Most lymphomas originate from lymph nodes, while up to a quarter develop from extra-lymph node lymphoid or non-lymphoid tissue. Primary extranodal lymphoma (PEL) has been reported to account for 25%–40% of all cases of lymphoma in Western countries (1) and 45.9% in Taiwan respectively (2). The most commonly involved sites in PEL are the gastrointestinal tract, central nervous system, and skin (3). Lymphoma originating from the endocrine system accounts for 3% of cases of PEL, and primary adrenal lymphoma (PAL) accounts for only 0.2% of those lymphomas (4). There are only 250 cases described in the English-language literature worldwide to date (5); the majority of published articles about PAL are case reports or case-series studies with only a limited number of patients. The common features of PAL are male sex, older age, bilateral lesions, adrenal insufficiency, and poor outcomes, based on data mostly from Western countries (6). Due to the extreme rarity of this disorder, difficulty in differential diagnosis such as adrenocortical carcinoma or pheochromocytoma, and the lack of guidelines, physicians may face the difficulty in diagnosing and treating PAL.

The objective of this study is to summarize the clinical features, biological and imaging characteristics, and outcomes of 26 patients with PAL in the northern and southern regions of China in order to characterize this entity, which may improve the differential diagnosis of adrenal masses and finally improve prognosis through early diagnosis and treatment.

Nineteen and seven patients with PAL were diagnosed at the Chinese People’s Liberation Army General Hospital in Beijing and the First Affiliated Hospital of Xiamen University in Xiamen, respectively, from July 2007 to July 2017. The diagnostic criteria for PAL were as follows (5): (a) histologically proven lymphoma that involves at least one adrenal gland; (b) no prior history of lymphoma; and (c) adrenal lesions are unequivocally dominant if lymph nodes or other associated organs involved. The demographics, clinical manifestations, biochemical examination, imaging features, pathological type, and prognosis of 26 patients with PAL were retrospectively reviewed. The diagnosis of adrenal insufficiency (AI) was based on an 8 am cortisol value <5 µg/dl in combination with a high adrenocorticotropic hormone level.

Statistical analyses were performed using the IBM Statistical Package for the Social Sciences version 16.0. Mean ± standard deviation (SD) and median (interquartile range) are used to describe variables with normal and non-normal distributions, respectively. Frequency and percentage are used to describe categorical data. Group variables with a normal distribution were compared using the t-test, while categorical data were compared using the χ ² test.

We discussed the demographic findings, clinical presentation, biological evaluations, imaging characteristics, pathology, treatment, and prognosis of PAL in two centers from China during the last 10 years. To our best knowledge, the current study is the only reported double center experience of PAL in China.

PAL usually develops in elderly male patients, with a median age at presentation ranging from 48 to 68 years and male/female ratio of 1.8:1–7:1 (5–9); our findings were consistent with the reported age and sex ratio ranges. Dobrinja et al. suggest that the highest incidence occurs in adults approximately 60 years old (10), which corresponds with the present series. The BMI was similar to the existing literatures noted by Yumi, Horiguchi and Huang (11–13), while it was lower than that reported by Laurent et al. (6). This may be attributed to the difference of ethnic, diet structure, and environment.

The median time from symptom onset to the initial diagnosis of PAL was 1 month, which is slightly shorter than that reported for Asian cases (median time, 1.5 months; range, 0.25–12 months) (14–24). Since the adrenal glands are concealed in the retroperitoneum and endocrine inactivity, the initial signs and symptoms are often unspecific. As established by findings from a meta-analysis (5), the most common symptoms were B-symptoms, which include fever, weight loss, night sweats (68%), pain (42%), and fatigue (36%), which corresponds with our data. Regarding signs, adenopathy, splenomegaly, and hepatomegaly were present in 18%, 14%, and 11% in a cases series from Laurent et al. (6), which was slightly higher than the rates in our case series (15%, 4%, and 4%). More specific symptoms and signs, such as hyperpigmentation (41%–74%), salt craving (38%–74%), and postural hypotension (55%–58%), were related to AI in a previous review (25); these signs were present in 42%, 25%, and 50%, respectively, in our population, suggesting that there were few endocrinology consultations or not all patients were managed by the Endocrinology Department. In addition, AI often presented in patients with bilateral adrenal involvement. In the 12 confirmed cases of AI in 19 assessed patients, no patient with unilateral involvement had AI, which is in accordance with the principle that >90% adrenal parenchymal destruction will lead to AI given the huge reserve in adrenal function (26). Consequently, endocrinology evaluation should be performed in patients with bilateral adrenal involvement and/or clinical symptoms or signs of AI. Immune system dysfunction has been proposed as an etiology of PAL (27). Wang et al. reviewed 55 patients with PAL and found that 13% had autoimmune disease (28). However, none of our patients had any prior history of carcinoma or autoimmune disease, which is in accordance with the literatures noted by Kasaliwal and Rashidi (5, 9).

In our series, 75% (15/20) of patients had increased LDH levels, which is in accordance with data shown by Laurent et al. (74%, 20/27) (6), indicating that tumor burden increases with cell turnover but lower than that reported by Rashidi et al. (88%, 70/80) (5), which may be due to the small sample size in the current series. Elevated serum β₂-MG levels may indicate hematological disease, which was present in 100% (10/10) of our cases, higher than the incidence reported by Laurent el al. (71%, 15/21) (6). In addition, serum β₂-MG and CRP levels were the most important predictive factors for overall survival in DLBCL (29–31), which explains the lower median survival in our study compared to that noted by Laurent et al. (6). The ESR and ferritin levels may indicate an inflammatory syndrome, but neither of them lead to a diagnosis of DLBCL or correlate with prognosis.

Diagnostic imaging includes CT, magnetic resonance imaging (MRI), and PET-CT. CT is considered to be the most important imaging modality in evaluating adrenal masses as it can be used for their localization, visualization, and characterization. On CT, 81% of patients (21/26) had bilateral involvement, which was a slightly higher rate than that reported in previous related studies (32); the delayed diagnosis in our series may reflect that unilateral involvement is the process of bilateral lesions. The mean tumor diameter at the time of diagnosis in our case series was 7.31 ± 3.35 cm, which is similar to that in previous related studies (33). The Cleveland Clinic performed a large retrospective study including 299 cases and determined a threshold of 10 HU on non-enhanced CT to distinguish benign and malignant adrenal masses, with a sensitivity and specificity of 79% and 96%, respectively (34). In our series, the median attenuation of PAL was 37 HU, which is in accordance with the density reported by Zhou et al. (35). In addition, the dominant pattern of enhancement after intravenous injection of the medium showed that 88% of our patients had a “slight to moderate enhancement pattern”, which was reported to occur in 78%–100% of cases in previous reports (5, 35), given that PAL is not a hypervascular tumor. This pattern is different from adrenocortical carcinoma and pheochromocytoma, which are hypervascular lesions and show significant enhancement. Furthermore, 71% of patients displayed “homogeneous enhancement.” Conversely, previous studies showed that PAL tends to exhibit a heterogeneous enhancement pattern (36), whereas a study that included 28 cases demonstrated that most had homogeneous or slightly inhomogeneous enhancement (32). ¹⁸F-FDG PET-CT provides anatomical and functional information, both in the adrenal gland and in other involved sites. Twenty-one patients underwent ¹⁸F-FDG PET-CT, which makes our study the largest collection of patients with PAL examined using PET-CT. Due to the metabolic hyperactivity in PAL, SUV levels were elevated with a mean value of 17.72 ± 8.64 and 11.82± 6.08 in adrenal and extra-adrenal lesions, which is slightly lower than the values in a previous report (6). In addition, compared with CT and MRI, PET-CT provides more precise evaluation of PAL extension. Eighty-one percent (17/21) of our cases exhibited ex-adrenal extension on PET-CT, which is higher than the rate reported in the study by Laurent, consistent with the aggressive biological characteristics of PAL.

While clinical manifestations, biological, and imaging can be helpful, a definitive diagnosis can only be made histologically using tissue obtained via needle core biopsy, incisional or excisional biopsy, or autopsy. The DLBCL phenotype was predominant (92%) in our series and ranges 78%–94% in previous reports (12, 33, 37). PAL has a poor prognosis. Two decades ago, the median survival was 4 months (38), with the longest reported survival of 15 months (39). Recently, with the use of the R-CHOP regimen instead of the CHOP regimen, the clinical outcome has improved (40). Unfortunately, the mean survival in our case series was 7.20 ± 5.18 months, which was worse than that in earlier studies (40), suggesting hidden manifestation and that patients may have been diagnosed at a late stage of disease.

PAL is a rare entity that usually occurs in elderly men and more commonly presents with bilateral lesions. ¹⁸F-FDG PET-CT is a major tool in the diagnosis of adrenal lesions and extra-adrenal extensions. The dominant histological phenotype is DLBCL, which can lead to adrenal insufficiency, and has a poor prognosis. Better therapy is required to improve outcomes.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Ethics Committee of West China Hospital of Sichuan University (No. 2019-229). The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

JZ and FY: collected the data and wrote the manuscript draft. YC, LZ, KC, ZL, JD, YM, and ML: contributed to the discussion and revision. GY: designed the study and revised the submission. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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