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Correlations between MDCT features and clinicopathological findings of primary adrenal lymphoma
European Journal of Radiology 113 (2019) 110–115
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Research article
Correlations between MDCT features and clinicopathological findings of primary adrenal lymphoma Ling yanga, Mengni Zhangb, Shuang Zhaoa, Yajun Hua, Jin Yaoa, a b
T
⁎
Department of Radiology, West China Hospital of Sichuan University, 37# Guoxue Street, Wuhou District, Chengdu, Sichuan 610041, China Department of Pathology, West China Hospital of Sichuan University, 37# Guoxue Street, Wuhou District, Chengdu, Sichuan 610041, China
A R T I C LE I N FO
A B S T R A C T
Keywords: Lymphoma Adrenal gland Primary Computed tomography
Objective: To investigate the MDCT features of primary adrenal lymphoma (PAL) and correlate the results with clinicopathological findings. Materials and methods: Twenty eight patients (17 men, 11 women; median age, 61.5years) with pathologically confirmed PAL were included in this study. MDCT features of the lesions were retrospectively reviewed and correlated with clinicopathological findings. Results: All of the 28 cases were non-Hodgkin’s lymphoma (NHL), in which 25 cases were diffuse large B-cell lymphoma and 3 cases T-cell lymphoma. 21 (75%) patients had bilateral tumors with maximum diameter of 3.9–17.7 cm (median, 9.18 cm), and 7 (25%) patients had unilateral tumors with maximum diameter of 4.3–14.9 cm (median, 8.6 cm). The sign of infiltrating adjacent organs and encasing adjacent vessels were appeared in 10 and 15 patients respectively, in which 9 patients had both signs. 20 (71.4%) patients had the appearance of adeniform, and 3 (10.7%) patients showed infiltrating and embedding the adrenal gland. Among all the patients, 27 (96.4%) and 26 (92.9%) patients had mild enhancement on arterial and parenchymal phase, respectively; and 12 (42.8%) were homogenous, 14 (50%) slightly inhomogeneous and 2 (7.1%) heterogeneous on both phase. In addition, adrenal insufficiency was found in 33.3% (7/21) of the patients with bilateral lesions, and none in unilateral lesions. Conclusion: Large adrenal soft tissue mass with maintenance of adreniform shape, encasing vessels, homogenous or slightly inhomogeneous density with no calcification, and mild enhancement on both arterial and parenchymal phase could be seen as the main MDCT features of PAL. In addition, infiltrating and embedding the adrenal gland may be specific imaging characteristics of PAL.
1. Introduction Primary adrenal lymphoma (PAL) shares a small proportion (about 3% [1]) of extranodal lymphomas arising from non-lymphoid tissues or at sites other than the expected native lymph nodes or lymphoid tissues [2]. More and more PAL has been reported in the past decade (about 200 cases worldwide up to now), and they are often histologically aggressive in biological behavior [2–4]. Patients with PAL always have varied clinical symptoms such as local pain, fever, weight loss or adrenal insufficiency [5], and they may go to department of urology, hematology, endocrine or infection first, making it difficult to diagnose accurately for clinicians from these different departments. Under such circumstance, the radiologist may play an important role to guide the treatment in the right direction. So, comprehensive understanding of the clinical manifestation and imaging findings of PAL are very
⁎
important for all the clinicians of above departments, and especially radiologist, as the extensive application of imaging techniques nowadays. Although the clinic-pathological features of PAL are well characterized [3,5,6], the appearance of these tumors on imaging is not well documented. To date, the most extensive reports regarding the imaging characteristics of PAL is by Zhou et al. [7] and others focused on case reports [8–11]. To better characterize the radiological features of this disease, we present the multi-detector computed tomography (MDCT) features of 28 cases PAL, and correlated them with the clinic-pathological findings. To our knowledge, this is the largest and most detailed radiologic case series reported to date.
Corresponding author. E-mail address: [email protected] (J. Yao).
https://doi.org/10.1016/j.ejrad.2019.02.003 Received 6 January 2019; Received in revised form 29 January 2019; Accepted 1 February 2019 0720-048X/ © 2019 Published by Elsevier B.V.
European Journal of Radiology 113 (2019) 110–115
L. yang, et al.
Fig. 1. Profile of patient enrollment.
2. Materials and methods
2.2. CT protocol
2.1. Study population
All patients had undergone plain and enhanced MDCT examination, and the scan technique varied somewhat owing to the retrospective nature of the study. After performing unenhanced imaging, Ominipaque contrast agent was injected through the cubital vein. 100–150 ml of contrast agent at a rate of 3 ml/s was administered by power injection. Then arterial and parenchymal phase scans were initiated at 20–30 and 60–80 s after the start of the injection, respectively. In general, examinations were performed using a spiral technique with 2–5 mm collimation and 2–5 mm reconstruction intervals. 13 patients were scanned using 64 multi-detector CT (Philips Brilliance) with 120 kV voltage, 210 mA current and width of collimator 64 × 0.625 mm, and 14 patients were scanned using dual source CT (Somaton Definition; Siemens Medical Solutions, Forchheim, Germany) with 120 kV voltage, 200 mA current.
This study was approved by the local institutional review board with waiver of individual consent. From January 2010 to September 2018, 3280 patients with pathologically proved lymphoma who were treated at our institution were screened out. We only included patients with PAL. Patients were excluded if they had no involvement of the adrenal gland; had a history of leukemia or lymphoma elsewhere, involvement of non-adjacent organs and lymph nodes [5–7] or insufficient imaging evidence. If the adjacent organs including spleen, liver, kidney, pancreas and lymph nodes were involved and adrenal lesions were unequivocally dominant, the patients were still judged as PAL [5,6]. Finally, 28 patients (17 men, 11 women; mean age 61.5 years; age range 20–82 years) were enrolled (Fig. 1). At the time of initial diagnosis, 21 patients had symptoms which included abdominal and low back pain (48.1%, 13/27), fever (18.5%, 5/27), weak (7.4%, 2/27), weight loss and hyperpigmentation (3.7%, 1/27). One patient had a history of clear cell renal cell carcinoma, and adrenal lymphoma appeared simultaneously with the renal tumor and progressed during the follow-up with symptoms of fever. One patient had a history of hepatitis with symptoms of fever, and another one had a history of HIV with symptoms of back pain. Adrenal insufficiency was defined as low baseline cortisol or normal baseline cortisol which fails to rise sufficiently upon ACTH stimulation [3].
2.3. Imaging analysis The images were reviewed by two radiologists with more than 5 years’ experience in abdominal imaging by consensus, and both of them were aware of the clinical data. The CT images were evaluated for bilateral or unilateral, symmetry, size, preservation of “adeniform” shape [6], density in plain and enhanced images, degree and patterns of enhancement, involvement of adjacent vessels and organs. When bilateral lesions were presented, we measured tumor size of the larger side. The preservation of “adeniform” shape (V-shape) was defined as tumor with a triangular or forking shape displayed in any of the axial, coronal or sagittal position. Density was measured on the maximum level of the 111
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Fig. 2. 60-year-old man with primary bilateral adrenal B-cell lymphoma. Unenhanced (A), arterial (B) and parenchymal (C, D) phase CT images show symmetrical adrenal masses with mildly homogenous enhancement; and sagittal image (D) shows a triangular shape of the right adrenal mass.
Fig. 3. 56-year-old man with primary unilateral adrenal B-cell lymphoma. Unenhanced (A), arterial (B) and parenchymal (C, D) phase CT images show a slightly inhomogeneous left adrenal mass with mild enhancement which encased the left renal artery (thick arrow). Enhanced axial (C) and coronal (D) images show that the tumor infiltrated and embedded the adrenal gland (fine arrow). 112
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Table 1 MDCT features of patients with primary adrenal lymphoma on different phases. Phase
UE AP PP
CT value
enhanced
homogeneity (n)
enhanced degree (n)
(HU)
value(HU)
homogeneous
SI
heterogeneous
mild
moderate
marked
34.5 (26-39) 49.0(32-74) 59.0 (41-81)
none 13.8(4-32) 24.5 (12-50)
12(42.8%) 12(42.8%) 12(42.8%)
15(53.6%) 14(50%) 14(50%)
1(3.6%) 2(7.1%) 2(7.1%)
none 27(96.4%) 26(92.9%)
none 1(3.6%) 2(7.1%)
none none none
UE, unenhanced; AP, arterial phase;PP, parenchymal phase;HU, Housefield unit;SI,slightly inhomogeneous.
data on radiological diagnosis is insufficient [5–7]. Strict definition of PAL must be confined to the adrenal gland and its contiguous lymph node group at the time of diagnosis, and without involvement of other organs before and after treatment [4,7]. The etiology of PAL is unclear at present, and several factors such as prior autoimmune adrenalitis, EBV infection, immune dysfunction, mutations in the p53 and c-kit genes have been implicated in the pathogenesis of PAL [3,5,6]. And in our study, five patients were positive for EBV-encoded small RNAs, another two patients had HIV infection and hepatitis respectively. However, the relationship between different kinds of infection and lymphoma are still unclear up to now [5,6,13,14]. Previous researches thought that the adrenal gland contained no lymphoid tissue, and the follicle center cell origin of this lymphoma suggested that the tumor might have arisen on a background of previous autoimmune adrenalitis [11], but it cannot explain the cases without adrenal insufficiency and follicle center. Indeed, there are small lymphatic channels drained from both cortex and medulla to the hilum where larger caliber lymphatic channels drained directly into the lateral groups of para-aortic nodes as described in the Gray’s anatomy [15], which means that normal adrenal gland contains lymphocyte. We may suggest that adrenal lymphoma is the result of lymphocytic reactive response of adrenal gland, but not only adrenal autoimmune inflammation, as the similar way reported in central nervous system lymphoma [16]. The clinical data including gender, age, abdominal pain and B symptoms were similar to the previous reports [3,5–7]. The elderly patients with typical B symptoms or adrenal insufficiency were more common and suggestive of adrenal lymphoma. However, adrenal insufficiency caused by malignant tumors requires destruction about 90% of adrenal parenchyma due to large adrenal reserve, and it was uncommon in other localized malignant tumors [6,17]. Some authors believe that PAL may rise on a background of previous autoimmune adrenalitis, and lymphoma cells also produce cytokine mediated paracrine to effect on the adrenal cell microenvironment, which both will cause adrenal insufficiency [6,11]. This assumption can explain the presence of adrenal insufficiency even in PAL patients with small masses [3,6]. Our study showed that adrenal insufficiency was appeared in 33.3% of the bilateral adrenal lymphomas with the minimum diameter of 3.9 cm, which may indicate that adrenal insufficiency was not just appeared in huge bilateral lesions. Our study demonstrated that bilateral involvement occurred in 75% (21/28) of our patients, 2 of the 21 bilateral patients were almost symmetric and others were unsymmetrical when initially diagnosed. The mechanism of bilateral adrenal lymphoma may be “homing theory” and previous autoimmune adrenalitis history, while the unilateral lymphoma may be derived from haemopoetic tissue [3,18]. The lesion sizes in our study were large, but it doesn’t mean that all the lymphomas were huge because we only measured the bigger side, and part of the reason is that it is difficult to diagnose when the lesions are small. However, adrenal lymphoma grows rapidly with high ki-67 value. So it should be taken into consideration when rapid growth occurs. This sign may be confused with adrenal metastasis since it may be appeared as bilateral lesions and rapid growth too. Whether there was extra-adrenal malignancy was not an absolute condition to diagnose metastasis or lymphoma as one of our case accompanied by renal cell carcinoma.
lesion in the axial image, and enhanced value was measured on the arterial and parenchymal phase respectively. The degree of tumor enhancement similar to that of muscles, livers and kidneys were graded mild, moderate or marked enhancement, respectively. The enhancement patterns were divided into homogeneous, slightly inhomogeneous, and heterogeneous. 3. Results The prevalence of PAL in our institution was 0.85% (28/3280), and secondary adrenal lymphoma less than 5.4% (178/3280). All of the 28 cases were non-Hodgkin’s lymphoma (NHL), in which 25 cases were Bcell lymphoma and 3 cases were T-cell lymphoma. The average value of ki-67 was 78.8% (40–95%) and 68.3% (60–75%), respectively. The Bcell lymphomas were all diffuse large B-cell lymphoma (DLBCL) phenotype positive for CD 20, in which two cases was associated with Epstein-Barr virus (EBV), and seventeen were source of non-germinal center. All of the lesions with T-cell lymphoma were associated with EBV. In addition, seven patients had lymphadenopathy in the adjacent retroperitoneal area, and all of them were B cell subtype. Of the 28 patients, 75% (21/28) of them were bilateral, and 25% (7/28) were unilateral. The maximum diameters of the bilateral and unilateral lesions were 9.18 (3.9–17.7) cm and 8.6 (4.3–14.9) cm, respectively. Two of the 21 patients with bilateral lesions were almost symmetrical (Fig. 2), and the others were asymmetrical. Adrenal insufficiency was found in 33.3% (7/21) of the patients with bilateral lesions, with the maximum diameters of 8.54 (3.9–13.2) cm. 20 of the 28 patients had the appearance of adeniform shape. In addition, there is another phenomenon worth mentioning, that is another 3 patients including two B cell and one T cell lymphoma showed the feature of infiltrating and embedding the adrenal gland (Fig. 3). The MDCT features of patients with PAL on different phases were demonstrated in Table 1. On unenhanced CT images, all the lesions were slight hypodensity which was slightly lower than that of muscle, and most of them were homogeneous or slightly inhomogeneous. On both arterial and parenchymal phase, most of the lesions demonstrated mild enhancement with homogeneous or slightly inhomogeneous patterns. And the average maximum diameters of the lesions with homogenous, slightly inhomogeneous and heterogeneous enhancement were 6.56 cm, 10.24 cm and 15.45 cm, respectively. In addition, calcification was not demonstrated in all the lesions; and there was no significant difference of the MDCT features between B and T cell lymphoma. The sign of infiltrating adjacent organs, encapsulating adjacent vessels and both of them were appeared in 10 (35.7%), 15 (53.6%) and 9 (32.1%) patients, respectively (Fig. 4). Among them, 10 patients had the symptom of low back pain. 4. Discussion Although lymphomas are generally thought of as tumors of lymph nodes, about 25–40% of them arise at the extranodal site [4,12]. Previous studies showed that the prevalence of secondary adrenal lymphoma is about 5% and PAL was less than 1% of all non-Hodgkin lymphomas [5–7], which was in consistent with our findings. More and more PAL was reported systematically in recent years; however, the 113
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FDG PET/CT play an important role in distinguishing them because PAL limited to adrenal alone while adrenal metastases always involved other organs [18,19]. In addition, adrenal metastasis always has similar density, enhancement patterns and treatment outcome or evolution with the primary tumors or other metastasis. The adeniform shape was emphasized by many authors to strongly suggestive of lymphoma, which could represent the characteristics of diffuse lymphomas infiltration [3,6,7], and was appeared in most of our patients. As far as we know, this sign rarely appeared in other type of huge occupying lesions, but could be seen in hyperplasia and infection which could usually be determined by clinical history and laboratory data [7,17,18,20]. In our study, three patients had the characteristics of infiltrating and embedding the adrenal gland which had not been reported in previous literatures, and it may be speculated that the origin of lymphoma may be the rich lymphatics of adrenal capsule. Although the morphology, density and growth pattern of PAL in our study have been mentioned in some of previous case reports and small sample studies [20–22], herein we provide the most detailed and comprehensive results. Some huge lesions might be heterogeneous because of necrosis which should take pheochromocytoma and adrenal cortical carcinoma (ACC) into consideration. However, pheochromocytoma and ACC are more likely to be unilateral, have calcification and cortical or medullary related endocrine abnormalities [1,8,17,18]. In addition, pheochromocytoma is more likely to be cystic and solid components of the tumor usually show intense enhancement that is greater than 110 HU in the arterial phase [1,23]. And ACCs are commonly accompanied by necrosis, hemorrhage, heterogeneous enhancement, and vascular invasion [1]. The common treatment for PAL was chemotherapy, surgery and radiation therapy, in which the first two methods were significantly associated with longer survival [3]. However, multivariable analysis showed that administration of chemotherapy was independent predictor of outcome [3]. It is worth mentioning that operative treatment might base on incorrect diagnosis. In addition, previous studies have pointed out that poor prognostic factors for PAL are advanced age, large tumor size, elevated lactate dehydrogenase level, bilateral adrenal involvement and adrenal insufficiency [3,5]. In conclusion, PAL should be considered in patients with large adrenal mass with maintenance of adreniform shape, encasing vessels, homogenous or slightly inhomogeneous density with no calcification, mainly mild enhancement on both arterial and parenchymal phase, especially in patients with bilateral lesions, adrenal insufficiency and without history of malignant tumor. In addition, infiltrating and embedding the adrenal gland may be specific imaging characteristics of PAL. Grants No concerning grants were received. Conflict of interests The authors declare that there is no Conflict of Interests References [1] K. Herr, V.F. Muglia, W.J. Koff, A.C. Westphalen, Imaging of the adrenal gland lesions, Radiol. Bras. 47 (2014) 228–239. [2] S.S. Hedgire, S. Kudrimoti, I.S. Oliveira, et al., Extranodal lymphomas of abdomen and pelvis: imaging findings and differential diagnosis, Abdom. Radiol. (N. Y.) 42 (2017) 1096–1112. [3] A. Rashidi, S.I. Fisher, Primary adrenal lymphoma: a systematic review, Ann. Hematol. 92 (2013) 1583–1593. [4] S.C. Chua, F.I. Rozalli, S.R. O’Connor, Imaging features of primary extranodal lymphomas, Clin. Radiol. 64 (2009) 574–588. [5] C. Laurent, O. Casasnovas, L. Martin, et al., Adrenal lymphoma: presentation, management and prognosis, QJM 110 (2017) 103–109. [6] R. Kasaliwal, M. Goroshi, K. Khadilkar, et al., Primary adrenal lymphoma: a single-
Fig. 4. 53-year-old woman with primary bilateral adrenal B-cell lymphoma. Unenhanced CT image (A) shows slightly inhomogeneous bilateral adrenal masses; Arterial (B) and parenchymal (C) phase CT images show heterogeneously enhanced adrenal masses which encase the superior mesenteric artery and inferior vena cava (arrow) and infiltrate the right kidney (arrow). Histopathologic photograpy (D, H&E staining, original magnification at 40×). 114
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[16] X. Wang, D. Huang, X. Huang, et al., Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): a lymphocytic reactive response of the central nervous system? a case report, Neuroimmunology 305 (2017) 68–71. [17] S.A. Aziz, B.A. Laway, I. Rangreze, et al., Primary adrenal lymphoma: differential involvement with varying adrenal function, Indian. J. Endocrinol. Metab. 15 (2011) 220–223. [18] P. Gupta, A. Bhalla, R. Sharma, Bilateral adrenal lesions, J. Med. Imaging Radiat. Oncol. 56 (2012) 636–645. [19] E. Bednaruk-Młyński, J. Pieńkowska, A. Skórzak, et al., Comparison of positron emission tomography/computed tomography with classical contrast-enhanced computed tomography in the initial staging of Hodgkin lymphoma, Leuk. Lymphoma 56 (2015) 377–382. [20] S. Pongpornsup, P. Eksamutchai, W. Teerasamit, Differentiating between abdominal tuberculous lymphadenopathy and lymphoma using multidetector computed tomography (MDCT), J. Med. Assoc. Thai. 96 (2013) 1175–1182. [21] S. Murao, T. Kiuchi, Adrenal lymphoma presenting with the CT angiogram sign, Intern. Med. 57 (2018) 1945–1946. [22] T.P. Tanpitukpongse, S. Kamalian, M. Punsoni, et al., Radiology-pathology conference: primary adrenal lymphoma, Clin. Imaging 36 (2012) 156–159. [23] M. Shaunagh, J.M. Colin, A.B. Michael, Images of pheochromocytoma in adrenal glands, Gland. Surg. 4 (2015) 350–358.
center experience, Endocr. Pract. 21 (2015) 719–724. [7] L. Zhou, W. Peng, C. Wang, et al., Primary adrenal lymphoma: radiological; pathological, clinical correlation, Eur. J. Radiol. 81 (2012) 401–405. [8] A. Ozimek, J. Diebold, R. Linke, et al., Bilateral primary adrenal non-Hodgkin’s lymphoma and primary adrenocortical carcinoma–review of the literature preoperative differentiation of adrenal tumors, Endocr. J. 55 (2008) 625–638. [9] F. Karimi, Primary adrenal lymphoma presenting with adrenal failure: a case report and review of the literature, Int. J. Endocrinol. Metab. 15 (2017) e12014. [10] J.P. Wang, H.R. Sun, Y.J. Li, et al., Imaging features of primary adrenal lymphoma, Chin. Med. J. (Engl.) 122 (2009) 2516–2520. [11] R.D. Ellis, D. Read, Bilateral adrenal non-Hodgkin’s lymphoma with adrenal insufficiency, Postgrad. Med. J. 76 (2000) 508–509. [12] A.T. Ilica, K. Kocacelebi, R. Savas, A. Ayan, Imaging of extranodal lymphoma with PET/CT, Clin. Nucl. Med. 36 (2011) e127–138. [13] Z. Zhao, L. Sun, S. Liu, et al., Characterization of Epstein-Barr virus-encoded small RNA gene variations in virus associated lymphomas in Northern China, Arch. Virol. 162 (2017) 1609–1616. [14] M. Fabrizio, S. Enea, M. Alfonso, A.C. Carmelo, P. Alessandro, The association of hepatitis B virus infection with B-cell non-Hodgkin lymphoma – a review, Am. J. Blood. Res. 2 (2012) 18–28. [15] Jeremiah C. Healy, Neil R. Borley, Abdomen and pelvis, in: Susan Standring (Ed.), Gray’s Anatomy, Elsevier Inc, Philadelphia, 2008, p. 1123.
115
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Research article
Correlations between MDCT features and clinicopathological findings of primary adrenal lymphoma Ling yanga, Mengni Zhangb, Shuang Zhaoa, Yajun Hua, Jin Yaoa, a b
T
⁎
Department of Radiology, West China Hospital of Sichuan University, 37# Guoxue Street, Wuhou District, Chengdu, Sichuan 610041, China Department of Pathology, West China Hospital of Sichuan University, 37# Guoxue Street, Wuhou District, Chengdu, Sichuan 610041, China
A R T I C LE I N FO
A B S T R A C T
Keywords: Lymphoma Adrenal gland Primary Computed tomography
Objective: To investigate the MDCT features of primary adrenal lymphoma (PAL) and correlate the results with clinicopathological findings. Materials and methods: Twenty eight patients (17 men, 11 women; median age, 61.5years) with pathologically confirmed PAL were included in this study. MDCT features of the lesions were retrospectively reviewed and correlated with clinicopathological findings. Results: All of the 28 cases were non-Hodgkin’s lymphoma (NHL), in which 25 cases were diffuse large B-cell lymphoma and 3 cases T-cell lymphoma. 21 (75%) patients had bilateral tumors with maximum diameter of 3.9–17.7 cm (median, 9.18 cm), and 7 (25%) patients had unilateral tumors with maximum diameter of 4.3–14.9 cm (median, 8.6 cm). The sign of infiltrating adjacent organs and encasing adjacent vessels were appeared in 10 and 15 patients respectively, in which 9 patients had both signs. 20 (71.4%) patients had the appearance of adeniform, and 3 (10.7%) patients showed infiltrating and embedding the adrenal gland. Among all the patients, 27 (96.4%) and 26 (92.9%) patients had mild enhancement on arterial and parenchymal phase, respectively; and 12 (42.8%) were homogenous, 14 (50%) slightly inhomogeneous and 2 (7.1%) heterogeneous on both phase. In addition, adrenal insufficiency was found in 33.3% (7/21) of the patients with bilateral lesions, and none in unilateral lesions. Conclusion: Large adrenal soft tissue mass with maintenance of adreniform shape, encasing vessels, homogenous or slightly inhomogeneous density with no calcification, and mild enhancement on both arterial and parenchymal phase could be seen as the main MDCT features of PAL. In addition, infiltrating and embedding the adrenal gland may be specific imaging characteristics of PAL.
1. Introduction Primary adrenal lymphoma (PAL) shares a small proportion (about 3% [1]) of extranodal lymphomas arising from non-lymphoid tissues or at sites other than the expected native lymph nodes or lymphoid tissues [2]. More and more PAL has been reported in the past decade (about 200 cases worldwide up to now), and they are often histologically aggressive in biological behavior [2–4]. Patients with PAL always have varied clinical symptoms such as local pain, fever, weight loss or adrenal insufficiency [5], and they may go to department of urology, hematology, endocrine or infection first, making it difficult to diagnose accurately for clinicians from these different departments. Under such circumstance, the radiologist may play an important role to guide the treatment in the right direction. So, comprehensive understanding of the clinical manifestation and imaging findings of PAL are very
⁎
important for all the clinicians of above departments, and especially radiologist, as the extensive application of imaging techniques nowadays. Although the clinic-pathological features of PAL are well characterized [3,5,6], the appearance of these tumors on imaging is not well documented. To date, the most extensive reports regarding the imaging characteristics of PAL is by Zhou et al. [7] and others focused on case reports [8–11]. To better characterize the radiological features of this disease, we present the multi-detector computed tomography (MDCT) features of 28 cases PAL, and correlated them with the clinic-pathological findings. To our knowledge, this is the largest and most detailed radiologic case series reported to date.
Corresponding author. E-mail address: [email protected] (J. Yao).
https://doi.org/10.1016/j.ejrad.2019.02.003 Received 6 January 2019; Received in revised form 29 January 2019; Accepted 1 February 2019 0720-048X/ © 2019 Published by Elsevier B.V.
European Journal of Radiology 113 (2019) 110–115
L. yang, et al.
Fig. 1. Profile of patient enrollment.
2. Materials and methods
2.2. CT protocol
2.1. Study population
All patients had undergone plain and enhanced MDCT examination, and the scan technique varied somewhat owing to the retrospective nature of the study. After performing unenhanced imaging, Ominipaque contrast agent was injected through the cubital vein. 100–150 ml of contrast agent at a rate of 3 ml/s was administered by power injection. Then arterial and parenchymal phase scans were initiated at 20–30 and 60–80 s after the start of the injection, respectively. In general, examinations were performed using a spiral technique with 2–5 mm collimation and 2–5 mm reconstruction intervals. 13 patients were scanned using 64 multi-detector CT (Philips Brilliance) with 120 kV voltage, 210 mA current and width of collimator 64 × 0.625 mm, and 14 patients were scanned using dual source CT (Somaton Definition; Siemens Medical Solutions, Forchheim, Germany) with 120 kV voltage, 200 mA current.
This study was approved by the local institutional review board with waiver of individual consent. From January 2010 to September 2018, 3280 patients with pathologically proved lymphoma who were treated at our institution were screened out. We only included patients with PAL. Patients were excluded if they had no involvement of the adrenal gland; had a history of leukemia or lymphoma elsewhere, involvement of non-adjacent organs and lymph nodes [5–7] or insufficient imaging evidence. If the adjacent organs including spleen, liver, kidney, pancreas and lymph nodes were involved and adrenal lesions were unequivocally dominant, the patients were still judged as PAL [5,6]. Finally, 28 patients (17 men, 11 women; mean age 61.5 years; age range 20–82 years) were enrolled (Fig. 1). At the time of initial diagnosis, 21 patients had symptoms which included abdominal and low back pain (48.1%, 13/27), fever (18.5%, 5/27), weak (7.4%, 2/27), weight loss and hyperpigmentation (3.7%, 1/27). One patient had a history of clear cell renal cell carcinoma, and adrenal lymphoma appeared simultaneously with the renal tumor and progressed during the follow-up with symptoms of fever. One patient had a history of hepatitis with symptoms of fever, and another one had a history of HIV with symptoms of back pain. Adrenal insufficiency was defined as low baseline cortisol or normal baseline cortisol which fails to rise sufficiently upon ACTH stimulation [3].
2.3. Imaging analysis The images were reviewed by two radiologists with more than 5 years’ experience in abdominal imaging by consensus, and both of them were aware of the clinical data. The CT images were evaluated for bilateral or unilateral, symmetry, size, preservation of “adeniform” shape [6], density in plain and enhanced images, degree and patterns of enhancement, involvement of adjacent vessels and organs. When bilateral lesions were presented, we measured tumor size of the larger side. The preservation of “adeniform” shape (V-shape) was defined as tumor with a triangular or forking shape displayed in any of the axial, coronal or sagittal position. Density was measured on the maximum level of the 111
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Fig. 2. 60-year-old man with primary bilateral adrenal B-cell lymphoma. Unenhanced (A), arterial (B) and parenchymal (C, D) phase CT images show symmetrical adrenal masses with mildly homogenous enhancement; and sagittal image (D) shows a triangular shape of the right adrenal mass.
Fig. 3. 56-year-old man with primary unilateral adrenal B-cell lymphoma. Unenhanced (A), arterial (B) and parenchymal (C, D) phase CT images show a slightly inhomogeneous left adrenal mass with mild enhancement which encased the left renal artery (thick arrow). Enhanced axial (C) and coronal (D) images show that the tumor infiltrated and embedded the adrenal gland (fine arrow). 112
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L. yang, et al.
Table 1 MDCT features of patients with primary adrenal lymphoma on different phases. Phase
UE AP PP
CT value
enhanced
homogeneity (n)
enhanced degree (n)
(HU)
value(HU)
homogeneous
SI
heterogeneous
mild
moderate
marked
34.5 (26-39) 49.0(32-74) 59.0 (41-81)
none 13.8(4-32) 24.5 (12-50)
12(42.8%) 12(42.8%) 12(42.8%)
15(53.6%) 14(50%) 14(50%)
1(3.6%) 2(7.1%) 2(7.1%)
none 27(96.4%) 26(92.9%)
none 1(3.6%) 2(7.1%)
none none none
UE, unenhanced; AP, arterial phase;PP, parenchymal phase;HU, Housefield unit;SI,slightly inhomogeneous.
data on radiological diagnosis is insufficient [5–7]. Strict definition of PAL must be confined to the adrenal gland and its contiguous lymph node group at the time of diagnosis, and without involvement of other organs before and after treatment [4,7]. The etiology of PAL is unclear at present, and several factors such as prior autoimmune adrenalitis, EBV infection, immune dysfunction, mutations in the p53 and c-kit genes have been implicated in the pathogenesis of PAL [3,5,6]. And in our study, five patients were positive for EBV-encoded small RNAs, another two patients had HIV infection and hepatitis respectively. However, the relationship between different kinds of infection and lymphoma are still unclear up to now [5,6,13,14]. Previous researches thought that the adrenal gland contained no lymphoid tissue, and the follicle center cell origin of this lymphoma suggested that the tumor might have arisen on a background of previous autoimmune adrenalitis [11], but it cannot explain the cases without adrenal insufficiency and follicle center. Indeed, there are small lymphatic channels drained from both cortex and medulla to the hilum where larger caliber lymphatic channels drained directly into the lateral groups of para-aortic nodes as described in the Gray’s anatomy [15], which means that normal adrenal gland contains lymphocyte. We may suggest that adrenal lymphoma is the result of lymphocytic reactive response of adrenal gland, but not only adrenal autoimmune inflammation, as the similar way reported in central nervous system lymphoma [16]. The clinical data including gender, age, abdominal pain and B symptoms were similar to the previous reports [3,5–7]. The elderly patients with typical B symptoms or adrenal insufficiency were more common and suggestive of adrenal lymphoma. However, adrenal insufficiency caused by malignant tumors requires destruction about 90% of adrenal parenchyma due to large adrenal reserve, and it was uncommon in other localized malignant tumors [6,17]. Some authors believe that PAL may rise on a background of previous autoimmune adrenalitis, and lymphoma cells also produce cytokine mediated paracrine to effect on the adrenal cell microenvironment, which both will cause adrenal insufficiency [6,11]. This assumption can explain the presence of adrenal insufficiency even in PAL patients with small masses [3,6]. Our study showed that adrenal insufficiency was appeared in 33.3% of the bilateral adrenal lymphomas with the minimum diameter of 3.9 cm, which may indicate that adrenal insufficiency was not just appeared in huge bilateral lesions. Our study demonstrated that bilateral involvement occurred in 75% (21/28) of our patients, 2 of the 21 bilateral patients were almost symmetric and others were unsymmetrical when initially diagnosed. The mechanism of bilateral adrenal lymphoma may be “homing theory” and previous autoimmune adrenalitis history, while the unilateral lymphoma may be derived from haemopoetic tissue [3,18]. The lesion sizes in our study were large, but it doesn’t mean that all the lymphomas were huge because we only measured the bigger side, and part of the reason is that it is difficult to diagnose when the lesions are small. However, adrenal lymphoma grows rapidly with high ki-67 value. So it should be taken into consideration when rapid growth occurs. This sign may be confused with adrenal metastasis since it may be appeared as bilateral lesions and rapid growth too. Whether there was extra-adrenal malignancy was not an absolute condition to diagnose metastasis or lymphoma as one of our case accompanied by renal cell carcinoma.
lesion in the axial image, and enhanced value was measured on the arterial and parenchymal phase respectively. The degree of tumor enhancement similar to that of muscles, livers and kidneys were graded mild, moderate or marked enhancement, respectively. The enhancement patterns were divided into homogeneous, slightly inhomogeneous, and heterogeneous. 3. Results The prevalence of PAL in our institution was 0.85% (28/3280), and secondary adrenal lymphoma less than 5.4% (178/3280). All of the 28 cases were non-Hodgkin’s lymphoma (NHL), in which 25 cases were Bcell lymphoma and 3 cases were T-cell lymphoma. The average value of ki-67 was 78.8% (40–95%) and 68.3% (60–75%), respectively. The Bcell lymphomas were all diffuse large B-cell lymphoma (DLBCL) phenotype positive for CD 20, in which two cases was associated with Epstein-Barr virus (EBV), and seventeen were source of non-germinal center. All of the lesions with T-cell lymphoma were associated with EBV. In addition, seven patients had lymphadenopathy in the adjacent retroperitoneal area, and all of them were B cell subtype. Of the 28 patients, 75% (21/28) of them were bilateral, and 25% (7/28) were unilateral. The maximum diameters of the bilateral and unilateral lesions were 9.18 (3.9–17.7) cm and 8.6 (4.3–14.9) cm, respectively. Two of the 21 patients with bilateral lesions were almost symmetrical (Fig. 2), and the others were asymmetrical. Adrenal insufficiency was found in 33.3% (7/21) of the patients with bilateral lesions, with the maximum diameters of 8.54 (3.9–13.2) cm. 20 of the 28 patients had the appearance of adeniform shape. In addition, there is another phenomenon worth mentioning, that is another 3 patients including two B cell and one T cell lymphoma showed the feature of infiltrating and embedding the adrenal gland (Fig. 3). The MDCT features of patients with PAL on different phases were demonstrated in Table 1. On unenhanced CT images, all the lesions were slight hypodensity which was slightly lower than that of muscle, and most of them were homogeneous or slightly inhomogeneous. On both arterial and parenchymal phase, most of the lesions demonstrated mild enhancement with homogeneous or slightly inhomogeneous patterns. And the average maximum diameters of the lesions with homogenous, slightly inhomogeneous and heterogeneous enhancement were 6.56 cm, 10.24 cm and 15.45 cm, respectively. In addition, calcification was not demonstrated in all the lesions; and there was no significant difference of the MDCT features between B and T cell lymphoma. The sign of infiltrating adjacent organs, encapsulating adjacent vessels and both of them were appeared in 10 (35.7%), 15 (53.6%) and 9 (32.1%) patients, respectively (Fig. 4). Among them, 10 patients had the symptom of low back pain. 4. Discussion Although lymphomas are generally thought of as tumors of lymph nodes, about 25–40% of them arise at the extranodal site [4,12]. Previous studies showed that the prevalence of secondary adrenal lymphoma is about 5% and PAL was less than 1% of all non-Hodgkin lymphomas [5–7], which was in consistent with our findings. More and more PAL was reported systematically in recent years; however, the 113
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FDG PET/CT play an important role in distinguishing them because PAL limited to adrenal alone while adrenal metastases always involved other organs [18,19]. In addition, adrenal metastasis always has similar density, enhancement patterns and treatment outcome or evolution with the primary tumors or other metastasis. The adeniform shape was emphasized by many authors to strongly suggestive of lymphoma, which could represent the characteristics of diffuse lymphomas infiltration [3,6,7], and was appeared in most of our patients. As far as we know, this sign rarely appeared in other type of huge occupying lesions, but could be seen in hyperplasia and infection which could usually be determined by clinical history and laboratory data [7,17,18,20]. In our study, three patients had the characteristics of infiltrating and embedding the adrenal gland which had not been reported in previous literatures, and it may be speculated that the origin of lymphoma may be the rich lymphatics of adrenal capsule. Although the morphology, density and growth pattern of PAL in our study have been mentioned in some of previous case reports and small sample studies [20–22], herein we provide the most detailed and comprehensive results. Some huge lesions might be heterogeneous because of necrosis which should take pheochromocytoma and adrenal cortical carcinoma (ACC) into consideration. However, pheochromocytoma and ACC are more likely to be unilateral, have calcification and cortical or medullary related endocrine abnormalities [1,8,17,18]. In addition, pheochromocytoma is more likely to be cystic and solid components of the tumor usually show intense enhancement that is greater than 110 HU in the arterial phase [1,23]. And ACCs are commonly accompanied by necrosis, hemorrhage, heterogeneous enhancement, and vascular invasion [1]. The common treatment for PAL was chemotherapy, surgery and radiation therapy, in which the first two methods were significantly associated with longer survival [3]. However, multivariable analysis showed that administration of chemotherapy was independent predictor of outcome [3]. It is worth mentioning that operative treatment might base on incorrect diagnosis. In addition, previous studies have pointed out that poor prognostic factors for PAL are advanced age, large tumor size, elevated lactate dehydrogenase level, bilateral adrenal involvement and adrenal insufficiency [3,5]. In conclusion, PAL should be considered in patients with large adrenal mass with maintenance of adreniform shape, encasing vessels, homogenous or slightly inhomogeneous density with no calcification, mainly mild enhancement on both arterial and parenchymal phase, especially in patients with bilateral lesions, adrenal insufficiency and without history of malignant tumor. In addition, infiltrating and embedding the adrenal gland may be specific imaging characteristics of PAL. Grants No concerning grants were received. Conflict of interests The authors declare that there is no Conflict of Interests References [1] K. Herr, V.F. Muglia, W.J. Koff, A.C. Westphalen, Imaging of the adrenal gland lesions, Radiol. Bras. 47 (2014) 228–239. [2] S.S. Hedgire, S. Kudrimoti, I.S. Oliveira, et al., Extranodal lymphomas of abdomen and pelvis: imaging findings and differential diagnosis, Abdom. Radiol. (N. Y.) 42 (2017) 1096–1112. [3] A. Rashidi, S.I. Fisher, Primary adrenal lymphoma: a systematic review, Ann. Hematol. 92 (2013) 1583–1593. [4] S.C. Chua, F.I. Rozalli, S.R. O’Connor, Imaging features of primary extranodal lymphomas, Clin. Radiol. 64 (2009) 574–588. [5] C. Laurent, O. Casasnovas, L. Martin, et al., Adrenal lymphoma: presentation, management and prognosis, QJM 110 (2017) 103–109. [6] R. Kasaliwal, M. Goroshi, K. Khadilkar, et al., Primary adrenal lymphoma: a single-
Fig. 4. 53-year-old woman with primary bilateral adrenal B-cell lymphoma. Unenhanced CT image (A) shows slightly inhomogeneous bilateral adrenal masses; Arterial (B) and parenchymal (C) phase CT images show heterogeneously enhanced adrenal masses which encase the superior mesenteric artery and inferior vena cava (arrow) and infiltrate the right kidney (arrow). Histopathologic photograpy (D, H&E staining, original magnification at 40×). 114
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