Laparoscopic Trans-Abdominal Right Adrenalectomy for a Large Primitive Adrenal Oncocytic Carcinoma: A Case Report and Review of Literature

Background

Oncocytic neoplasms (ONs), or oncocytomas, are tumors that are mainly composed of oncocytic cells. Oncocytic cells were described for the first time by Hamperl in 1931 as large, highly eosinophilic, granular cells with pyknotic nucleus, typically associated with a Hurtle cell tumor of the thyroid gland [1,2]. The cytoplasmic granularity is characterized by a striking accumulation of mitochondria, as demonstrated through electron microscopy in 1986, that can occupy up to 60% of the cytoplasm volume [3,4]. ONs arise in various organs, including kidney, thyroid, pancreas, parathyroid, salivary, lacrimal, pituitary glands, paraganglia, respiratory tract, paranasal sinuses, pleura, liver, pancreatobiliary system, stomach, colon, rectum, central nervous system, female and male genital tracts, skin, and soft tissues [5–21]. ONs arising from adrenal glands are extremely rare and were first described by Kakimoto et al. in 1986 [22]. Adrenocortical oncocytic neoplasms (AONs) are usually observed to be non-functional and mostly benign tumors. AONs are classified as: oncocytoma (AO), oncocytic neoplasm of uncertain malignant potential (AONUMP), and oncocytic carcinoma (AOC) [23]. Since the first description, a total of 162 cases of AONs have been reported, with 30 cases described as AOC [23,24]. Tumor size is considered to be a practical sign to differentiate benign from malign disease in adrenocortical carcinomas (diameter <4–5 cm suggests a benign mass). However, in case of AONs, the size of the mass and the imaging findings (through abdominal CT scan and MRI) are not pathognomonic or related to malignancy [24]. Because AONs are non-functional, differential diagnosis should be done with indeterminate adrenal tumors (incidentalomas). AONs are usually detected as a large mass with an average diameter of 8 cm (range 2–20 cm) [25]. Adrenalectomy is the treatment of choice for AONs. Surgical approaches to adrenal gland include laparotomy, combined thoraco-abdominal access, retroperitoneal posterior access, laparoscopy, and robotic surgery [27]. Since the first successfully laparoscopic adrenalectomy (LA) performed by Gagner in 1991 [28], the lateral trans-abdominal approach has become the most common therapeutic strategy for adrenal neoplasms [29–34]. To the best of our knowledge, this is the first case report of laparoscopic lateral trans-abdominal adrenalectomy for a large AOC (12 cm) (Supplementary Video 1).

Case Report

A 48-year-old man was admitted to our Surgical Department for a primitive 12-cm mass affecting the right adrenal gland. The mass was detected by abdominal ultrasound during annual follow-up for liver cirrhosis (Child-Turcotte-Pugh score A). The patient was submitted to contrast-enhanced abdominal CT scan in our hospital (Figure 1) and contrast-enhanced abdominal MRI in another institute with evidence of a capsulated solid adrenal mass (diameters: 120×95×110 mm) with an irregular vascularization pattern, compressing the inferior vena cava, and dislocating the right lobe of the liver. A cleavage plane between the liver and the right kidney was evident with no lymphonodal or any other intra-abdominal neoplastic involvement. Preoperative laboratory tests (including cortisol, 17-ketosteroids, and 17-hydrocorticosteroids serum levels), dexamethasone test, complete blood count test results, and renal function were all normal, while liver enzyme levels were mildly elevated. The patient was a non-smoker, chronic alcohol abuser (1–2 bottles of wine per day). No endocrinopathy sign or symptoms were identified. Therefore, a non-functional adrenal mass was diagnosed, but no preoperative US- or CT-guided fine-needle aspiration cytology was performed because of the wide size of the mass, which made surgery mandatory. Considering the presence of a clear cleavage plane between the adrenal lesion and the liver, the kidney, and the surrounding vascular structures, and the absence of evident lymphonodal or other visceral involvement, a laparoscopic approach was attempted. In fact, despite the size of the lesion, no signs of malignancy or infiltration were found preoperatively, thus making the laparoscopic approach laborious but feasible and oncologically radical in skilled hands. The patient underwent lateral trans-abdominal laparoscopic right adrenalectomy with a standard 4-trocars technique in left lateral decubitus position. During the operation, the IVC was easily dissociated from the lesion, and en-bloc right adrenalectomy was completed with no capsule rupture. Extraction was performed in toto. No major bleeding and no major intraoperative complications were encountered. The patient remained hemodynamically stable during the procedure. The postoperative course was uneventful and the patient was discharged on the 5th postoperative day in good condition. Macroscopic examination of the specimen revealed a solid mass, measuring 123×98×113 mm, weighting 300 g, with several necrotic areas. Microscopic examination reported a primitive oncocytic adrenal carcinoma (Figure 2). Several atypical mitotic figures and high mitotic index (10/50 HPFs) were observed, together with diffuse pattern of growth and venous invasion. The patient’s Weiss score was 5 and, according to modified Weiss score, the patient had an AOC. The tumor cells were immunopositive for vimentin and presented typical oncocytic architecture. KI-67 and MIB1 rate was 20%. The patient was not eligible for therapy with mitotane (RS)-1-chloro-2-[2,2-dichloro-1-(4-chlorophenyl)-ethyl]-benzene due to the chronic liver disease. He was submitted to follow-up with an abdominal CT scan performed every 6 months for the first year and once during the second year. No recurrence was evidenced during 24-month follow-up.

Discussion

Adrenocortical carcinoma (AC) is a rare and aggressive tumor of the adrenal cortex that accounts for 0.2% of all malignancies (prevalence 1–2 cases per million) [35]. AONs are an extremely rare subtype of AC, with 162 cases reported in the literature since the first description in 1986 [18]. AONs are usually incidental [36–41] with only 17% cases described as functional [42]. AONs do not have a precise peak incidence, with a mean age at diagnose of 47 years (range 27–72 years) [25]. AONs occurs more frequently in females (F/M: 2.5/1) and on the left side (L/R: 3.5/1) [25]. AONs are located in the adrenal cortex, with only 1 case reported within the adrenal medulla and 1 within heterotopic adrenal tissue [43,44]. To date, no specific risk factors have been identified and the pathogenesis of oncocytosis is still unclear. Krech et al. [45] demonstrated the role of N-nitrosomorpholine, an airborne contaminant, as a chemical inducer of oncocytosis in renal tissue of Sprague-Dawley rats, managing to generate an in vivo model resembling human oncocytoma. However, no further experimental studies have been reported using this rat model. Oncocytes have characteristic severe mitochondrial anomalies: mitochondria are numerous with an excess of cristae mitochondriales. The shape varies from round and oval to extremely elongated, slender, or cup-shaped, often piled up to form complex bodies; mitochondria can rarely form large ramifying organelles [45]. Some authors reported a role of mitochondrial genome mutation in oncocytosis pathogenesis [46,47]. Duregon et al. analyzed the presence of the mtDNA 4977 bp “common deletion”, present in 50% of AOCs, as a potential pathogenetic interest, but to date, it has no practical diagnostic value [47]. Macroscopically, AOCs are large, rounded, encapsulated, brown-yellow, and well-circumscribed masses with an average diameter of 8 cm (range 2–20 cm) and a thin rim of normal adrenal gland. The mean AOCs weight is 281 g (range 8–865 g) [48]. Microscopically, AOCs can appear with solid, trabecular, tubular, or papillary patterns. AOCs are characterized by: diffuse proliferation of polygonal cells with abundant granular and eosinophilic cytoplasm, large nuclei and prominent nucleoli, occasional mono-nuclear and binucleated giant cells, extracapsular extension with blood vessel invasion and necrosis, and variable atypia and mitotic figures [49]. The immunophenotypic profile of AONs is diffuse positivity for vimentin, melan-A, synaptophysin, and alpha-inhibin [50–52]. AONs are classified as oncocytoma (AO), oncocytic neoplasm of uncertain malignant potential (AONUMP) [48], and oncocytic carcinoma (AOC) [19,53–56]. The Weiss Criteria are considered the standard tool for diagnosis of AC [57]. This system considers 9 criteria (nuclear grade III–IV; mitotic rate >5/50 HPFs; atypical mitotic figures; eosinophilic tumor cell cytoplasm (>75% of tumor cells); diffuse architecture (>33% of tumor); necrosis; venous invasion, sinusoidal and capsular invasion) (Table 1). A 1-point score is given to each parameter. Malignancy can be suspected when 4 or more of the 9 criteria are met. However, care should be taken in applying these criteria during pathological evaluation of the rare and peculiar AOC. Bisceglia et al. proposed a review of the Weiss Criteria, proposing major and minor criteria for AOC diagnosis (Table 2) [58]. AOC is characterized by the presence of 1 of the following 3 (major criteria): mitotic rate >5/50 HPF, atypical mitotic figures, and/or venous invasion. AONUMP is characterized by at least 1 of the following 4 (minor criteria): size >10 cm and/or weight >200 mg, necrosis, capsular invasion, and/or sinusoidal invasion. AO is characterized by the absence of both major and minor criteria. Several molecular and biological studies have been performed on AC to characterize the malignancy and establish new ocnological parameters [59–64]. However, no established premalignant condition has been documented in the human adrenal cortex and no adrenocortical adenoma to AC transition has been described. Furthermore, there are very few cases of AOC described in the literature, with few molecular studies. In addition, ACs are markedly heterogeneous morphologically and functionally, even within the same tumor [65]. Among several molecular and/or cytological markers that may contribute to the differential diagnosis of adrenocortical carcinoma, the cell proliferation markers, such as Ki-67 and topoisomerase, and oncoprotein p53, can be of most value [59–64,66–69]. Unfortunately, the role of either Ki-67 or p53 as biomarkers remains uncertain due to the availability of so few of these tumors [70,71]. However, according to Mearini et al., MIB1 and Ki- 67 are of practical value in order to achieve a differential diagnosis between benign mass and adenocarcinoma [25].

The size and the function of the lesion are considered the most important factors in the diagnosis of an adrenal mass. In a report on 887 patients who had adrenal incidentalomas, a diameter greater than 4 cm was shown to have a 90% sensitivity for the detection of AC, but a low specificity (only 24% of the lesions were malignant) [72]. Increase in size over time is another indication for surgery. Generally, resection is recommended for adrenal masses > 6 cm. Biochemical analyses should be undertaken to rule out the presence of a primary functioning mass, which requires resection despite the size.

Imaging has a major role during differential diagnosis between AC, included AONs, from adrenal adenomas. Fat concentration may be used as a tool to differentiate between benign and malignant adrenal lesions: with the first being lipid-rich. The CT criteria for the diagnosis of adrenal adenoma are unenhanced attenuation of 10 or fewer HUs [73] and absence of necrotic or cystic areas, which can be seen in some malignant lesions and adrenal cysts [74]. However, it has not been demonstrated to be a characteristic imaging for AON; therefore, CT imaging findings are generally nonspecific [75–77]. MRI with chemical shift subtraction [78] provides a high confidence level in distinguishing adrenal adenomas from other disease [79,80]. However, MRI is considered not specific for AON detection [81].

Although the use of contrast-enhanced ultrasound has shown an excellent sensitivity and specificity in the differential diagnosis between benign and malignant adrenal mass, no typical pattern has been described for AONs [82].

Fine-needle aspiration cytology and open biopsy are helpful during perioperative diagnosis of AC; however, they are not able to specifically characterize and define AONs [83,84].

Adrenalectomy is the treatment of choice for AON. Different surgical approaches are available to treat adrenal masses. The surgical approach choice depends on several parameters: tumor size, malignancy, patient condition, and surgical experience [85]. The surgical approach to adrenal gland includes laparotomy, combined thoraco-abdominal access, retroperitoneal posterior access, laparoscopy, and robotic surgery [86]. Since the first successfully laparoscopic adrenalectomy (LA) performed by Gagner in 1991 [28], the lateral trans-abdominal approach has become the most common therapeutic strategy for adrenal neoplasm [28–34]. LA is associated with lower postoperative pain, reduced ileus, shorter hospitalization, earlier return to work, and a better cosmetic result, guarantying a lower morbidity (5–20%) and mortality rate (below 0.5%) compared to open adrenalectomy [25,31,34]. In contrast, open adrenalectomy is associated with higher mortality (2–4%) and morbidity rates (bleeding, pulmonary and cardiac complications, pulmonary thromboembolism, and wound infections) and is reserved worldwide only for large tumors (diameter >6 cm) and primary malignancies, based on the radicality of resection, minor tumor local recurrence, and major survival [27,87,88]. The mainstay of the surgical procedure is to perform a complete resection of the adrenal gland without disruption of the adrenal capsule. Therefore, the presence of capsular or vascular invasion, infiltration of surrounding tissues, and lymphonodal involvement represent the major contraindications to LA. Several different laparoscopic techniques have been proposed and are currently used for the resection of adrenal tumors [27]. Each technique has its own advantages and disadvantages. Lateral trans-abdominal adrenalectomy (LTA) is the most common adrenalectomy technique used by general surgeons. Compared with the retroperitoneal approach, LTA provides more working space, which can be beneficial for large tumors and morbidly obese patients. In addition, the lateral decubitus position used during this approach enables excellent exposure of the adrenal gland because of the effect of gravity on the abdominal organs. Posterior retroperitoneoscopic adrenalectomy (PRA) [27] is characterized by enhanced visualization following the use of higher insufflation pressures in the retroperitoneal cavity, as well as direct access to the adrenal gland (avoiding the intra-abdominal cavity), making it attractive in case of prior abdominal surgery. Additionally, the prone position facilitates equal access to the right and left sides, allowing bilateral procedures without the need for patient intra-operative repositioning. The disadvantages include lack of access to the intra-abdominal cavity for evaluation, difficult removal of large tumors, and increased difficulty with increasing body mass index (BMI). Anterior trans-abdominal adrenalectomy [27] is a sub-mesocolic approach and is the least common technique used for adrenalectomy; its main appeal is the conventional abdominal laparoscopic view, familiar to all general surgeons. However, the operating times are generally longer, and more ports are needed for a successful operation. Lateral retroperitoneoscopic adrenalectomy (LPA) [27] is the most common technique used by urologic surgeons for adrenalectomy, likely due to their familiarity with the anatomy of laparoscopic nephrectomy. Similar to PRA, LPA is advocated for patients with prior abdominal surgery.

AONs are very rare lesions, with 162 reported cases in the literature and only 30 cases reported as AOCs. To the best of our knowledge, this is the first reported case of laparoscopic adrenalectomy for a voluminous AOC (120×95×110 mm). Following CT and MRI imaging, a well-encapsulated tumor, with no evidence of invasion of the surrounding tissues and no regional adenopathy, was detected. In our case, laparoscopic approach with 4-trocar placement was chosen. The patient was positioned in left lateral decubitus position at a 60° angle. The table was flexed for space widening between the 12th rib and the iliac crest. Four ports were used. The procedural steps included: mobilization of the right triangular ligament of the liver, incision between the retroperitoneal attachments of the right hepatic lobe and the lateral border of the inferior vena cava (IVC), dissection of the lateral edge of the IVC, and taking of the right adrenal vein at the takeoff from the IVC. Mobilization of the gland was performed with an inferior-to-superior and medial-to-lateral approach. The surgical procedure was safe and effective and the postoperative period was uneventful. The 24-month follow up was negative for disease recurrence. Macroscopic examination of the specimen revealed a solid mass weighting 300 g, with several necrotic areas. Microscopic examination showed a primitive oncocytic adrenal carcinoma. Several atypical mitotic figures and high mitotic index (10/50 HPFs) were observed, together with diffuse pattern of growth and venous invasion. The specimen was evaluated with a final Weiss score of 5 (necrosis, high mitotic rate >5/50 HPF, atypical mitotic figures, diffuse architecture, and venous invasion). According to modified Weiss score, an AOC was diagnosed (mitotic rate >5/50 HPF, atypical mitotic figures, and venous invasion). The tumor cells were immunopositive for vimentin and presented typical oncocytic architecture. In our case, the neoplastic cells had a KI-67 and MIB1 rate of 20%.

In 2013, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) presented guidelines for minimally invasive treatment of adrenal pathology [27]. However, these guidelines are limited to a retrospective analysis of published case series, with no specificity for AONs. In our case, we performed an effective laparoscopic approach to a voluminous AOC, with 24-month follow-up negative for recurrence. In light of our result, a prospective multicentric observational study should be performed to better define the aims and limits of minimally invasive surgery for AON. Due to the scarcity of cases, it is difficult to establish precise guidelines on the management of adrenal oncocytic neoplasms. Our case report is fully compliant with SCARE criteria [89].

Conclusions

Adrenocortical oncocytic tumors must be taken into account in the differential diagnosis of adrenal masses due to their different prognosis compared to non-oncocytic tumors. Adrenocortical oncocytic carcinoma are a rare presentation of AONs. Only 30 cases are described in the literature. Laparotomic adrenalectomy is the treatment of choice for AOC. We report the first case of laparoscopic lateral trans-abdominal adrenalectomy for AOC, despite the large size of the mass (120×95×110 mm). Laparoscopy performed by an experienced surgeon is safe and effective for AOC. Despite the rarity of AOC, a case series should be performed to confirm the results of our case report.