Abstract
Background/Aim: Primary adrenal lymphoma (PAL) is rare and aggressive. The aim of this retrospective study was to compare the results of surgery and chemotherapy compared to chemotherapy alone for the treatment of this condition. Patients and Methods: Sixteen patients, 10 men and 6 women of a median age of 63 years (IQR=56-70.5 years), admitted for the treatment of PAL, were retrospectively reviewed. Six patients (37.5%) underwent surgical resection of the mass followed by CHOP (cyclophosphamide, doxorubicin, vincristine, bleomycin and prednisone) – based chemotherapy (Group A). Ten patients (62.5%) underwent chemotherapy alone, consisting of CHOP alone in one case and Rituximab-CHOP (R-CHOP) in 9 cases (Group B). As primary study endpoints of the study, overall survival (OS) and progression-free survival (PFS) were considered. Results: At two years follow-up, OS was 50% in Group A and 60% in group B (p=0.69). The PFS was 50% in group A and 30% in group B (p=0.42). Conclusion: PAL exhibits overall a dismal prognosis. Chemotherapy remains the most appropriate treatment, although unable to ensure long-term survival. Surgery combined with chemotherapy is ineffective in improving survival and may, at best, have a limited role in relieving the pain related to the local mass effect.
Primary adrenal lymphoma (PAL) is extremely rare, as it accounts for less than 1% of all non-Hodgkin lymphomas (1-4). At a review published in 2013, less than 200 cases had been reported (5). PAL tends to be frequently bilateral (6, 7) and quite aggressive, bearing overall a poor prognosis (5). Due to its often-unspecific clinical presentation and to the difficulty of distinguishing it from other primary adrenal masses such as carcinoma and pheochromocytoma at diagnostic imaging, appropriate treatment may be delayed (3, 6-8). Such rarity also accounts for a relative lack of guidelines on the optimal treatment of this condition (3) and, in particular on the efficacy of surgery followed by chemotherapy compared to chemotherapy alone. Overall, adrenalectomy is thought to add no significant advantage in the treatment of PAL (3), nonetheless it may have a role especially in case of large masses causing difficult-to-control pain.
The purpose of the present study was to retrospectively evaluate our experience on the diagnosis and treatment of PAL, in order to contribute to a better definition of the most appropriate treatment of this rare and aggressive condition.
Patients and Methods
The records of patients addressed to a tertiary care academic hospital and an affiliated oncologic hospital for a primary, isolated and histologically proven adrenal lymphoma, from January 2000 to December 2020 were retrospectively reviewed. Patients presenting associated extra-adrenal localizations of the disease, adrenal masses either metastatic, histologically undetermined or other than lymphoma and patients with a previous history of neoplasms at extra-adrenal localizations were excluded from the study. Due to the retrospective nature of the study, institutional ethical approval was waived. Sixteen patients, 10 men and 6 women with a median age of 63 years (IQR=56-70.5 years) were entered in the study, representing 4.3% of the overall 373 patients treated for adrenal masses at the same institutions during the same time period.
Clinical presentation. No patient had a history or a diagnosis of autoimmune disease nor presented immunosuppression. No patient presented neurological symptoms. Thirteen patients (81.2%) presented abdominal discomfort. Symptoms suggestive of a systemic disease such as fever, night sweats, and weight loss were present in 2 (12.5%), 10 (62.5%) and 12 (75.0%) patients, respectively. In addition, 12 patients (75.0%) presented anorexia and 6 patients (37.5%) presented back pain. Presenting symptoms are summarized in Figure 1. Six patients (37.5%) were assuming antihypertensive drugs, 5 patients (31.2%) were current smokers, 4 patients (25.0%) were diabetic, 2 patients (12.5%) had a history of coronary artery disease, one patient (6.2%) presented peripheral arterial disease, and one patient (6.2%) presented chronic renal insufficiency (plasma creatinine level >1.5 mmol/l). Median body mass index (BMI) was 23.8 Kg/m2 (IQR=21.9-26.2 Kg/m2). Demographics and baseline patients’ characteristics are shown in Table I.
Presenting symptoms of primary adrenal lymphoma.
Demographics and baseline patients’ characteristics.
At biological and endocrinological examinations, C-reactive protein (CRP) was elevated (>50 mg/l) in 12 (75.0%) of the patients, 5 patients (31.2%) presented hypercalcemia (ionized serum calcium level >1.30 mmol/l), serum lactate dehydrogenase (LDH) was elevated in 10 (77.0%) out of 13 patients tested, ferritinemia was elevated (>1,000 mg/l) in 2 (28.7%) of 7 patients tested, hydroxybutyrate dehydrogenase (HBDH) was elevated (>182 U/l) in 2 (40.0%) out of 5 patients tested, and one patient (6.2%), with bilateral PAL, presented initial adrenal insufficiency with hypotension, hyponatremia, and serum cortisol level <140 mmol/l.
Imaging. All the patients were studied with a CT-scan of the head, chest, abdomen and pelvis, which revealed an adrenal mass of a median density of 40 HU (IQR=36.5-46 HU) and of a median diameter of 63.5 mm (IQR=48.5-69 mm). The mass was bilateral in 7 patients (43.7%) (Figure 2). Nine patients (56.2%) also underwent magnetic resonance imaging, revealing an adrenal mass hypointense in T1 and hyperintense in T2 (Figure 3). No patient presented with radiological signs of infiltration of local organs or tissues.
Computed tomography scan of the abdomen, sagittal sequence, showing a bilateral adrenal mass, without extension to the surrounding tissues.
Magnetic resonance imaging study of the abdomen, showing a bilateral adrenal mass.
Surgery. The first six patients of the series (37.5%), underwent surgical resection of the mass from January 2000 to October 2009. Access was gained through an extraperitoneal route, via a lombotomy on the 11th rib in 3 patients bearing a unilateral PAL. Two patients presenting with a bilateral PAL underwent resection via a bi-subcostal, trans-peritoneal approach. One patient bearing a unilateral PAL of 4.0 cm in diameter underwent laparoscopic resection. Before surgery, all the patients received 25 mg/day of oral cortisone acetate for a week.
Pathology. Pathological diagnosis of lymphoma was done on the resected surgical specimen in the 6 operated patients and on the tissue collected through fine needle aspiration (FNA) in 10 non-operated patients. Histological diagnosis was performed and revised in agreement with the WHO criteria (9).
Chemotherapy. All the patients, 6 after surgical resection of the mass and 10 non-operated ones, received six cycles of chemotherapy over 4 months, including cyclophosphamide, doxorubicin, vincristine, bleomycin and prednisone (CHOP). CHOP was associated with Rituximab (R-CHOP) in the latest 9, non-operated patients of the series. For the study’s purposes, the patients were divided into two groups. Patients in Group A (n=6) underwent surgical resection of the mass followed by CHOP-based chemotherapy, whereas patients in Group B (n=10) underwent chemotherapy alone, consisting of CHOP alone in one case and R-CHOP in 9 cases. No patient in either group underwent complementary radiation therapy. Patients were followed-up for a median length of 25 months (IQR=18.5-31) with clinical, laboratory investigations and CT-imaging according to standard oncological protocols.
Primary endpoints. As primary endpoints of the study, overall survival (OS) and progression-free survival (PFS) were considered. The efficacy of adding Rituximab to standard CHOP chemotherapy was also evaluated. Eventual, statistically significant, correlations of elevated humoral markers with late survival were investigated, as well as the unilateral or bilateral localization of the PAL.
OS was defined as global survival minus any death related to the adrenal disease, whereas PFS was defined as the overall surviving population minus any surviving individual with evidence of recurrent or progressing neoplastic disease at CT-imaging.
Secondary endpoints. As secondary endpoints, postoperative mortality, morbidity, and postoperative length of hospital stay, in patients undergoing surgical resection of the mass, were considered. Durable relief of pain at primary tumor site was also considered as secondary endpoint. Durable pain relief was defined as no need for analgesic administration during the whole length of follow-up for pain related to the primary tumor site.
Statistical analysis. Continuous data were expressed as the median and interquartile range (IQR) with 95% confidence interval (CI). Categorical data were presented as percentages with 95%CI. Continuous data were compared with the Student’s t-test, whereas categorical variables between groups were compared with the chi-square test. To evaluate and compare OS and PFS, the Kaplan–Meier method was used. Differences were considered statistically significant at a p-value <0.05. The data of the study were analyzed using the IBM SPSS Statistics v. 24 (IBM Corporation, Armonk, NY, USA).
Results
Primary endpoints. At two years follow-up, OS was 50% in Group A and 60% in group B (p=0.69) (Figure 4). The PFS was 50% in group A and 30% in group B (p=0.42) (Figure 5). Patients presenting hypercalcemia at the time of referral had both a worse OS and PFS, as none survived up to 2 years compared to the rest of the study population, presenting at 2 years a OS of 63.6% (p=0.02) and a PFS of 54.5% (p=0.04). No significant difference was observed in patients presenting with elevated levels of serum LDH in terms of OS (50%) and PFS (20%), compared to the rest of the study population presenting both an OS and a PFS of 67%, (p=0.37 and p=0.12). OS and PFS at two years, in patients treated with CHOP and patients treated with R-CHOP, were 57% and 43%, and 56% and 33%, respectively (p=0.95 and 0.69). OS and PFS in patients presenting with a monolateral localization of the PAL were 67% and 44%, compared to 57% and 29% in patients presenting with a bilateral localization of the condition (OS, p=0.61; PFS, p=0.006).
Kaplan–Meier estimate of overall survival (OS) of the two study groups (Group A, surgery+chemotherapy; Group B chemotherapy alone). The numbers at the bottom of the curves indicate the number of patients at risk for each time interval. Red line, Group A; Blue line, Group B.
Kaplan–Meier estimate of progression–free survival (PFS) of the two study groups (Group A, surgery+chemotherapy; Group B chemotherapy alone). The numbers at the bottom of the curves indicate the number of patients at risk for each time interval. Red line, Group A; Blue line, Group B.
Secondary endpoints. No patient died in the postoperative period. One patient operated for bilateral PAL via a bi-subcostal laparotomy presented a delayed return to normal intestinal motility, requiring prolonged naso-gastric aspiration, which resolved without the need for redo surgery. Overall, the incidence of postoperative morbidity was 16.7%. The median postoperative length of hospital stay was 9 days (IQR=7-10.5 days).
Durable relief of pain at the primary tumor site was obtained in 5 out of 6 patients in Group A (83.3%) and in 5 out of 10 in Group B (50.0%) (p=0.18). All the 4 non-operated patients, with local pain resistant to chemotherapy alone, presented with a bilateral PAL exceeding 68 mm in diameter at diagnostic imaging.
Discussion
The results of this study show that adding surgical resection to chemotherapy does not improve both OS and PFS compared to chemotherapy alone. This observation is in agreement with other, previous reports (3, 4, 10), and in fact, surgery was limited to the early years of the present series, as in the latest ten years, chemotherapy alone was the treatment of choice. Nonetheless, we observed that surgery followed by chemotherapy may be more effective than chemotherapy alone in controlling local pain, in patients with large, bilateral PAL. Therefore, surgery could still be considered prior to chemotherapy in the treatment of PAL in selected cases of large adrenal masses whose prevalent presenting symptom is persistent back pain or intense abdominal discomfort, provided that resection of the mass can be accomplished with satisfactory postoperative results (3, 11). The results of surgery followed by a relatively uneventful postoperative course in this series, seem to support this assumption.
Hypercalcemia and elevated plasma levels of LDH are usually thought to be a marker of poor prognosis (4). In the present series, we observed a poorer prognosis in patients with hypercalcemia, but were unable to find this correlation with elevated serum levels of LDH, probably due to the small patient number analyzed. On the other hand, a correlation was observed according to the localization of the disease at the time of diagnosis, as patients with a bilateral adrenal mass exhibited a significantly shorter PFS, although OS was not significantly different.
The addition of rituximab to the standard CHOP chemotherapy is overall deemed to significantly improve OS and PFS (2, 10, 12). In the present series, we failed to demonstrate such advantage with statistical significance, but again, this non-conclusive result must be related to the small cohort of patients analyzed in this study. Nonetheless, over the last ten years, the association of rituximab to CHOP remains the standard treatment of PAL, according to current protocols (10, 13). A possible, alternative treatment protocol, based on the association rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) has also been proposed and may be more appropriate in young patients or as a second line treatment with the aim of prolonging survival (14-16).
Radiation therapy combined with chemotherapy for local control of PAL would be appealing, especially in patients with large, unresectable adrenal masses associated with pain and infiltration of adjacent organs, for which isolated chemotherapy may be insufficient. Unfortunately, radiation therapy has not proven to be effective in this setting and, therefore, is not indicated (17). None of our patients was treated with radiation therapy.
The main limitation of this study is its retrospective nature, which, combined with the long-time span and the small number of patients, does not allow to consider the results conclusive, nor to define a standardization of treatments. However, given the rarity of PAL, large and prospectively studied patient cohorts are actually absent, as most studies consist of isolated case reports or small, retrospective case series. One further limitation of the study is the difference in the chemotherapy administered; CHOP only in the surgical group and R-CHOP in all but one non-surgical patients. On the other hand, one minor strength of this study is that no patient was lost at follow-up, which allowed a reliable and objective data collection and assessment.
Conclusion
In conclusion, the results of this study show that PAL exhibits overall a dismal prognosis. Chemotherapy remains, at the moment, the most appropriate treatment, although unable to ensure long-term survival. Surgery combined with chemotherapy is ineffective in improving survival and may, at best, have a limited role, in selected cases, in the relief of pain related to the local mass effect.
Footnotes
Authors’ Contributions
Giulio Illuminati, Carla Giordano, Marco Girolami, Fabio Carboni: Conceptualization; Priscilla Nardi, Chiara Fratini, Rocco Pasqua: Data curation; Giulio Illuminati, Carla Giordano, Marco Girolami, Fabio Carboni: Formal analysis; Priscilla Nardi, Chiara Fratini, Rocco Pasqua: Software; Giulio Illuminati: Supervision; Giulio Illuminati, Carla Giordano, Fabio Carboni: Validation; Giulio Illuminati: Writing - review & editing; Giulio Illuminati, Priscilla Nardi, Chiara Fratini, Rocco Pasqua, Carla Giordano, Marco Girolami, Fabio Carboni: Final approval.
Conflicts of Interest
The Authors declare no conflicts of interest related to this study.
- Received March 1, 2021.
- Revision received April 9, 2021.
- Accepted April 12, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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