Diagnostic challenges associated with adrenocortical neoplasms arising from adreno-hepatic fusion: a case report of two patients and a literature review

Introduction

Adrenal tissues can be present in atypical locations, extending into contiguous organs or existing as an ectopic adrenal gland that is separate from the normal adrenal tissue. A right adrenal gland that is attached to the liver can be classified as either adrenal-liver adhesion or adreno-hepatic fusion (AHF), depending on the presence of a connective tissue between the two organs (1). AHF is defined as adrenal cells intermingled with hepatocytes, with a connective tissue septum being either wholly or partially absent (1-3). The etiology of AHF remains poorly understood, largely due to insufficient evidence supporting the hypotheses that it is either a congenital heterotopia or an age-dependent phenomenon (1,2). Clinically, an adrenal mass arising in AHF may be misdiagnosed as hepatic or adrenal carcinoma on the basis of imaging studies, because the irregular border between the two organs may resemble tumor invasion (4-6). There is limited evidence regarding the prognosis of adrenal lesions associated with AHF. However, few studies have indicated that direct metastasis or spread of infection may occur through the fusion, as there is no anatomical barrier between the liver and the adrenal gland (7,8).

In this study, we present two cases in which an adrenocortical neoplasm that arose from AHF mimicked an intrahepatic tumor and an adrenocortical carcinoma with liver invasion. Despite thorough preoperative work-ups, including biopsy with immunohistochemistry (IHC) staining and [¹⁸F]-fluorodeoxyglucose-positron emission tomography (¹⁸F-FDG PET), we found that the clinical diagnosis still can be uncertain or misguided if AHF is not initially suspected. We present this case in accordance with the CARE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-24-367/rc).

Case presentation

This case report was conducted in accordance with the ethical standards of the Institutional Review Board of Seoul National University Bundang Hospital (IRB No. B-2408-916-701) and in compliance with the Declaration of Helsinki (as revised in 2013). Informed consent for publication of this case report and associated images was obtained verbally through telecommunication from both patients, as outpatient follow-up had concluded in the Department of Surgery. Documentation of the consent is available for review by the editorial office of this journal.

Case 1

A 44-year-old woman had an incidental finding of a liver mass at segment 7 (S7) on computed tomography (CT). Unenhanced CT showed an attenuation of the tumor of –3.0 HU. The patient did not have hepatitis B infection and was not a heavy alcohol consumer. Gadoxetic acid-enhanced liver magnetic resonance imaging (MRI) revealed a 3.1-cm fat-containing intrahepatic mass with heterogeneous arterial enhancement and washout during the portal phase (Figure 1A,1B). The differential diagnoses were the following: (I) hepatic adenoma; (II) hepatocellular carcinoma (HCC); and (III) angiomyolipoma. ¹⁸F-FDG PET imaging revealed an isometabolic, low attenuated lesion in liver S7 [2.1 maximum standardized uptake values (SUVmax)], consistent with a non-malignant lesion (Figure 1C). A liver biopsy was performed, and histopathologic examination and IHC revealed an epithelioid cell neoplasm with clear cytoplasm. IHC of the tumor was negative for arginase-1, hepatocyte, and HMB45, but positive for smooth muscle actin (SMA). Therefore, the possibility of an angiomyolipoma or a perivascular epithelioid cell tumor was considered based on the expression of SMA.

Figure 1 Images and pathologic findings for patient 1. (A) T2-magnetic resonance image showing a heterogenous intrahepatic tumor with a fatty component. (B) Axial gadoxetic acid-enhanced magnetic resonance image showing an intrahepatic mass with a connection to the right adrenal gland. (C) Poorly attenuating tumor (2.1 SUVmax) on 18F-fluorodeoxyglucose positron emission tomography/computed tomography. (D) Macroscopic feature of the 3.0 cm × 2.5 cm × 2.0 cm-sized yellowish tumor. Red arrow: tumor; white arrow: liver resection margin on the gross specimen. SUVmax, maximum standardized uptake value.

Because the diagnosis remained uncertain and the patient strongly desired surgical removal, a laparoscopic S7 tumorectomy was performed. During the surgery, the tumor and the right adrenal gland were found to be severely adhered. Therefore, a partial right adrenal resection was also performed. The patient was uneventfully discharged on postoperative day 6.

Gross examination of the resected liver and adrenal gland revealed a 3.0 cm × 2.5 cm × 2.0 cm-sized yellowish tumor that was centered on the adrenal gland and adjacent to hepatic parenchyma (Figure 1D). Microscopically, the tumor cells harbored clear cytoplasm, and IHC was positive for synaptophysin and inhibin-α, but negative for chromogranin, thereby confirming the adrenocortical origin of the tumor. AHF was also noted, as well as tumor capsular invasion into hepatic parenchyma and a high nuclear grade. The margin of the liver resection was focally involved by tumor cells. Because tumor capsular invasion of the liver parenchyma was evident through the AHF, a final pathologic diagnosis of adrenocortical neoplasm with uncertain malignant potential was made, despite a low Weiss score of 2. Since adrenocortical neoplasm was not initially suspected, an assessment of functionality was only performed postoperatively, and this revealed no abnormality. Currently, the patient remains free of disease 2 years after surgery and is satisfied with the postoperative outcomes.

Case 2

In a healthy 67-year-old man, a 4 cm × 3 cm hypodense lesion was incidentally identified in the right suprarenal region on CT. The lesion had a mean of −4.9 HU on unenhanced CT. The differential diagnoses were an adrenal tumor with hepatic invasion and an exophytic hepatic tumor. For further evaluation, gadoxetic acid-enhanced liver MRI was performed, which revealed a 4.6-cm irregular mass with hyper-arterial enhancement and delayed washout in the right adrenal gland. The tumor showed diffusion restriction and an intermediate-to-high signal intensity, with an internal fat component, on T2 image. An adrenocortical tumor was suspected, with the possibility of liver invasion. The patient then underwent an ¹⁸F-FDG PET scan, which revealed a mild hypermetabolic nodule in the right adrenal gland with 2.9 SUVmax. Laboratory examinations revealed normal concentrations of plasma metanephrine, normetanephrine, 3-methoxytyramine, renin, aldosterone, and cortisol. Because of the possibility of liver invasion, the patient was suspected to have an adrenocortical carcinoma and was referred for surgery.

The patient underwent open right adrenalectomy with liver wedge resection as an en bloc resection. An adequate liver resection margin was achieved. Macroscopically, a 3.3 cm × 3.1 cm × 1.6 cm-sized yellowish adrenal tumor that was tightly adherent to the hepatic parenchyma was observed (Figure 2). Microscopic examination revealed an adrenocortical neoplasm that arose in AHF. Similar to case 1, the tumor showed capsular invasion into the hepatic parenchyma. Therefore, a diagnosis of adrenocortical neoplasm with uncertain malignant potential was made, despite a Weiss score of 2 with presence of high nuclear grade and capsular invasion. On postoperative day 3, the patient developed obstructive pneumonia involving the mucoid obstruction of the right bronchus intermedius. After recovering from this pneumonia following medical management, the patient was discharged on postoperative day 11. The patient has been satisfied with the final diagnosis and currently remains without recurrence 1 year following surgery.

Figure 2 Images and pathologic findings for patient 2. (A) Computed tomography image showing a hypoattenuating lesion with an irregular border suggestive of liver invasion. (B) Gadoxetic acid-enhanced magnetic resonance image showing the irregular border with the liver. (C) Poorly attenuating tumor (2.9 SUVmax) on 18F-fluorodeoxyglucose positron emission tomography/computed tomography. (D) Macroscopic appearance of the 3.3 cm × 3.1 cm × 1.6 cm-sized yellowish tumor, which is tightly adherent to the liver. Red arrow: tumor; white arrow: liver resection margin. SUVmax, maximum standardized uptake value.

Discussion

Literature review

As shown in this study, similar diagnostic challenges were encountered upon review of the literatures regarding adrenal lesions arising in AHF. A total of 26 studies were found using PubMed using “adrenohepatic fusion” as the search term, of which 10 were of human cases of primary adrenal lesions arising in AHF. Adrenal masses arising in ectopic adrenal tissue, also known as an “adrenal rest tumor”, were excluded, as well as hepatic tumors arising in AHF. Upon review of the literature, 4 more articles regarding adrenal lesions arising in AHF were identified. The detailed imaging and pathologic findings of a total of 16 patients in 14 case reports or series are summarized in Table 1 (4-6,8-18). The mean age of the patients was 59.3 years and 10 (62.5%) patients were female. Of the 16 patients, 8 were diagnosed with adrenocortical adenoma and 3 with adrenocortical carcinoma. Other lesions, such as adrenal tuberculosis or adenocarcinoma derived from an AHF-related cyst, were also described (8,16). All of the patients except one underwent surgical resection, and some required additional treatment, such as radiofrequency ablation or additional surgery to complete radical resection (12,13). Four (25.0%) patients had a functioning adrenal tumor, of which 2 had primary aldosteronism and 2 had a cortisol- and sex hormone-producing carcinoma (11-13). One (6.3%) of the patients presented with adrenal insufficiency (8).

The literature review revealed that various adrenal tumors derived from AHF have been reported, from adrenocortical adenoma to adrenocortical carcinoma, and these were either functional or non-functional. While the incidence of AHF varies from 1.0% to 9.9% in previous autopsy studies, AHF is not often encountered in everyday practice, and therefore such diagnoses can be missed (1,2). Some have argued that AHF is a phenomenon that develops during aging, because it is mostly found in people of ≥40 years of age, while others have argued that it is a congenital phenomenon, involving a retroperitoneal mesenchymal defect which fail to promote capsule formation (2,6,18,19). The present case report and review of previous studies has shown that AHF was found in patients of ≥40 years. However, considering that most of the lesions were found incidentally on imaging performed in aged individuals, caution is needed when extrapolating conclusions regarding the pathophysiology of AHF. Moreover, because AHF is not uncommon, it is important for clinicians to consider the possibility of this anatomic variation preoperatively, to avoid unnecessary treatment or treatment failure.

Case discussion

Upon retrospective review of the first case, a connection between the tumor and normal adrenal tissue was observed on MRI (Figure 1B). However, the intrahepatic location of the tumor made it difficult to suspect the possibility of an adrenal neoplasm preoperatively. Despite a needle biopsy and IHC having been performed, a definitive diagnosis could not be made, because an adrenal tumor was not initially suspected. The molecular markers that were evaluated for the first patient were for detecting liver origin tumors, including clear-cell HCC and angiomyolipoma; IHC for Melan A, inhibin-α, or calretinin, which are markers of an adrenal origin, was not performed. Although some may argue that preoperative biopsies are diagnostically useful, we failed to make a definitive diagnosis since an adrenal neoplasm was not initially suspected. Previous reports have often encountered misdiagnoses of HCC on preoperative biopsy, because the clear-cell features of an adrenal neoplasm may often be mistaken for clear-cell type HCC (4,9). In the present case, the clear-cell features with negativity for a hepatocyte marker, and positivity for a marker of SMA led to a diagnosis of either angiomyolipoma or perivascular epithelioid cell tumor. Although the SMA marker is a useful indicator for tumors of a myoepithelial origin, positivity for this marker for the first patient may have been the result of the complex sinusoidal plexus that characterizes adrenocortical neoplasms (20). Our experience with this case emphasizes the need for clinicians to consider the possibility of an adrenal neoplasm arising in AHF, especially when the biopsy results show clear-cell features, in order to avoid a misdiagnosis. Moreover, given that adrenal mass biopsy is not routinely performed, because of the possibility of pheochromocytoma, a suspicion of AHF when peripheral nodules are present in liver segment 6 or 7 is crucial to avoid any complications following biopsy.

By contrast, the second patient was suspected to have an adrenocortical carcinoma, owing to the features of invasion into the liver. As also reported previously, the features of AHF can often mimic malignant lesions, and this can lead to over-treatment. Moreover, the CT features of adrenocortical adenoma are sometimes similar to those of HCC, with hyperattenuation during the arterial phase and rapid washout during the delayed phase, rendering the differential diagnosis challenging (21). ¹⁸F-FDG PET scan can be useful to differentiate malignancy and an adenoma that has arisen in AHF (22,23). The ¹⁸F-FDG PET scan performed on the second patient revealed a tumor SUVmax of 2.9, which is below the cut-off value of 3.4 that is used to differentiate adrenocortical adenoma and carcinoma (22). However, because an irregular border was evident on both CT and MRI images, we suspected malignancy with liver invasion, rather than adrenocortical adenoma. Therefore, en bloc resection with liver tumorectomy was performed to achieve a sufficient surgical margin. If the tumor had been further into the liver, more substantial liver resection could have been performed, which would have been unnecessary. For example, if the tumor had been misdiagnosed as a clear-cell HCC on the basis of preoperative imaging and biopsy, liver segmentectomy would have been performed, rather than liver tumorectomy, which would have caused an unnecessary impairment of liver function. Therefore, we believe that performing an ¹⁸F-FDG PET scan in patients with adrenal tumor and liver adhesions would assist with the differentiation of AHF from malignant liver invasion.

Still, it remains important to obtain an adequate surgical margin during the resection of adrenocortical neoplasms arising from AHF. Because there is no anatomic barrier between the adrenal gland and liver, invasion of the contiguous organ readily occurs. For example, a previous study revealed adrenal tuberculosis in AHF that resulted in the spread of the infection into the liver (8). Another study showed the direct metastasis of an HCC into the adrenal gland via the fusion (7). In both of the present patients, despite a low Weiss score, malignant potential of the lesion could not be ruled out because of the presence of obvious capsular invasion into the liver parenchyma. The achievement of an adequate resection margin to remove all of the adrenal cells from the liver is necessary both to make a definitive diagnosis and to reduce the risk of locoregional recurrence. This is particularly crucial, as adrenocortical carcinoma carries a poor prognosis with a high recurrence rate of 25–61%, occurring at an average of 2–3 years post-surgery (24,25). Additionally, there is no molecular biomarker for recurrence, and adjuvant therapy shows limited efficacy (24,25). Perhaps, early surgery for adrenal lesions arising in the AHF may be considered due to the high risk of liver invasion from the absence of an anatomic barrier. However, further studies are needed to evaluate this contention.

Limitations

There were several limitations to the present study. First, we have described a small number of patients, who may not be representative of the entire patient population. Second, we followed the patients for 1–2 years, and therefore their long-term outcomes are unknown. This is especially critical, as recurrence of adrenocortical carcinoma typically occurs around 2–3 years after surgery (25). Given that both patients’ tumors were designated as having “unknown malignant potential”, despite their low Weiss scores, owing to the capsular invasion into the liver, the patients’ long-term outcomes should be studied to better understand the prognosis of such conditions. Third, this report did not explore the cost-effectiveness or quality of life in the treatment of patients with AHF. Since most previous studies on AHF patients are case reports, and only 16 patients were included in this review, the overall economic implications and health-related quality of life could not be investigated. Further studies are necessary to gain a comprehensive understanding of patient care for those with adrenal neoplasms arising in AHF.

Conclusions

In conclusion, adrenal lesions arising in AHF are rare, but misdiagnosis is easy if clinicians are not aware of this phenotype. Non-standard imaging modalities, such as ¹⁸F-FDG PET, may help clinicians to distinguish between malignant invasion and adrenocortical adenoma arising in AHF. The practical diagnostic role of preoperative biopsy is uncertain when AHF is not suspected initially, as clear-cell features of adrenal lesion often mimic those of clear-cell HCC. However, early suspicion of AHF would be helpful for the clinician to perform proper adrenal functioning tests before biopsy and choose appropriate markers for IHC. Once surgical resection is planned, adequate resection margins should be achieved to minimize the risk of locoregional recurrence and maximize subsequent liver function, while obtaining a definitive diagnosis.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-24-367/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-367/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-367/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This case report was conducted in accordance with the ethical standards of the Institutional Review Board of Seoul National University Bundang Hospital (IRB No. B-2408-916-701) and in compliance with the Declaration of Helsinki (as revised in 2013). Informed consent for publication of this case report and associated images was obtained verbally through telecommunication from both patients, as outpatient follow-up had concluded in the Department of Surgery. Documentation of the consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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