Adrenal metastasis of hepatocellular carcinoma after liver transplantation: Case report and systematic review of literature

Abstract

BACKGROUND

Adrenal metastasis of hepatocellular carcinoma (AM-HCC) after liver transplantation (LT) is an infrequent entity, especially when it is the only site of recurrence. We present patients with these characteristics and systematically review previously published cases. No systematic review adhering to PRISMA criteria has been previously performed.

AIM

To systematic review of isolated AM-HCC after LT.

METHODS

Adhering to PRISMA guidelines, we performed unrestricted search for AM-HCC after LT in several databases, with no language restriction, updated through December 31, 2024.

RESULTS

We obtained 38 articles. Only 14 articles, comprising 20 patients, were evaluated, to which we added our own case. Fourteen were single-case reports, and one was a series of seven retrospective cases. The median age was 56.1 years [interquartile range (IQR): 23-72]. The gender distribution was predominantly male (84.6%). The indications for LT were hepatocellular carcinoma (HCC) plus hepatitis B virus cirrhosis (11), hepatitis C virus (6), alcohol (3), and cryptogenic cirrhosis (1). The median HCC tumor size was 4.6 cm (IQR: 3.8-13). One third of patients did not meet the Milan criteria. The median time between LT and the appearance of adrenal metastasis (AM) was 39.9 months (IQR: 18-42.6). The AM was located on the left (11) and right side (10). Nineteen patients were treated with adrenalectomy, and two were treated with radiotherapy. After a median follow-up of 30 months, 25% of patients were alive without recurrence. The median survival time was 29 months (IQR: 24-38).

CONCLUSION

In the case of AM-HCC after LT, occurring as the solitary site of extrahepatic metastasis, adrenalectomy could be a therapeutic option for surgical candidates. It is safe, appears to increase survival, and reduces recurrence in selected patients.

Key Words: Adrenal; Metastasis; Hepatocellular carcinoma; Liver transplantation; Review

Core Tip: We present a systematic review of isolated adrenal metastasis of hepatocellular carcinoma after liver transplantation, including a patient who was treated at our center. Previous manuscripts on this topic have not included a PRISMA-based systematic review; therefore, this is the first systematic review conducted. Our findings clearly demonstrate that there is currently a lack of consensus on how to treat these patients, indicating the need for an international consensus.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third most lethal, and an increase in its incidence is expected in the coming years[1-9]. HCC is the most frequent primary liver tumor and usually develops in the context of chronic liver diseases such as cirrhosis associated with alcohol consumption, obesity, or viral infections[1,3]. There are multiple treatments for HCC; liver transplantation (LT) is the most effective, but it is only feasible in selected patients[1,2,4-8,10-14]. After LT for HCC, strict follow-up must be performed because of the risk of hepatic recurrence and/or extrahepatic metastases (EHM)[4-6,10-12].

HCC EHMs are common and occur via hematogenous or lymphatic dissemination[8,15,16]. Between 10% and 15% of patients with HCC present with synchronous EHM, and up to 40% develop them metachronously[3,8,9,16-18]. Patients with advanced tumors, microscopic vascular invasion, and elevated tumor markers are at greater risk of EHM[8]. The most frequent locations of HCC EHMs are the lungs (50%-60%), lymph nodes (30%-40%), bones (20%), and adrenal glands (4%-12.5%)[1,3,4,6-8,11,15-18]. The treatment for EHM in the context of HCC is not standardized, and even less so for EHM after LT[5,11,15]. Patients with HCC EHMs have a poor prognosis, with a median survival of approximately 6 months (range: 0-36 months)[2,6,9,10,17].

The incidence of EHM in HCC after LT (EHM-HCC-LT) varies significantly across published series (10%-40%)[7,16]. This incidence has decreased considerably in recent years following the application of the Milan criteria, as the variability of transplant indications has narrowed. Possible causes for the appearance of EHM after LT include microscopic extrahepatic disease in the lymph nodes or other organs at the time of transplantation and/or peritoneal or hematogenous dissemination during the procedure. Most cases are diagnosed in the first two years after LT; when the diagnosis is delayed, it typically occurs in patients with smaller, more differentiated tumors and at a lower stage[7]. EHM-HCC-LT implies a decrease in survival (13%-35% at 5 years). Some authors claim that these metastases behave more aggressively than those appearing in patients who have not undergone LT, although they tend to appear later[8,15]. When there are several EMH foci, local or palliative therapies are applied; however, when only one organ is affected, surgical resection can be performed, which appears to increase survival[1,7].

Adrenal metastasis of HCC (AM-HCC) after LT is an infrequent entity[2-6,10-13,18,19], especially as a solitary location, since other EHM foci present at the time of diagnosis. Its presentation as a retroperitoneal hemorrhage makes it even more unusual. We present a case with these characteristics and systematically review the published literature on isolated AM-HCC after LT, evaluating the treatment performed and the survival obtained. No systematic review adhering to the PRISMA guidelines has been previously performed on this topic.

MATERIALS AND METHODS

Case report

A 62-year-old male with a history of liver cirrhosis due to hepatitis C virus (HCV) infection was followed for two liver lesions (segment 4B, 25 mm; and segment 8, 18 mm) compatible with HCC. He was classified as Child A. His pre-LT alpha-fetoprotein (AFP) was 29.06 ng/mL. In 2018, LT was indicated and performed without notable complications. The initial immunosuppressive regimen included tacrolimus, mycophenolate, and corticosteroids. No recurrence was observed during the follow-up imaging tests, and AFP levels remained stable.

At 48 months after LT, he visited the emergency room due to sudden abdominal pain in the left flank, dizziness, and hypotension. A computed tomography scan revealed a hyperintense collection of 133 mm × 118 mm × 134 mm was seen in the left adrenal space, compatible with a large hematoma, and a 42 mm × 30 mm heterogeneous tumor that showed signs of active bleeding, compatible with adrenal metastasis of the left adrenal gland. Urgent embolization was performed, successfully stopping the bleeding (Figure 1A). At that time, his only immunosuppression was tacrolimus. The AFP had risen to 42115.26 ng/mL. Left adrenalectomy via lumbotomy was performed as scheduled. The postoperative period was uneventful, and histological examination confirmed adrenal metastasis of HCC with lymphovascular invasion and free margins.

Figure 1 Computed tomography scan. A: Coronal computed tomography scan showed a hyperintense collection, compatible with a large hematoma, and a heterogeneous tumor consistent with adrenal metastasis of hepatocellular carcinoma. Adrenal metastasis (T) and hematoma (H); B: Recurrence after 14 months. A 1 cm tumor compatible with local recurrence in the left adrenal space.

Everolimus was administered after surgery. At 14 months, a 1 cm local recurrence was diagnosed, and the patient underwent surgery again to resect the lesion (Figure 1B). Following this, we changed the everolimus to sirolimus. At six months, there was an AFP increase of 20000 ng/mL, which subsequently decreased to 712 ng/mL during the following 13 months. Thoracoabdominal scans and bone scintigraphy showed no further signs of recurrence.

Methods

Adhering to PRISMA guidelines[20], we performed an unrestricted search for articles on AM-HCC after LT in the MEDLINE (PubMed), EMBASE, Cochrane, Latindex, Scielo, and Koreamed databases, with no language restriction, updated through December 31, 2024. The search terms were: (“adrenal metastasis”, “hepatocellular carcinoma”, AND “liver transplantation”). The Ethics Committee of the Hospital General Universitario Dr. Balmis waived the need for ethics approval because this was a systematic review.

The sole inclusion criterion was any study that included adult patients with isolated AM-HCC after LT. The exclusion criteria were studies that combined different types of surgery (liver surgery and LT), studies on EHM from HCC that did not present data for adrenal metastasis separately, duplicate series, surveys, and editorials. We extracted the following data: Author, year of publication, study type, Ottawa-Newcastle scale score, number of patients, age and sex, primary disease leading to LT, pre-LT AFP, Child-Pugh score, HCC size (cm), AFP at adrenal metastasis (AM) diagnosis, AM size, location, treatment, and follow-up.

Articles were included or rejected based on predefined criteria, and three authors (Franco M, Ramia JM, and Alcazar C) screened titles and abstracts. Duplicate series were searched, and full texts were read in case of doubt. The references of selected articles were also checked, although no additional articles were identified in the initial search. The Newcastle-Ottawa Scale will be employed to assess the quality of the included studies. A score of 0-2 was considered poor quality, 3-5 fair, and 6-9 good or high.

RESULTS

After the bibliographic search, we obtained 38 articles, 25 of which were on the topic under study. Only 14 articles, which included 20 patients, were evaluated (Figure 2). We added data for our case, bringing the total to 21 patients. At the bibliometric level, none of the studies were randomized controlled trials; 13 were single-case reports and one was a series of seven retrospective cases (Table 1). The Newcastle-Ottawa Scale was not utilized because its design is specifically tailored for evaluating analytical observational studies, such as cohort and case-control designs. Since the studies included in this review consist of case reports without a comparator group, applying this scale would be neither methodologically appropriate nor valid.

Figure 2  PRISMA algorithm.

Table 1 Description of published cases of adrenal metastasis from hepatocellular carcinoma after liver transplantation.

Ref.	Age/gender	Indication for LT	AFP PreLT (ng/mL)	Child-Pugh	HCC (cm)	Time from LT-AM (meses)	AFP PreAM (ng/mL)	AM size (cm)	Adrenal location	Treatment	Follow up after am treatment	Other comments
Castroagudín et al[14]	51/male	Alcohol + HCC	2.9	NA	4	5	NA	4.4	Left	Surgical, open	43 months, alive without recurrence	Right AM after 8 months of follow-up
Mourad et al[4]	53/male	HCV + HCC	756	NA	3.3	24	143	8	Left	Surgical, open	NA
Pandey et al[19]	64/male	HBV + HCC	NA	NA	15	3	NA	6	Left	Surgical, open	24 months, alive without recurrence	Gemcitabine and 5FU after surgery
Rubio et al[2]	23/male	HBV + HCC	NA	NA	11	36	NA	2.7	Right	Surgical, open	NA	Adriamycin after LT. Everolimus after adrenalectomy
Chen et al[10]	60/male	HBV + HCC	7812	B	NA	39	55,8	4	Left	Surgical, Laparoscopic	30 months, alive without recurrence	Capecitabine and oxaliplatin after LT. Gemcitabine and 5 after adrenalectomy. Lung metastases after 30 months of LT
Choi et al[11]	71/male	HCV + HCC	87.96	A	Multiple	11	6,02	5	Left	Surgical, open	16 months, deceased after recurrence
Ha et al[15]	56.1/NA	HBV + HCC (6), HCV + HCC (1)	NA	NA	4/7 Milan criteria	42.6	NA	3.4	3 × left, 4 × right	Surgical 6 open and 1 Laparoscopic	OS after 5 years of follow-up: 85.7%. Recurrence after 3 years of follow-up: 28.6%	7 patients, 5 × living donor LT +, 2 × deceased LT
Shimokawa et al[13]	47/female	HBV + HCC	2.6	C	4 lesions (3, 2, 2 and NA)	30	319.4	3	Left	Surgical, open	38 months, alive without recurrence	Double liver recurrence (surgery + RF). Bone recurrence. Living donor LT
Jalbani et al[5]	61/male	HCV + HCC	Normal	NA	3.5	15	1,0	5.5	Right	Surgical, Laparoscopic	24 months, alive without recurrence	Everolimus after adrenalectomy
Sormaz et al[18]	55/female	Cryptogenic + HCC	NA	B	4 T3bN0M0	138	NA	10	Right	Surgical, open	36 months, alive without recurrence
Ince et al[1]	61/male	HBV + HCC	187	B	25	12	275	4	Left	Surgical, open + left nephrectomy	10 months, deceased after lung recurrence	Living donor LT. Lung recurrence after 4 months of adrenalectomy. Sorafenib
Mikulic et al[6]	56/male	Alcohol + HCC	1.3	NA	4.5	30	Normal	11.5	Left	Surgical, open	24 months, alive without recurrence	Bleeding of right AM after 12 months
Zeineddine et al[3]	72/male	HCV + HCC	NA	NA	4.2	60	13.8	4.1	Right	SBRT	NA
Kim et al[12]	49/male	Alcohol + HBV + HCC	9.3	NA	4.7	18	2.0	NA	Right	RT + mTOR inhibitor	53 months, deceased after bone and IH recurrence	Adrenal recurrence after 5 months of follow-up
This article	62/male	HCV + HCC	29.06	A	2.5 and 1.8	48	42115.26	4.2	Left	Surgical, open	27 months, alive without recurrence with high AFP	Adrenal recurrence after 14 months treated with surgery. Everolimus/siroilimus

LT: Liver trasplantation; AFP: Alpha-fetoprotein; HCC: Hepatocellular carcinoma; AM: Adrenal metastases; HBV: Hepatitis B virus; HCV: Hepatitis C virus; NA: Not available; SBRT: Stereotactic Body Radiation Therapy; RT: Radiotherapy.

The median patient age was 56.1 years [interquartile range (IQR): 23-72]. The sex distribution (available for 13 patients) was 11 men (84.6%) and 2 women. Indications for LT were HCC and cirrhosis secondary to hepatitis B virus (11), HCV (6), alcohol (3), and cryptogenic cirrhosis (1). Pre-LT AFP level (available for 9 patients) was 48.6 ng/mL (IQR: 2.9-187), with five patients (55.5%) having pathological values. The Child-Pugh stage was defined in only six patients (two A stage, three B stage, and one C stage). The median HCC tumor size was 4.6 cm (IQR: 3.8-13), as stated in 12 patients. Seven of 21 patients did not meet the Milan criteria. Fourteen LTs were performed using a brain-dead donors (66%), and seven transplants were from living donors.

The median time between LT and AM was 39.9 months (IQR: 18-42.6). Median AFP at AM diagnosis (available for 9 patients) was 99.4 ng/mL (IQR: 6.0-319.4). Metastases were located on the left (11) and right sides (10). Unlike our case, only one was diagnosed as a result of a hematoma; the rest were incidental findings. Nineteen patients were treated with adrenalectomies; two of them underwent a laparoscopic approach, one patient underwent a nephrectomy, and two were treated with radiotherapy.

After a median follow-up of 30 months (13 patients), 10 patients were alive without recurrence, and three died due to disease progression (adrenal, bone, and intrahepatic recurrence, pulmonary recurrence, and intrahepatic recurrence) (Figure 3). Two patients had contralateral AM at 8 and 12 months, respectively, which were removed; both remained alive without recurrence. Our patient presented with a local recurrence that was removed and is also alive without recurrence. The median survival time was 29 months (IQR: 24-38). In the series by Ha et al[15], the 5-year survival rate was 85.7% and the 3-year recurrence rate was 28.6%. Of the two patients treated with radiotherapy, one lacked survival data and the other died due to multiple recurrences at 53 months. Various chemotherapy and immunotherapy regimens have been used, but their effectiveness cannot be defined.

Figure 3  Survival curve of published cases of adrenal metastasis of hepatocellular carcinoma after liver transplantation.

DISCUSSION

Manuscripts on isolated AM-HCC after LT are scarce, comprising only 21 cases, usually presented as single cases, except for the series by Ha et al[15] of 7 patients[2,4-6,11,13,19]. The exact incidence of AM-HCC after LT is unknown because most publications are single cases, without specifying the number of transplants performed at the centers. Teegen et al[8] reported a series of 10 patients with AM-HCC that includes seven patients who underwent LT at 303 LT, which implies an incidence of 2.3%. In our center, we treated one patient after 485 LTs (0.2%).

The diagnosis of AM-HCC after LT is usually incidental, discovered through rising tumor markers and/or imaging performed during LT follow-up[4,14,17,18]. Only 50% of the reviewed patients had elevated AFP levels. There is no consensus regarding the most frequent location (left vs right)[4,5]. The distribution of the patients included in the review was 50%. It has been postulated that right-sided AM-HCC may be caused by seeding during LT, while left-sided lesions arise from hematogenous dissemination[3]. When AM-HCC is diagnosed, a PET-CT is recommended to rule out other sites of metastasis. Notably, one-third of the included LT did not meet the Milan criteria, a fact associated with a higher risk of recurrence.

Symptoms of AM-HCC are nonspecific and appear only when the lesion is large, presenting as compressive symptoms, flank pain, or adrenal insufficiency[4]. Adrenal hemorrhage is an exceptional complication. In a review of adrenal hemorrhagic masses, only 1 of 133 cases was caused by HCC[6,17]. Only one patient presented with a hematoma in the form of a debut without active bleeding; thus, the exceptional nature of our case. The factors linked to bleeding are rapid tumor growth, neovascularization, and tissue fragility[17].

There are different treatment options for AM-HCC: Surgical resection, ablative therapies (e.g., radiofrequency, embolization), radiotherapy, systemic therapies (e.g., sorafenib, everolimus), or palliative treatment[2,3,5-8,13,14,17]. Surgical resection is an accepted therapeutic strategy if liver function is preserved, there is no evidence of liver recurrence and/or other EHMs, and the patient is suitable for surgery[1,3-5,8,16,18]. Currently, the laparoscopic approach is the treatment of choice in patients with adrenal lesions[8,15,16,18]. In patients with previous abdominal surgery, LT can be complex. In our case, the previous LT, the large hematoma, and the size of the lesion led us to decide on an open approach. Only two of the published patients were treated using a minimally invasive approach. There is currently no international consensus on how to manage a single-location recurrence after a previous adrenalectomy for AM-HCC after LT, as in our case.

The theoretical survival rate of patients with AM-HCC is 11-13 months, though this does not distinguish between treatment types. Median survival after resection of an AM-HCC after LT in the series by Teegen et al[8] was 81 months[3,8,17], but with a local recurrence or in another location, the 1-year survival rate was 37.5% and the 3-year survival rate was 75%, with a median onset of 20 months after adrenalectomy. In the series by Ha et al[15] of 7 patients, the 5-year survival rate was 85.7%, with one recurrence at 3 years of 28.6%. Staubitz et al[16] presented four patients with a survival of 66 months. In all published series, the results obtained in patients with HCC treated with LT are superior to those obtained in patients previously treated with surgery or ablative treatments[8,15,16]. Of the 13 unique cases published with a mean follow-up of 30 months, 10 were alive without recurrence, and three died after a recurrence. Two patients presented with adrenal contralateral metastasis that was resected, and they were alive with recurrence. The diversity of adjuvant treatments and modifications of immunosuppression used do not allow conclusions to be drawn about whether there is a more effective treatment.

Considering this systematic review, it supports a proactive approach to surveillance and management of isolated adrenal metastases after LT. The incidental detection of AM-HCC highlights the importance of postoperative imaging to enable timely surgical referral. When disease is confined to a single adrenal location, and the patient is fit for surgery, adrenalectomy should be considered a valid therapeutic option, as it appears to confer meaningful survival benefit. These findings may inform future surgical decision-making by encouraging early operative assessment and individualized selection of surgical approach in this rare but potentially treatable setting.

The main limitation of this review is the existence of some publications that include some cases of AM-HCC after LT (approximately 25) but do not specify the detailed results without differentiating whether it is after liver resection or LT, or specific surgical and survival data, which we have not been able to include in the review[7,8]. The strength of this study is that the first systematic review used the PRISMA rules.

CONCLUSION

Isolated AM-HCC after LT as the only location of EHM, adrenalectomy is a viable therapeutic option that can be considered a therapeutic option if the patient is suitable for surgery. It is safe, appears to increase survival, and reduces recurrence in selected patients. While an open approach is often used, an international consensus is required to define the best therapeutic options.