Primary adrenal lymphoma (PAL) is a rare adrenal malignancy constituting 1% of non-Hodgkin’s lymphoma (NHL), and its most common histological type is diffuse large B cell lymphoma (DLBCL) (1, 2). PAL refers to histopathologically confirmed adrenal lymphoma with no previously diagnosed lymphoma at other sites or with coinstantaneous less-predominant lesions at sites other than the adrenal glands (3, 4). With no past history of lymphoma, PAL is more difficult to diagnose. The overall survival (OS) rate for PAL patients is 19.17% at 5 years and drops to 3.33% at 10 years (1, 5). Disappointingly, the manifestations of PAL are not discriminating, leaving a diagnostic challenge for patients, endocrinologists and surgeons to distinguish PAL from other adrenal masses (6).

Approximately 4% of the general population has adrenal masses (7). Though only 5-10% of them are malignant, the prognoses of these adrenal malignancies are dismal (8). Furthermore, among these adrenal malignancies, the therapeutic regimen for PAL is different (4, 5, 9). Therefore, early diagnosis of PAL is essential. To date, hormone-secreting adrenal lesions, such as adrenal Cushing’s syndrome (ACS), aldosterone-producing adrenocortical adenoma (APA), and aldosterone-producing adrenocortical carcinoma (APC), can be easily screened by hormonal measurements and functional tests. However, it has been reported that PAL and pheochromocytoma (PCC) might simultaneously develop in the same adrenal gland (10). Some PALs can mimic PCC, presenting with moderate to clear elevation of catecholamines (11, 12). PCC preoperative preparation is time-consuming, but the progression of PAL can be extremely aggressive, and patients may even die before receiving chemotherapy (13). Moreover, the diagnosis of hormonally inactive diseases, such as PAL, adrenal metastasis, or silent adrenocortical carcinoma, remains elusive. However, some studies have indicated that nonenhanced computed tomography (CT) has good sensitivity in distinguishing malignant adrenal lesions from benign lesions. Adrenal masses that are smaller than 4 cm and have a density less than 10 Hounsfield units (HUs) are unlikely to be malignant (14). The density of PAL lesions can be variable, and the diameter of PAL ranges from one centimeter to over 10 cm (15–17). In addition, few studies have focused on the differentiation of malignant tumors. In such cases, adrenal biopsy or fine needle aspiration (FNA) may be a diagnostic option when PCC can be fully excluded (14). Therefore, to diagnose PAL, it is essential to screen for PAL in patients with positive catecholamine results and to distinguish patients with PAL from patients with other nonfunctional adrenal masses.

To our knowledge, though not discriminating, PAL is an entity that mainly affects elderly males and both adrenal glands (2). Patients with PAL usually experience fever, abdominal or lumbar pain, weight loss, and adrenal insufficiency (AI) (18). Elevated serum lactate dehydrogenase (LDH) and immune deficiency are common in PAL patients (2). Peripheral lymphocytopenia and a reduction in high-density lipoprotein cholesterol (HDL-C) levels have been reported to be frequent in NHL (19, 20). Additionally, absolute monocyte count was shown to be an independent determinant for central nervous system relapse in patients with DLBCL (21). Nevertheless, few studies have focused on the diagnostic utilities of these variables alone or in combination for PAL.

Thus, in this study, we retrospectively reviewed the medical records of two independent cohorts of patients with nonfunctional adrenal masses and functional PCC from the same institution and aimed to establish a novel diagnostic model for PAL based on clinical, laboratory and radiological data.

PAL is an extremely aggressive adrenal malignancy. Early diagnosis of PAL is essential, but no quick diagnostic method is available. Patients with PAL might die before pathological confirmation (13, 35). In addition, recent studies suggested that unlike other adrenal malignancies, adrenalectomy preceding surgery provided no benefit to PAL patients (4, 5, 9). In contrast, surgery may expose PAL patients to the risk of delay in starting chemotherapy (36). It is recommended that adrenal biopsy should be performed only if the expected findings are likely to alter the management of the individual patients and PCC has been excluded (14). Adrenal masses are detected in approximately 4%-10% of patients receiving cross-sectional imaging (37, 38). The questions are, among patients with adrenal masses, who may have PAL and who should undergo an adrenal biopsy? Imaging studies, such as CT and magnetic resonance imaging (MRI), are capable of revealing adrenal malignancies; however, further diagnosis of PAL is impossible (14). Furthermore, some PAL lesions can be small and hypodense, overlapping with the imaging features of benign disease (17, 36). In addition, up to 40% of adrenal adenomas have an unenhanced attenuation level over 10 (39). This study was the first to develop an individualized and user-friendly model for the diagnosis of PAL and the management of adrenal incidentaloma.

In our study, compared with patients suffering from other adrenal diseases, patients with PAL were more likely to be elderly males; to experience lumbar pain; to have bilateral lesions; to experience B symptoms; and to have a larger D-max, higher LDH levels, lower monocyte counts, lower lymphocyte counts and lower HDL-C levels ( Table 2 ). More importantly, after adjusting the interaction effects, our results showed that older age, bilateral masses, lower HDL-C level and higher LDH level were independently associated with PAL discrimination. However, in the study conducted by Lomte et al., age and bilateral proclivity showed poor discrimination because of their overlaps with PAL, adrenal metastasis and pheochromocytoma (40). Indeed, bilateral adrenal incidentaloma affects 0.3-0.6% of the general population (41). The etiologies of bilateral adrenal incidentaloma are diverse. These studies indicated that a single indicator might not be strong enough to screen PAL. Ozimek et al. reported that LDH levels increased in both PAL and ACC, but they concluded opposite results to our study (16). As their result was merely derived from a comparison between 2 patients, one with PAL and another with ACC, we found that their findings were not reliable. A case-control study unveiled the reverse association of statins, HDL-C stimulators, and NHL (OR 0.61, 95% CI 0.45-0.84) (42). Recently, studies further validated that NHL was an inflammation-induced lymphoma with low circulating HDL-C (42, 43). More specifically, HDL-C is capable of inhibiting the cytokine-triggered endothelial cell adhesion and blocking the activity of lymphocytes and monocytes, thus attenuating the inflammatory response (44). The adrenal gland has a different histological behavior than nodal or extra-adrenal lymphomas in that the adrenal gland does not have lymphatic tissue (2). The pathogenesis of PAL is not yet well understood. No study has investigated the HDL-C level of PAL patients. Derived from multivariate regression analysis, our study showed that a lower HDL-C level was the strongest determinant of PAL. We inferred that HDL-C might also have an important role in the lymphomagenesis of the adrenal gland.

The real-world data of individual patients can be sophisticated. The use of a single index has many drawbacks. Briefly, a significant age difference was observed between patients with PAL and patients with other adrenal diseases, and the age span of patients with PAL and that of patients with other adrenal diseases overlapped (40). Patients of the same age might have different adrenal problems. Individual indices linked PAL diagnosis only to descriptive variables, not to determinant variables. Our study showed that HDL-C was the most powerful indicator, but with much lower discrimination efficiency (compared with that of the nomogram, P < 0.001). Namely, patients with lower HDL-C levels were merely more likely to have PAL without incorporating other variables, such as bilateral proclivity. Given the limitation of the simple index, the nomogram can incorporate variables into an individualized, simple, numeric estimate (30). We established a nomogram to assess the possibility of PAL combined with demographic, radiological and laboratory findings, with an AUC of 95.4%.

Our study showed that 11.09% of the included patients (11.68% in the primary study and 9.36% in the validation study) had bilateral adrenal masses. These findings were slightly inferior to those of previous studies (41, 45). The results of some studies suggested differences in patients with bilateral adrenal disease and unilateral adrenal disease (45). In agreement with former studies, our data showed that patients with PCC and NAA were prone to unilateral lesions, while more patients with PAL or ATB had bilateral disease. However, we found that unilateral adrenal metastasis was more frequent. Further validation tests verified the efficacy of the nomogram, with an AUC of 99.0%. For nonfunctional patients who score over 50 points, direct surgery should be avoided, and an adrenal biopsy should be arranged as soon as possible. Moreover, our findings indicated that the specificity of the nomogram was not significantly weakened by different disease distributions between the unilateral and bilateral groups, and the predictive specificity in patients with unilateral lesions, bilateral lesions, and both was 99.4%, 100%, and 99.35%, respectively. That is, patients who score less than 50 points are less likely to have PAL. In this condition, unilateral adrenalectomy can be considered for unilateral adrenal incidentaloma with suspicious malignant features on imaging, as well as certain tumors larger than 4-6 cm (14). Other causes, such as tuberculosis, should be taken into consideration and carefully evaluated. Similar to the case reported by Cao et al., the 4 patients who were highly suspected of having PCCs in our primary study and the undiagnosed patient in the validation study were ultimately revealed to have PALs based on postoperative pathology (12). According to the nomogram, patients in our validation study scored over 50. Therefore, we want to warn that physicians and surgeons should be cautious about PAL when the score of catecholamine-elevated patients exceeds 50. For these patients, surgery should be arranged as soon as possible to confirm the diagnosis so that chemotherapy can be started early if necessary. The results also revealed that the diagnostic specificity did not considerably decrease in the nonfunctional group (99.2%), was retained perfectly in the functional group (100%) and was higher than that of metanephrines and epinephrines (46). In other words, a score of less than 50 would almost always indicate PCC. Surgery is less urgent for the latter condition, since most PCCs are benign.

The current study had some limitations. First, this analysis was based on data from a single center, and the sample size was relatively small. However, owing to the low incidence of PAL and the application of bootstrapping and external validation, we still found our model to be helpful in clinical practice. However, additional studies and more profiles from other institutions or populations are warranted. Second, owing to the nature of the retrospective study, no PAL patients with unilateral lesions or with overt catecholamine-elevated lesions were included in the validation cohort. More data are needed to evaluate the efficacy of the nomogram in such patients. However, the results of our study did show concordance in the diagnostic specificity of the developed nomogram. In addition, we found the nomogram to be meaningful in clinical practice. Third, some variables were not included in our analysis due to data limitations, such as beta2-microglobulin, C-reactive protein, and mass density on CT imaging.

In the present study, we incorporated independent determinant variables, including age, bilateral masses, lower HDL-C and higher LDH, into a nomogram to distinguish PAL from nonfunctional adrenal masses and functional PCC. This nomogram exhibited good discriminations. We found that the developed nomogram was capable of guiding the decision-making of adrenal incidentaloma and functional PCC.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This study was approved by the Ethics Committee of West China Hospital of Sichuan University and adhered to the Declaration of Helsinki (No. 2019-556).

KY and YR designed the study. KY and FZ collected and cleaned the data. KY, FZ, and TC reviewed the medical records. KY and QPX analyzed the data and wrote the manuscript. QX helped in data collection. HT and YR supervised the study. All authors contributed to the article and approved the submitted version.

This study was funded by the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYGD18022).

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.