Pseudo‐Progression Observed During Immune Checkpoint Inhibitor Therapy for Advanced Adrenocortical Carcinoma

ABSTRACT

Introduction

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. Recent studies suggest that immune checkpoint inhibitors exhibit antitumor activity in selected ACC patients.

Case Presentation

We report a case of a 49‐year‐old man with advanced ACC and pulmonary metastasis treated with EDP‐M chemotherapy, followed by pembrolizumab based on high tumor mutational burden (TMB, 27.1/Mb). Despite suspected pseudo‐progression, transient tumor shrinkage was observed. However, the patient died of liver failure 9 months after diagnosis.

Conclusion

This case suggests a therapeutic role for ICIs in ACC. Moreover, it highlights the importance of TMB and immune RECIST criteria in evaluating treatment response.

Keynote Message.

Immune checkpoint inhibitors may be effective in selected patients with advanced adrenocortical carcinoma. This case highlights pseudo‐progression during pembrolizumab therapy, emphasizing the need for careful radiologic assessment. Immune‐related response criteria may be useful for evaluating treatment response in ACC.

1. Introduction

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, with an estimated incidence of 0.2–2 per million population per year [1]. ACC can occur at any age; however, it exhibits a bimodal distribution, with one peak in childhood and a second peak in the fourth to fifth decades of life [2, 3]. Current first‐line systemic therapy includes the etoposide, doxorubicin, cisplatin, and mitotane (EDP‐M) regimen; however, its efficacy is limited. Immune checkpoint inhibitors (ICI) have demonstrated clinical benefit in a variety of malignancies. Herein, we present a case of advanced ACC treated with EDP‐M followed by pembrolizumab, with a clinical course suggestive of pseudo‐progression.

2. Case Presentation

A 49‐year‐old man with no significant past medical history and independent activities of daily living presented to a local clinic with right flank pain. Abdominal computed tomography (CT) demonstrated an 85‐mm mass located in the right adrenal gland (Figure 1a). He was referred to our department for further evaluation of the mass. Magnetic resonance imaging also suggested ACC. Endocrinological assessment revealed no evidence of hormone hypersecretion (Table 1).

FIGURE 1.

Longitudinal assessment of tumor size using CT.

TABLE 1.

Laboratory findings including endocrinological evaluation.

Category	Parameter	Value	Unit	Reference range
Hematology	White blood cell count	8300	/μL	3300–8600
	Hemoglobin	12.9	g/dL	13.5–17.6
	Platelet count	42.6	×104/μL	15–35
Biochemistry	Aspartate aminotransferase (AST)	17	U/L	13–33
	Alanine aminotransferase (ALT)	22	U/L	8–42
	Lactate dehydrogenase (LDH)	630	U/L	124–222
	Total bilirubin	0.6	mg/dL	0.4–1.5
	Blood urea nitrogen (BUN)	9	mg/dL	8–20
	Creatinine	0.61	mg/dL	0.65–1.07
	Sodium	139	mEq/L	138–145
	Potassium	4.5	mEq/L	3.6–4.8
Endocrinology	Cortisol (morning)	13.2	μg/dL	6.2–19.4
	ACTH	20.2	pg/mL	7.2–63.3
	Aldosterone	6	pg/mL	4.0 ~ 82.1
	Plasma renin activity	1.3	ng/mL/h	0.2–3.9
	DHEA‐S	294	μg/dL	80–560

One month after the initial visit, CT revealed an increase in tumor size to 110 mm, with infiltration into the liver and inferior vena cava (IVC) as well as a 40 mm mass in the right upper lung lobe, raising suspicion of pulmonary metastasis (Figure 1b). Percutaneous biopsy of the right adrenal tumor confirmed the diagnosis of ACC, and transbronchial biopsy confirmed pulmonary metastasis. The Ki‐67 labeling index was > 70%, and the tumor fulfilled the Weiss criteria for malignancy. Based on these findings, systemic chemotherapy was initiated.

Two months after initial presentation, EDP‐M therapy was initiated. During the first course, the tumor enlarged with associated lymph node enlargement. After three cycles of EDP‐M, tumor size remained largely unchanged compared with baseline (Figure 1c), and the response was classified as stable disease (SD). However, no meaningful tumor shrinkage was observed, suggesting a limited treatment response. Given this limited response, further tumor control with EDP‐M was considered unlikely. Comprehensive genomic profiling using the Foundation One CDx assay revealed a high tumor mutational burden (TMB) of 27.1 mutations per megabase, supporting the use of pembrolizumab. This assay detects somatic alterations and does not assess germline variants. The tumor was microsatellite stable, with no mismatch repair gene alterations. After discussion with the patient, pembrolizumab (400 mg every 6 weeks) was selected as second‐line therapy while the patient's performance status was preserved.

CT after the first course of pembrolizumab showed tumor progression involving IVC invasion and the lymph nodes (Figure 2b). According to RECIST version 1.1, this was classified as progressive disease (PD), whereas under iRECIST it was considered immune unconfirmed progressive disease (iUPD), and treatment was continued. CT after the second cycle demonstrated tumor shrinkage to 100 mm, with partial regression of lymph node involvement, hepatic lesions, IVC invasion, and pulmonary metastases; therefore, it was classified as a partial response (Figure 2c). This was consistent with a response following initial iUPD.

FIGURE 2.

Longitudinal assessment of tumor size using CT after initiation of pembrolizumab.

During the third course of pembrolizumab, the patient developed anorexia. CT revealed tumor progression with an increase in tumor size to 110 mm, enlargement of lymph nodes, IVC obstruction, and worsening hepatic invasion. The patient subsequently developed liver failure and died 9 months after the initial diagnosis (Table S1). In this case, fatal liver failure was considered to be primarily caused by extensive tumor infiltration and vascular involvement, including obstruction of IVC and hepatic veins, leading to hepatic congestion and impaired venous outflow. Although immune‐related hepatitis could not be completely excluded, the imaging findings and clinical course strongly supported a tumor‐related mechanism.

3. Discussion

At diagnosis, most ACC patients present with advanced or metastatic disease. EDP‐M is the current first‐line systemic treatment and its efficacy was reported in a previous study [4]. However, prognosis remains poor, with reported 5‐year survival rates of 0%–11% in advanced cases [5, 6].

The role of ICIs in ACC remains unclear. Reported objective response rates are limited to 14%–23% [7, 8, 9]. A systematic review reported a median progression‐free survival of 2.8 months and overall survival of 13.9 months, indicating limited efficacy [10].

TMB has emerged as a potential biomarker for predicting the efficacy of ICIs. In particular, tumors with TMB ≥ 10 mutations/Mb have favorable responses to pembrolizumab therapy [11]. Similarly, Mota et al. reported a case of complete and durable response to pembrolizumab in an ACC patient with high TMB and mismatch repair deficiency due to an MSH2 mutation [12]. In the present case, comprehensive genomic profiling revealed a TMB of 27.1 mutations/Mb, supporting the use of pembrolizumab based on molecular indications. However, ACC generally exhibits a high baseline TMB, with average values exceeding 20 mutations/Mb [10, 13]. Therefore, TMB may not be a reliable predictive biomarker for ICI response in ACC compared with other tumor types, and its clinical utility remains under debate. Notably, in the present case, immunohistochemistry showed low CD3‐, CD8‐, and CD20‐positive cell infiltration, consistent with an immunologically “cold” tumor microenvironment, which may reflect impaired antigen presentation or insufficient T‐cell recruitment. This finding is consistent with previous reports in ACC [13], which indicate that high TMB does not necessarily correlate with an inflamed tumor microenvironment or response to ICI.

In the present case, the first post‐treatment CT after initiation of pembrolizumab showed a transient increase in tumor size, followed by subsequent shrinkage, suggesting suspected pseudo‐progression. However, definitive confirmation was not possible due to the lack of histopathological evidence of immune cell infiltration or tumor necrosis. Alternatively, this course may represent transient change followed by rapid true progression. Therefore, this case should be interpreted as a possible, rather than confirmed, pseudo‐progression. Pseudo‐progression during immunotherapy has been reported in approximately 6%–15% of solid tumors and typically occurs at first follow‐up [14, 15]. The clinical characteristics of pseudo‐progression in rare malignancies such as ACC remain poorly understood and warrant further investigation.

In the present case, alternative interpretations, such as mixed response or a transient response followed by rapid treatment failure, should be considered. The clinical course appears more consistent with the latter, as the tumor showed rapid regrowth during the third cycle of pembrolizumab and the patient ultimately died from disease progression. This clinical course emphasizes that establishing the efficacy of ICIs for advanced ACC requires optimal patient selection and identification of predictive biomarkers, and radiologic criteria that account for pseudo‐progression. Future large‐scale clinical trials and investigation of combination therapies to improve the efficacy and durability of treatment responses in this rare and aggressive malignancy are necessary.

4. Conclusion

This case demonstrates pseudo‐progression during pembrolizumab therapy in advanced adrenocortical carcinoma. Immune‐related response criteria are important for appropriate assessment of treatment response in this rare and aggressive disease.

Ethics Statement

The study protocol was approved by the Institutional Review Board of Yokosuka Kyosai Hospital (Approval No. YKH25‐72).

Consent

The requirement for written informed consent was waived, and an opt‐out consent process was implemented.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: Temporal changes in liver function tests during pembrolizumab treatment.

Data Availability Statement

Research data are not shared.