ELSEVIER
Annals of Diagnostic Pathology
journal homepage: www.elsevier.com/locate/anndiagpath
Annals of DIAGNOSTIC PATHOLOGY
Three cases of adrenocortical tumors mistaken for hepatocellular carcinomas/diagnostic pitfalls and differential diagnosis
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Won Young Parka,c,1, Hyung Il Seob,c,1, Kyung Un Choia,C, Ahrong Kima,C, Young Keum Kima,c, So Jeong Leea,C, Chang Hun Leea,c, Gi Yeong Huha,c, Do Youn Parka,c,*
a Department of Pathology, Pusan National University Hospital and Pusan National University School of Medicine, Busan, Republic of Korea
b Department of Surgery, Pusan National University Hospital and Pusan National University School of Medicine, Busan, Republic of Korea
” BioMedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
ABSTRACT
Adrenocortical adenomas and carcinomas in other parenchyma are extremely rare, with few cases reported and because of the rarity of these tumors, they occasionally cause problems during diagnosis. Adrenal cortical neoplasms in liver parenchyma can be present in 3 forms, including direct invasion or adhesion to liver parenchyma, tumors arising in adrenohepatic fusion tissue or in ectopic adrenal gland tissue. We report 3 cases of adrenal cortical tumors that were misdiagnosed as hepatocellular carcinoma in the preoperative state. The first case involved an adrenocortical adenoma arising in adrenohepatic fusion tissue. The remaining 2 cases involved an adrenocortical carcinoma and an adrenocortical oncocytoma arising in ectopic adrenal tissue in the liver. We describe the clinical presentations, gross, microscopic findings, immunohistochemical findings with respect to each case, with emphasis on differential diagnosis from hepatocellular carcinoma.
1. Introduction
Ectopic adrenal cortical tissue is not uncommon. According to Anderson and McLean Ross ectopic adrenal tissue is found in 50% of neonates and children and 1% of adults [1]. Ectopic adrenal tissue has been reported to be found in numerous locations, with the most common site being the retroperitoneal fat close to the adrenal gland. It has also been found in close proximity to the sex organs because of the spatial relationship between the adrenal primordium and the genital ridge in early embryogenesis [2]. Accessory adrenal tissue can be incorporated into adjacent organs as a result of the incomplete separation of cortical adrenal cells from the coelomic mesothelium, and this is often termed adrenal heterotopias. Further developmental abnormalities of the adrenal gland include renoadrenal and renohepatic fusion [3]. Occasionally these ectopic adrenals give rise to hyperplasia or neoplasia [4,5]. A dynamic contrast-enhanced computed tomogra- phy (CT) scan indicating adrenal adenoma is highly similar to a CT scan showing hepatocellular carcinoma (HCC), which contains a fatty component, arterial phase enhancement, and washout in delayed phase. Therefore, intrahepatic ectopic adrenal neoplasms are often misdiagnosed as HCCs. The 3 cases presented herein are adrenal tumors
closely related to hepatic tissue and had been misinterpreted to be HCC at the preoperative state.
2. Materials and methods
Three cases comprised of 3 surgically resected specimens and 1 needle biopsy specimen from Pusan National University Hospital in 2011 (case 1), and 2013 (case 2 and case 3). A review of patients’ medical records and histological slides was performed and their clinical information is summarized in Table 1. Four to 9 blocks were obtained from resection specimens and hematoxylin and eosin staining was performed. For the purpose of differential diagnosis and to validate that these lesions were adrenal tumors, we performed immunohistochemical staining for alpha-fetoprotein (AFP), hepatocyte specific antigen (HSA), CD34, glypican-3, synaptophysin, alpha-inhibin, and melan-A. Immu- nohistochemical staining for these anti-bodies were performed on formalin-fixed paraffin embedded 5-um-thick sections on the fully automated Bond Max automatic slide stainer (Leica Biosystem) using onboard heat-induced antigen retrieval in Bond epitope retrieval agent solution 1 and 2 (Leica Biosystem) for 20 min and DAB refine polymer detection system (Leica Biosystem). The information on each antibody
* Corresponding author at: Department of Pathology, Pusan National University Hospital and Pusan National University School of Medicine, 1-10 Ami-Dong, Seo-Gu, Busan 602-739, Republic of Korea.
E-mail address: pdy220@pusan.ac.kr (D.Y. Park).
1 Won Young Park and Hyung Il Seo equally contributed in this study.
http://dx.doi.org/10.1016/j.anndiagpath.2017.05.016
| Case 1 | Case 2 | Case 3 | |
|---|---|---|---|
| Age/Sex | 56/F | 75/M | 64/F |
| Symptom | Dyspepsia | None | None |
| Diabetes mellitus | − | − | + |
| Hypertension | − | + | + |
| HBs Ag/Ab | - | -/+ | |
| HBc Ab | + | + | + |
| AFP | 1.96 | 4.85 | 2.92 |
| PIVKA-II | 23 | 22 | 22 |
| Biopsy | None | None | Yes (hepatocellular carcinoma) |
HBs Ag/Ab, hepatitis B surface antigen/antibody; HBc Ab, hepatitis B core antibody; AFP: alpha-fetoprotein.
| Antibody | Manufacture | Source | Concentration | Positive control |
|---|---|---|---|---|
| AFP | Dako | Polyclonal rabbit | 1:500 | Hepatocellular carcinoma |
| HSA | Dako | Monoclonal mouse | 1:30 | Liver |
| CD34 | Dako | Monoclonal mouse | 1:200 | Tonsil |
| Glypican-3 | Cell marque | Monoclonal mouse | 1:100 | Hepatocellular carcinoma |
| Synaptophysin | Novocastra | Monoclonal rabbit | 1:250 | Pancreas |
| Alpha-inhibin | Dako | Monoclonal mouse | 1:100 | Testis |
| Melan-A | Novocastra | Monoclonal mouse | 1:50 | Melanoma |
AFP: alpha-fetoprotein; HSA: hepatocyte specific antigen.
is summarized in Table 2.
3. Results
3.1. Case 1
A 56-year-old-woman with an unremarkable medical history visited the local clinic after having experienced dyspepsia. An abdominal CT scan was performed and a 3.4-cm hepatic mass was identified. The patient was transferred to Pusan National University Hospital for further evaluation and surgery in December 2011. A repeat abdominal CT scan showed a 3.4-cm low attenuation hepatic mass with peripheral rim enhancement in segment 6 (Fig. 1A). Magnetic resonance imaging (MRI) of the liver showed a well enhanced mass with washout pattern at delayed phase. The radiological diagnosis at the time of interpreta- tion was hepatocellular carcinoma, however there was no evidence of liver cirrhosis. In addition, the patient had no history of viral hepatitis and laboratory tests for the hepatitis B and hepatitis C viruses yielded negative results. Serum AFP, carbohydrate antigen 19-9, and carci- noembryonic antigen were within the normal range. A right posterior segmentectomy was performed. Upon gross examination, the hepatic mass (3.2 * 3.1 * 2.5 cm) was bright yellow, solid, well circumscribed and showed nodular growth. Microscopic examination showed that, the mass consisted of sheets or vague nodules of tumor cells, with abundant, granular, oncocytic cytoplasm and centrally located round nuclei. Nucleoli were inconspicuous (Fig. 1B). In the periphery of the tumor, residual normal adrenal cortex and fibrous capsule was identi- fied which was continuous with the hepatic capsule (Fig. 1C).
This case was confirmed to be an oncocytic adrenal cortical adenoma (oncocytoma) arising from ectopic adrenal cortex in the liver. Immunohistochemically, the oncocytic tumor cells were positive for
alpha-inhibin, melan-A, and synaptophysin (Fig. 1D). The patient returned to the hospital in May 2012 and a follow up abdominal CT scan showed no evidence of local recurrence or significant lymphade- nopathy. The patient was diagnosed with lung cancer in September 2015 and is currently still undergoing treatment.
3.2. Case 2
A 75-year-old man with gallstones visited the local clinic. The patient had a history of heavy consumption of alcohol and eating raw fresh water fish. An ultrasonography was performed, and a hepatic mass with background of fatty liver was newly identified. The patient was transferred to Pusan National University Hospital in December 2012. A large hepatic mass in segments 6 to 7 was identified by CT scans. The mass was protruding into the abdominal cavity, and was attached to the right adrenal gland. An abdominal CT scan showed an arterially enhancing and delayed washout lesion with mosaic architec- ture and capsule, which is consistent with simple nodular type hepatocellular carcinoma (Fig. 2A). A posterior segmentectomy with cholecystectomy was performed in February 2013. The segmentectomy specimen revealed a well-defined, encapsulated solid mass (6.0 * 4.5 cm) in the subcapsular area. The cut surface of the mass was multi- nodular and had a confluent growth pattern (Fig. 2B), and was abutting the hepatic capsule and resection margin. At scanning magnification, tumor cells were arranged in solid sheets and cords. Furthermore, necrosis was evident, and tumor cells had abundant eosinophilic cytoplasm and a large nucleus with conspicuous nucleoli. There was occasional nuclear hyperchromasia and moderate cellular pleomorph- ism (Fig. 2C). The number of mitotic figures was 1-2 in 50 high power fields; atypical forms were identified. A tumor capsule was detected microscopically. Tumor cells were invading the capsule and hepatic parenchyma, and vascular invasion was also observed (Fig. 2D). Tumor cells demonstrated positive immunohistochemical staining for alpha- inhibin and melan-A, and negative staining for epithelial membrane antigen, S-100 protein, chromogranin, and HSA. The pathological diagnosis was adrenal cortical carcinoma. Remaining uninvolved adrenal tissue was identified and which supported the diagnosis. The patient did not undergo any additional chemotherapy. The patient revisited the hospital monthly after surgery until January 2015. During that period there was no evidence of disease recurrence or progression.
3.3. Case 3
A 64-year-old woman with a medical history of pulmonary tuber- culosis was admitted to Pusan National University Hospital with a urinary infection complicated by a renal abscess. An abdominal CT scanning identified a 2.2 cm hepatic mass in segment 6 that was abutting on the right adrenal gland (Fig. 3A). The radiological impression was hepatocellular carcinoma or adrenal adenoma arising from adrenohepatic fusion tissue. A percutaneous needle biopsy of the mass was conducted in November 2012, and the biopsy specimen showed tumor cells arranged in trabeculae with moderate nuclear atypia, eosinophilic and clear cytoplasm in the background with macro- fatty change of hepatocytes (Fig. 3B). Immunohistochemical staining for alpha-fetoprotein yielded negative result, however, tumor cells showed diffuse granular cytoplasmic staining for glypican (Fig. 3C). CD34 staining showed a well-visualized sinusoidal pattern. The histo- logical diagnosis at that time was hepatocellular carcinoma, and a hepatectomy was planned. The patient received surgery in January 2013, and in surgery, the mass appeared to be an adrenal mass that was attached to the liver capsule rather than a hepatic mass. An intrao- perative frozen section was obtained, and based on the operative finding, a frozen section diagnosis of adrenal adenoma was confirmed. Subsequently, a right adrenalectomy was performed. On gross exam- ination, the mass was encapsulated and had a golden yellow cut surface with multiple dark brown foci. Microscopic findings showed that, the
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mass consisted of sheets of tumor cells that had abundant clear and eosinophile cytoplasm. Occasionally cytoplasmic brownish pigmenta- tion was observed. Furthermore, the nuclei of tumor cells showed mild pleomorphism, and enlarged and hyperchromatic nuclei were fre- quently detected. Nucleoli were also evident in a number of tumor cells. Mitosis including atypical mitosis was not detected. Tumor cells were positive for synaptophysin, melan-A, and inhibin and were focally positive for glypican-3 (Fig. 3D). The tumor was confirmed to be an
adrenal adenoma arising from the adrenohepatic fusion tissue. The patient’s postoperative course was complicated by adrenal insuffi- ciency. The patient has been followed up in endocrine medicine without recurrence until March 2017.
4. Discussion
Ectopic adrenal cortical tissue in neonatal liver was first described
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by Vestfrid in 1980. The possible mechanism involved in the ectopia has been discussed as has its potential relevance with respect to neoplastic change [6]. Honma [7] reported that adrenohepatic fusion is a common incidental finding, observed in 9.9% of 636 autopsy studies. The developmental mechanism underlying adrenohepatic fusion has been proposed to be a differentiation failure of the intervening fat tissue between the two organs [8]; however, an increased incidence of adrenohepatic fusion detected in the autopsies of elderly patients suggests that adrenohepatic fusion may be an acquired age-related phenomenon [7].
There are several reports concerning cases of adenoma arising in adenohepatic fusion tissue [9,10] as well as those regarding ectopic adrenal adenoma within the liver [11,12].
Our first case is unique because of its ectopic adrenal gland origin and oncocytic nature. Adrenocortical oncocytomas are a rare morpho- logic variant of adenomas that are mostly asymptomatic, non-function- ing and typically benign. Therefore it is important to diagnose ectopic adrenal tissue and its neoplasm by use of a non-invasive method to avoid unnecessary surgery. Adrenal oncocytoma is morphologically similar to hepatocellular carcinoma as a result of its trabecular pattern with sinusoids, eosinophilic granular cytoplasm and nuclear atypia. If the clinical results of a patient are not consistent with hepatocellular carcinoma, a search for residual adrenal cortical tissue and performing immunohistochemical stains is useful.
The second case is adrenocortical carcinoma arising in ectopic adrenal tissue in liver. Adrenocortical carcinoma is a rare tumor with an annual incidence of 0.5-2 cases per million of the population, and is an aggressive cancer with a poor prognosis. The major requirement for differential diagnosis is between adrenal cortical adenoma and adreno- cortical carcinoma. A number of studies have proposed histological criteria to predict their malignant behavior. This case meets 7 of 9 criteria of the modified Weiss system [13]. In the case of a tumor arising from ectopic adrenal tissue or hepatoadrenal adhesion, a surrounding capsule may or may not be present. Therefore, the presence of capsular invasion is occasionally unclear, and tumor cells are observed to infiltrate the hepatic parenchyma. In such cases, parenchymal invasion
may not be possible to use as a malignant criteria, and pathologists should proceed to interpret results with a different method [14].
Ultrasonography-guided fine needle aspiration biopsy is a useful diagnostic tool for distinguishing adrenal masses. However, intrahepa- tic ectopic adrenal neoplasm is difficult to distinguish from adrenal adenomas and carcinomas. Furthermore, when the normal hepatic tissue is included in a biopsy sample, it becomes increasingly difficult to make an accurate diagnosis. The third case had been misdiagnosed as hepatocellular carcinoma at preoperative biopsy. In this case tumor cells showed positive staining for glypical-3. Glypican-3 is the latest specific marker of hepatocellular carcinoma, and has 97% specificity. It shows cytoplasmic, membranous, and canalicular positivity in hepato- cellular carcinomas as well as high grade dysplastic nodules [15]. In previous reports, adrenal tumors were not reactive to glypican-3.
It would be very difficult to diagnose an ectopic adrenal neoplasm on the basis of imaging findings because of its limitations. The radiological findings of intrahepatic ectopic adrenal neoplasms are similar to those of HCC, and it is more difficult to distinguish between the two in areas with high prevalence of HCC. According to previous reports, the intrahepatic adrenal neoplasms mimic HCC [9,10]. There are no other specific radiological findings, if the tumors did not arise from an adrenohepatic fusion or tumors did not show obvious stalk to the adrenal gland. The third case, also, manifested the stalk and it was barely visible in imaging reviews after surgery. Thus, in the event that a hepatic mass is found adjacent to the adrenal gland, and laboratory results show negative findings with respect to hepatic viral markers, and normal titers of serum markers such as AFP and PIVKA-II are detected, possible fusion between liver and adrenal gland should be investigated radiologically.
Pathologically, adrenal tumors in hepatic tissue can be successfully diagnosed based on their morphology and the presence of residual normal ectopic adrenal cortical tissue. Morphologic findings supporting the diagnosis of adrenocortical tumors apart from residual normal adrenal tissue are distinct cell borders and clear cells with abundant foamy cytoplasm filled with lipid droplets. Cytoplasmic brownish pigmentation also helps to raise suspicion for adrenocortical tumors.
Immunohistochemistry is useful to differentiate hepatocellular carcino- ma from adrenal tumors. Melan-A and alpha-inhibin are consistently positive in adrenocortical adenoma/carcinomas whereas glypican-3 and hepatocyte specific antigen are more commonly associated with HCC. However, there are limitations especially when dealing with needle biopsy specimens and when performing immunohistochemical stains that target HCC alone. Collection of clinical information, upon suspicion of an adrenal tumor, combined with the use of adequate immunohistochemical staining will be useful for the diagnosis of this disease.
Conflicts of interest
The authors have no conflicts of interest to disclose.
Acknowledgements
This study was supported by a grant from the National R & D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (0920050).
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