | 24 (23.1%) | 104 | n/s | 56.7 ±11.2 | |
| NH | 18 (64.3%) | 10 (35.7%) | 28 | n/s | 56.0 ±11.0 | |
| ACA/NH | 3 1(00.0%) | 0 (0.0%) | 3 | n/s | 43.0 ±11.3 | |
| PHEO | 24 (77.4%) | 7 (22.6%) | 31 | n/s | 54.9 ±11.0 | |
| AG w/o pathol. | 6 (85.7%) | 1 (14.3%) | 7 | n/s | 54.7 ±11.0 | |
| Myelolipoma | 8 (61.5%) | 5 (38.5%) | 13 | n/s | 55.2 ±11.2 | |
| Hematoma | 5 (83.3%) | 1 (16.7%) | 6 | n/s | 62.7 ±11.1 | |
| Cyst | 5 (62.5%) | 3 (37.5%) | 8 | n/s | 51.8 ±10.9 | |
| Hemangioma | 1 (50.0%) | 1 (50.0%) | 2 | n/s | 56.5 ±10.6 | |
| Ganglioneuroma | 1 (50.0%) | 1 (50.0%) | 2 | n/s | 35.0 ±9.9 | |
| Meta | 5 (29.4%) | 12 (70.6%) | 17 | 0.001 | 57.0 ±11.0 | |
| ACC | 2 (66.7%) | 1 (33.3%) | 3 | n/s | 68.0 ±12.4 | |
| Lymphoma | 0 (0.0%) | 1 (100.0%) | 1 | n/s | 55.0 | |
| Schwannoma | 0 (0.0%) | 1 (100.0%) | 1 | n/s | 25.0 | |
| Non-diagnostic | 4 (100.0%) | 0 (0.0%) | 4 | n/s | 66.0 ±10.9 |
n/s - non-significant, TU - non-functioning tumor, PHEO - pheochromocytoma, Meta - metastasis, REC - recurrence of a removed tumor, AG w/o pathol. - adrenal gland without any detected pathology.
uation. Polish guidelines from 2002 recommend surgical removal of an adrenal tumor measuring ≥ 4 cm and such an approach was taken in most of the cases described in this paper. Yet an American algorithm (National Institute of Health, 2003) al- lows observation of such tumors, recommending adrenalectomy only for tumors ≥ 6 cm, unless oth- er radiological features of malignancy are present. This relies on data indicating that the estimated risk of malignancy is about 2% in an adrenal tu- mor < 4 cm, but rises up to 25% in lesions ≥ 6 cm [10]. Similarly, the updated Polish guidelines from 2016 recommend 5 cm to be a more suitable cut- off value, but only some portion of the studied patient group was operated on after 2016 [2]. We also detected that patients in the non-functioning
tumor group were older than those in Cushing’s or Conn’s syndrome groups (p = 0.044 and p = 0.002, respectively).
The second main indication for adrenalectomy was hypersecretion of an adrenal cortex (47/230; 20.4%). Patients qualified due to Cushing’s syn- drome were significantly more often females (p = 0.009). Patients in the Conn’s syndrome group were significantly younger than those in PHEO (p = 0.005), non-functioning tumor (p = 0.002) and recurrent tumor groups (p = 0.043). The im- portant fact in a preoperative diagnosis of Conn’s syndrome is the discontinuation of specific drugs (including ACE inhibitors, angiotensin receptors blockers, progestogens, diuretics, spironolactone and eplerenone) for up to several weeks prior to
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any hormonal workup, since these substances may alter the aldosterone-to-renin ratio (ARR) [2, 5, 10]. The final determination as to the character of an excised adrenal mass is established by a histo- pathological examination [6, 11]. The scope of pos- sible diagnoses includes at least a dozen options.
Adrenocortical adenoma (ACA) is the most frequent diagnosis (70-94%). Typically ACAs are small (less than 50 g in weight), well-separable from surrounding tissues and golden/yellow in color (Figure 1 D). Most ACAs are hormonally in- active. Among hormonally active ACAs, aldoste-
rone-producing ACAs (APAs) are more common than cortisol-producing ACAs (CPAs), while an- drogen-producing ACAs are very rare [1, 4, 7, 12]. This is in accordance with our results: there were 72 (69.2%) hormonally inactive ACAs, 16 (15.4%) APAS, 16 (15.4%) CPAs and no androgen-produc- ing ACAs.
Another form of hormonally active adrenocorti- cal growth is nodular hyperplasia (NH). In our ob- servation there were 20 (71.4%) non-functioning NHs, 6 (21.4%) causing Cushing’s syndrome and 2 (7.1%) causing Conn’s syndrome [13]. In 3 cases discrimination between ACA and NH was impossi- ble due to fragmentation of a specimen.
In a group referred to as non-functioning tu- mors, the third most commonly recognized pa- thology was myelolipoma (13 cases, 10.2%). This was similar to the results of Al Harthi et al., who estimated the detection of this pathology to be 7% of adrenal incidentalomas. To date it remains unknown how this kind of tumor actually de- velops. It is usually a small, asymptomatic and non-functional lesion, a benign neoplasm contain- ing mature adipose tissue and hemopoietic ele- ments (but not producing actual blood cells) [14].
PHEO is usually a benign, sporadic, catechol- amine-producing adrenal tumor. However, in about 9-23% of cases (and even more in children) it develops in extraadrenal tissues close to sympa- thetic ganglia (so-called paraganglioma). Also up to 25% of patients may present with the hered- itary form of PHEO (e.g. in the course of multiple endocrine neoplasia type 2 (MEN-2) or von Hip- pel-Lindau (VHL) syndrome), with a tendency for extraadrenal and multifocal tumors. Additionally, in up to 26-35% of cases it is malignant, and at the time of diagnosis, about 10% of patients with PHEO present with a metastatic (disseminated) disease [15]. This is in opposition to our findings, as we did not observe a single case of malignant PHEO. Perhaps such patients were referred to oth- er departments for surgical treatment. According to Myśliwiec et al., biochemical diagnosis of PHEO is associated with a significant percentage of false positive (FP) results, reaching 33%. We can fully substantiate that statement, as in our observation PHEO had the lowest PPV (60.0%), making the re- maining 40.0% of cases FP (over-diagnosed). Such a high amount of FP diagnoses may result from various possible distractions in the diagnostic pro- cess. Diverse substances, including meals (banan- as, chocolate, cocoa, citrus fruits, vanillin), drinks (coffee, tea), drugs (e.g. a- and ß-blockers, sym- pathicomimetics, calcium channels antagonists, aminophylline, disulfiram, L-DOPA, methyldopa, insulin, tetracycline, erythromycin) and narcotics (cocaine, amphetamine, (pseudo)ephedrine) may artificially elevate levels of urinary metaneph-
rines and should definitely be discontinued before performing such diagnostics. The next reason for overdiagnosis may be a routine evaluation of uri- nary 24-hour metanephrines only and not plas- ma free metanephrines in a suspicion of PHEO. Testing for plasma metanephrine levels is slightly more sensitive and specific, yet it is also more ex- pensive and less available; therefore the urinary metanephrines remain the most commonly per- formed test. Moreover, the test for plasma meta- nephrines became available just a few years ago and our research dates back before this time. The diagnosis of PHEO should also be supported by imaging studies - in a CT PHEO exhibits a non-ad- enoma pattern (higher density: > 10 HU, usually > 30 HU, compared to < 10 HU for adenoma) [2, 10, 16]. One last issue here is the human factor, that is the fear of omission (under-diagnosis) of PHEO. Since it may be associated with serious complications, physicians are anxious about over- looking a single case of PHEO and may be prone to rather exaggeratedly qualify a patient for an operation than to risk letting go a dubious case.
Adrenal cysts are diagnosed in about 5-8% of incidentalomas, usually unilaterally (> 80%) and more commonly in females - as was the case in our observations (5 females and 3 males). Sever- al types of cysts can be distinguished, including endothelial (congenital or retentive, hemangio- mas and lymphangiomas), epithelial (associated with a parasitic infection) and pseudocysts (usu- ally resulting from a hemorrhage or necrosis). Some fraction of lesions classified as hemorrhag- ic pseudocysts may originate from an angioma, which structure has been destroyed by an internal hemorrhage. Adrenal cysts are associated with about 7% risk of malignancy [17, 18]. In our study a diagnosis of an adrenal cyst had a perfect PPV (100%), yet a relatively poor sensitivity (37.5%), indicating that most of these lesions are initially recognized as solid non-functioning tumors.
Ganglioneuroma is a rare, benign, and typically asymptomatic tumor of the autonomic nerve fi- bers (consisting of ganglion cells, Schwann cells and fibrous tissue). Apart from adrenal glands, it may be found within the retroperitoneal space, posterior mediastinum, head and neck. Macro- scopically it is usually a firm, solid, white tumor (Figure 1 E). Only symptomatic cases require sur- gical treatment. We had 2 ganglioneuromas in our observation, both initially diagnosed as non-func- tioning adrenal masses.
Adrenal glands are common sites of metasta- ses from various malignancies of other locations. In about 0.2% of cases an adrenal incidentaloma turns out to be the only manifestation of a pre- viously undiagnosed cancer. If an extra-adrenal malignancy is present, the risk of a co-existing
adrenal tumor being malignant increases from 0.1% to 50-75% [7]. According to the literature, the most common sources of metastases to ad- renal glands are: lung, renal, breast, gastrointes- tinal tract (gastric, colorectal) and liver cancers (hepatocellular carcinoma - HCC) as well as skin melanoma [19]. We observed similar proportions, as the source of most metastases was lung can- cer (7; 41.2%), followed by renal cancer (4; 23.5%; Figure 1 C), adenocarcinoma (site unknown; 2; 11.8%) digestive tract neoplasm (2; 11.8%), skin melanoma (1; 5.9%) and a neoplasm of unknown origin (1; 5.9%). In our observation the metastasis group had a high PPV as well as sensitivity (both 82.4%). We also detected that metastases were diagnosed predominantly in males, both pre- and postoperatively (both p = 0.001). Taking into ac- count that the most common sources of metas- tases are lung and renal cancer, which are more prevalent in males, this seems justified. Metastat- ic adrenal tumors may reach especially large di- mensions, such as those of lung cancer presented in Figure 1 F, measuring 10 and 11 cm (compara- ble to the removed spleen).
ACC is a malignant neoplasm originating from an adrenal cortex. It is found mostly in older fe- males, as we observed (2 females vs. 1 male; mean age 68.0 ±12.4). Despite its rarity (inci- dence 0.5-2/million/year), ACC is an aggressive neoplasm, lacking early symptoms and therefore often diagnosed at an advanced stage and asso- ciated with a poor prognosis. More than half of patients (43-69%, mean 54%) present with stage III/IV and almost half of them (38-40%) have metastases; therefore the overall 5-year survival ranges between only 16 and 44% (mean: 30%) [7]. In our study 2 ACCs were found in the non-func- tioning tumor group (constituting 1.6% of this group) and 1 was initially diagnosed as a recurrent adrenal tumor (100% of this group). The regrowth of a previously resected adrenal tumor should al- ways raise a suspicion of a malign neoplasm.
To sum up, the advantage of our study is a pre- sentable group of examined patients and speci- mens (214 and 230, respectively), since adrenal- ectomy is not routinely performed in local primary care surgical centers and such material is not easy to obtain. On the other hand, the limitation of our study is both the retrospective design and a sig- nificant time period of observation (2004-2018), during which much has changed in the area of qualifications as well as surgical approach to ad- renalectomy.
In conclusion, the majority of diagnoses of ad- renal tumors are characterized by both high PPV and sensitivity. Yet PHEO is characterized by both much lower PPV and sensitivity (60.0% and 67.7%, respectively), indicating that many cases are ei- ther over- or under-diagnosed, and closer preoper-
ative diagnostics are necessary to improve these rates. Meticulous preparation of a patient for hor- monal tests, including discontinuation of certain medications, is essential for obtaining accurate results. The diagnosis of an adrenal cyst is always confirmed postoperatively (PPV 100%), but some masses initially recognized as solid tumors also turn out to be cysts (sensitivity: 37.5%). Patients qualified for an adrenalectomy due to Cushing’s syndrome are significantly more often females (p = 0.009), while those with metastases (diag- nosed both pre- and postoperatively) are more of- ten males (both p = 0.001). Patients qualified due to non-functioning tumors are older than those with Cushing’s or Conn’s syndrome (p = 0.044 and p = 0.002, respectively). Adrenocortical carcinoma may initially be diagnosed as a non-functioning tumor (1.6% of such cases) or a recurrence of a previously resected tumor, which should always raise a suspicion of a malignant neoplasm.
Conflict of interest
The authors declare no conflict of interest.
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