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Original Article
EP14471.OR PRIMARY ADRENAL LYMPHOMA: A SINGLE CENTER EXPERIENCE
Rajeev kasaliwal DM1; Manjunath Goroshi MD1; Kranti Khadilkar MD1; Ganesh Bakshi Mch2 , Venkatesh Rangarajan MD2 , Gaurav Malhotra MD3 , Anurag Lila DM1, Tushar Bandgar DM1 , Nalini S Shah DM1 From: 1Dept. of Endocrinology KEM Hospital Mumbai, 2TATA Memorial Hospital Mumbai, 3 Radiation Medicine Centre Mumbai
Running Title: PAL single centre experience
Name of Corresponding author: Dr. Rajeev Kasaliwal MD Department of Endocrinology Seth G S Medical College KEM Hospital, Parel Mumbai-400012, INDIA Email: [email protected]
DOI:10.4158/EP14471.OR © 2015 AACE.
Key words: Primary adrenal lymphoma, Adrenal insufficiency, Chemotherapy
Word count: 1500 On behalf of all the contributors, I will act and guarantor and will correspond with the journal from this point onward. Prior publication: Nil Disclosure summary: There is nothing to disclose
Abstract: Objective: To describe the clinical presentation, biochemistry, imaging features and treatment outcome of patients with primary adrenal lymphomas (PAL) presented to a single tertiary care centre Methods: We performed a retrospective analysis of case records of seven patients diagnosed with PAL between January 2011 and May 2014 at our institution in Mumbai, India. DOI:10.4158/EP14471.OR © 2015 AACE.
Results: Median age of presentation in our series was 48 years (range: 41-60) with male to female ratio of 6:1. Bilateral adrenal involvement was seen in 4/7 patients (58%). Adrenal insufficiency (AI) was seen in 3/4 patients with bilateral involvement (75%). Computerised tomography showed slight to moderate contrast enhancement of adrenal masses 4/5 patients (80%). Diffuse large B cell lymphoma (DLBCL) was the most common immmunophenotype (85%). One patient died due to rapid disease progression even before starting of chemotherapy. Six patients were treated with chemotherapy ± external beam radiotherapy. After one year, two more patients were dead while four patients were in remission. Conclusion: PAL should always be considered in differential diagnosis of bilateral adrenal mass with AI. DLBCL is the most common histological subtype of PAL. Despite treatment, long term prognosis of PAL remains poor. Abbreviations: AI = Adrenal Insufficiency; DLBCL = Diffuse Large B Cell Lymphoma; EBRT = External Beam Radiotherapy; PAL = Primary Adrenal Lymphoma; PTCL = Peripheral T Cell Lymphoma.
Introduction:
DOI:10.4158/EP14471.OR © 2015 AACE.
Secondary adrenal gland involvement has been described radiologically in up to 5 % of cases. Non-Hodgkin’s lymphomas (NHL) which increases up to 25 % with inclusion of autopsy series. (1, 2, 3)
However, primary adrenal lymphoma (PAL) is a rare entity with less than 200 cases
described worldwide till date.
(4)
Although there has been no consensus on definition of PAL,
most experts define PAL as histologically proven lymphomas that involve one or both adrenal glands with two additional criteria: (1) there is no prior history of lymphoma elsewhere; (2) if lymph nodes or other organs are involved, adrenal lesions are unequivocally dominant. (4)PAL has been described to predominantly affect elderly males. Bilateral adrenal involvement has been described in about 70 % of cases of PAL. (5, 6) Non-germinal center type diffuse large B cell lymphoma (DLBCL) is the most common histological subtype (70 %) of PAL. (7, 8, 9) Indian data on PAL is sparse with one case series and three case reports published till date (total eight cases only).
(10, 11, 12, 13, 14)
We report here the clinical features, biochemistry, imaging
characteristics and treatment outcome of seven cases of PAL presented to our center. Material and methods: Between January 2011 to May 2014, seven cases of PAL were treated at single tertiary care center in Mumbai, western India. We retrospectively reviewed the medical charts of these patients for the current study after approval from institutional review board. The diagnosis of adrenal insufficiency (AI) was based on the 8 am cortisol value less than 5 µg/dl. Synacthen stimulation test was not done to diagnose AI due to its poor availability in our country.
DOI:10.4158/EP14471.OR © 2015 AACE.
Results: Presenting features, imaging characteristics and treatment outcomes of seven patients of PAL are described in detail in Table1& figure 1, 2. Presenting features: Median age of presentation was 48 years (range: 41-60) with male to female ratio of 6:1. Mean duration of symptoms was 13±8 weeks. All patients of PAL presented with localised abdominal pain (sometimes disproportionately severe) and B symptoms (weight loss, low grade fever) with or without features of adrenal insufficiency (nausea, vomiting, anorexia, hyper pigmentation, altered neurological status, electrolyte imbalance) depending on the extent of adrenal involvement Imaging features: Non contrast and contrast enhanced computerised tomography was available in seven and five patients respectively. Bilateral adrenal gland involvement was seen in 4/7 patients (58 %).In patient with unilateral disease, right and left adrenal involvement was seen in two and one patient respectively. Average maximum diameter of adrenal masse was 7.5 ± 3 cm on CT. Five out of six patients had slight to moderate contrast enhancement on CT (80%). Wherever available,
18
F-FDG PET CT showed intense metabolic activity in adrenal masses as
well as involvement of few regional lymph nodes. Follow up
18
F-FDG PET CT was used to
assess the metabolic as well as morphological response to treatment. Histology and other associations: Final diagnosis of PAL was based on histopathological examination and immunohistochemistry of adrenal tissue obtained by biopsy. Plasma free metanephrines were done in patients who did not have AI at presentation prior to adrenal biopsy. DLBCL and T/NK immuno-phenotype was seen in six and one patients respectively in our series. One patient was detected to have human immmuno deficiency virus (HIV) infection
DOI:10.4158/EP14471.OR © 2015 AACE.
during evaluation. None of the patients with PAL had any prior history of auto immune diseases in our series. Treatment: Six patients were treated with chemotherapy. Fourpatients with B cell variant received etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin along with rituximab (EPOCH-R regimen). Another patient with B cell variant received cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP regimen) initiallyand ifosfamide, carboplatin, etoposide (ICE regimen) as a salvage treatment for residual disease. Patient with T/NK cell variant was treated with dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide (SMILE regimen). One patient died even before starting the chemotherapy due to rapid disease progression. Five out of six patients had partial remission whileone patient had complete metabolic and morphological remission following chemotherapy. One patientdied after two cycle of chemotherapy due to disease progression despite showing good clinical response initially. Three patients with partial remission received EBRT for residual disease while one patient is awaiting EBRT
Discussion: We discussed here clinical presentation and treatment outcome of seven cases of PAL presented to our center during last three and half years. To our best knowledge, this is the largest case series of PAL reported from India.
DOI:10.4158/EP14471.OR © 2015 AACE.
Males were predominantly affected with male to female ratio of 6:1, much higher than earlier reports. In addition, our patients were comparatively younger than reported in world literature (mean age of presentation 48±8 Vs 62 ±12 years).(4)Patients with U/L adrenal involvement presented with B symptoms and localised abdominal pain (sometimes disproportionately severe) while presentation of patients with B/L PAL was dominated by symptoms of AI in our series. B/L adrenal involvement was seen in 4/7 (58 %) cases and AI was present in 3/4 (75%) cases of B/L PAL. PAL has been described to occur in association with autoimmune diseases in 20 % cases.
(4)
However, none of the patient in our series had any prior history of underlying
autoimmune disease. Adrenal insufficiency has been described to be more common in B/L PAL (61 %) compared to B/L adrenal metastasis (AM) (20-30 %).
(4, 15, 16)
In AM, cytochemically “inert” metastatic cell
leads to AI mostly by compressing or replacing the normally functioning adrenal parenchyma or by compromising the regional vascular supply to the gland, resulting in parenchymal hemorrhage, necrosis, or infarction. This requires destruction of around 90% of adrenal parenchyma to cause AI due very large adrenal reserve. In PAL, lymphoma cells, in addition to local mass effect, also produces cytokine mediated paracrine effect on adrenal cell microenvironment to cause AI. (4) This can also explain the presence of AI even in patients of PAL with smaller adrenal masses. NHL arises primarily in an endocrine organ in less than 3% case and the thyroid gland is the most commonly affected endocrine organ of origin.
(17, 18)
Various hypotheses have been
proposed in the past to explain the development of PAL. It can arise either from mesenchymal DOI:10.4158/EP14471.OR © 2015 AACE.
cells that exist as a part of the reticular framework in the adrenal or from hematopoietic tissue rests in the adrenal like adrenal myelo-lipoma.
(19)
Another interesting hypotheses suggest that
PAL may arise from background of autoimmune adrenalitis just like primary thyroid lymphoma developing on a background of autoimmune thyroiditis. This may also explain the unexpectedly high rate of adrenal insufficiency in PAL. (14, 20) However, we did not have any patient with prior history of autoimmune adrenal disease in our series. A large review recently also did not find a single case of PAL associated with prior history of autoimmune adrenal disease. (4) PALs have been described to present as homogeneous or heterogeneous adrenal masses with hypodense more common than hyperdense appearance on non-contrast CT. Another useful feature is frequent preservation of their normal “adeniform” shape in PAL, especially when they are smaller in size. PALs have been described to shows slight to moderate contrast enhancement. (14)
This is unlike other adrenal neoplastic lesion like pheochromocytoma which generally shows
good contrast enhancement. Four out of five patients (80%) in our series had shown slight to moderate contrast enhancement of adrenal masses. The data on the FDG PET CT in the PAL is scarce & limited to the case reports (13, 21, 22). In our series, 18F-FDG PET scan showed intense metabolic activity in adrenal mass lesions in PAL. Mean SUV of adrenal mass lesion was 32± 20 gm/ml on
18
F-FDG PET scan. In addition, it helps in ascertaining the involvement of regional
lymph nodes, leading to better mapping of disease. Post treatment 18F-FDG PET CT scan can be used to assess the tumor response to chemotherapy. These classical imaging characteristics, if present, can increase probability of adrenal mass being a lymphoma. However, final diagnosis of PAL can only be made by adrenal biopsy. DOI:10.4158/EP14471.OR © 2015 AACE.
DLBCL was the most common subtype of PALs in our series (6/7, 85%) followed by T/NK cell variant (1/7, 15 %). B cell subgroup has been much more commonly described than T cell subgroup in PAL. Most common B cell subtype is DLBCL, accounting for 75 % of the cases of PAL. Most common T cell subtype is PTCL followed by extra nodal NK/T cell lymphoma, nasal type, accounting for 10 % cases of PAL. (4) PAL is a high grade lymphoma; despite a good initial response, durable remission after chemotherapy is rare. Complete remission and partial remission to chemotherapy was seen in 17 % and 83 % respectively in our series. Three patients with partial remission were treated with EBRT for residual disease in our series. A recent review showed poor prognosis for PAL with 3-, 6-, and 12-month survival rates being only 67, 46, and 20 %, respectively. (4) Only chemotherapy and AI were shown to significantly predict the outcome in this review. (4) Another study reported 2-year overall and progression-free survival rates of 68% and 51%, respectively when treated with R-CHOP regimen. Out come in this study was better than earlier reported studies, suggesting the benefit of addition of rituximab.
(23)
Two out seven patients died within six
months of diagnosisin our study, with six months survival rate of 70%. In addition to chemotherapy, treatment of AI requires careful attention to decrease the mortality in these patients. Conclusion: All patients with adrenal mass, particularly those with bilateral involvement, preservation of “adeniform” shape and adrenal insufficiency, should raise the suspicion of PAL. PAL is an aggressive neoplasm with relatively poor prognosis and requires better chemotherapeutic regimen to improve the outcome. DOI:10.4158/EP14471.OR © 2015 AACE.
References: 1. Paling MR, Williamson BR. Adrenal involvement in non-Hodgkin lymphoma. AJR Am J Roentgenol. 1983;141:303–5. 2. Rosenberg SA, Diamond HD, Jaslowitz B, Craver LF. Lymphosarcoma: a review of 1269 cases. Medicine (Baltimore). 1961;40:31-84. 3. Straus DJ, Filippa DA, Lieberman PH, Koziner B, Thaler HT, Clarkson BD. The nonHodgkin’s lymphomas. I. A retrospective clinical and pathologic analysis of 499 cases diagnosed between 1958 and 1969. Cancer. 1983;51:101–9. 4. Rashidi A, Fisher SI. Primary adrenal lymphoma: A systematic review. Annals of Hematology. 2013. p. 1583–93 5. Wang J, Sun NCJ, Renslo R, Chuang CC, Tabbarah HJ, Barajas L, et al. Clinically silent primary adrenal lymphoma: A case report and review of the literature. Am J Hematol. 1998;58:130–6.
DOI:10.4158/EP14471.OR © 2015 AACE.
6. Wu HC, Shih LY, Chen TC, Chu SH, Tsai CC. A patient with bilateral primary adrenal lymphoma, presenting with fever of unknown origin and achieving long-term disease-free survival after resection and chemotherapy. Ann Hematol.1999;78:289–292 7. Al-Fiar FZ, Pantalony D, Shepherd F. Primary bilateral adrenal lymphoma. Leukemia & lymphoma. 1997. p. 543–9. 8. Grigg AP, Connors JM. Primary adrenal lymphoma.Clin Lymphoma. 2003;4:154-60. 9. Ozimek A, Diebold J, Linke R, Heyn J, Hallfeldt K, Mussack T. Bilateral primary adrenal non-Hodgkin’s lymphoma and primary adrenocortical carcinoma--review of the literature preoperative differentiation of adrenal tumors. Endocrine Journal. 2008. p. 625–38. 10. Singh D, Kumar L, Sharma A, Vijayaraghavan M, Thulkar S, Tandon N. Adrenal involvement in non-Hodgkin’s lymphoma: four cases and review of literature. Leukemia & lymphoma. 2004. p. 789–94. 11. Panchani R, Goyal A, Varma T, Gupta N, Tripathi S, Kumar S. Adrenal incidentalomas: A collection of six interesting cases and brief review of literature. Indian J Endocrinol Metab [Internet]. 2012;16(Suppl 2):S378–81. 12. Aziz SA, Laway BA, Rangreze I, Lone MI, Ahmad SN. Primary adrenal lymphoma: Differential involvement with varying adrenal function. Indian J Endocrinol Metab. 2011;15:220–3. 13. Santhosh S, Mittal BR, Shankar P, Kashyap R, Bhattacharya A, Singh B, Das A, Bhansali. A. (18) F-FDG PET/CT in bilateral primary adrenal T-cell lymphoma. Hell J Nucl Med. 2011;14:166-7.
DOI:10.4158/EP14471.OR © 2015 AACE.
14. Reddy SV, Prabhudesai S, Gnanasekaran B. Origin of primary adrenal lymphoma and predisposing factors for primary adrenal insufficiency in primary adrenal lymphoma.Indian J Endocrinol Metab. 2011;15:350-1. 15. Redman BG, Pazdur R, Zingas AP, Loredo R. Prospective evaluation of adrenal insufficiency in patients with adrenal metastasis. Cancer. 1987;60:103–7. 16. Seidenwurm DJ, Elmer EB, Kaplan LM, Williams EK, Morris DG, Hoffman AR. Metastases to the adrenal glands and the development of Addison’s disease. Cancer. 1984. p. 552–7. 17. Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer. 1972;29:252–60. 18. López-Guillermo A1, Colomo L, Jiménez M, Bosch F, Villamor N, Arenillas L et al.Diffuse large B-cell lymphoma: clinical and biological characterization and outcome according to the nodal or extranodal primary origin.J Clin Oncol. 2005 Apr 20;23:2797-804. 19. Dutta P, Bhansali A, Venkatesan R, Mittal BR, Kumar V. Primary adrenal lymphoma. Endocrinologist 2005;15-340-2. 20. Osei K, Falko JM, Pacht E, Wall R, Goldberg RF. Primary adrenal insufficiency manifesting as malignant lymphoma. Archives of internal medicine. 1983;1791–2 21. Kumar R, Xiu Y, Mavi A, El-Haddad G, Zhuang H, Alavi A. FDG-PET imaging in primary bilateral adrenal lymphoma: a case report and review of the literature. Clin Nucl Med. 2005;30:222–30. 22. Wu H-B, Wang Q-S, Wang M-F, Li H-S, Zhou W-L, Ye X-H, et al. Utility of 18F-FDG PET/CT for staging NK/T-cell lymphomas. Nucl Med Commun. 2010;31:195–200. DOI:10.4158/EP14471.OR © 2015 AACE.
23. Kim Y, Kim J, Min Y, HyunYoon D, Shin H-J, Mun Y-C, et al. Prognostic factors in primary diffuse large B-cell lymphoma of adrenal gland treated with rituximab-CHOP chemotherapy from the Consortium for Improving Survival of Lymphoma (CISL). Journal of Hematology & Oncology. 2012. p. 49.
DOI:10.4158/EP14471.OR © 2015 AACE.
Table 1: Clinical, biochemical, imaging characteristics and treatment outcome of seven patients of PALs
Age/ sex
Clinical Presentation
Duratio n of sympto ms (weeks)
P. ACTH (pg/ml)
S. Cortisol (μg/dl)
Lateralisation and Size
Enhancement pattern on contrast CT
18
F-FDG PET CT (SUVmax )
Histologic al subtype
Treatment
Outcome
Died due to disease progression one year after treatment completion Initial response after two cycles then relapse and died due to disease progression Died before starting of chemotherapy due to rapid disease progression
BS
AI
AP
44/F
N
N
Y
4
44
14
Unilateral Lt: 10*8cm
Heterogeneous and mild to moderate
NA
DLBCL
Six cycles of REPOCH+ EBRT
60/M
Y
Y
Y
2
>1200
0.5
Bilateral Rt: 4.4*4cm Lt :7.8*7.3 cm
NA
NA
DLBCL
Two cycles of R-EPOCH
42/M
Y
Y
Y
16
245
4.5
Bilateral Rt : 6.9*6.3cm Lt : 9.0*7.9 cm
Heterogeneous and moderate
Baseline: Lt: 15.9 Rt: 15.1 Para aortic LN: 24
DLBCL
Only symptomatic treatment
41/M
Y
N
Y
12
43
17
Unilateral Lt :8.*6.9 cm
Heterogeneous and mild to moderate
Baseline: Lt: 63gm/ml Periportal LN: 19 Post Rx scan: Complete metabolic and partial morphological response
NK/T cell type
Six cycles of SMILE +EBRT
Alive after 6months of completing the chemotherapy
Table 1: Clinical, biochemical, imaging characteristics and treatment outcome of seven patients of PALs
Age/ sex
54/M
48/M
60/M
Clinical Presentation BS
AI
AP
Y
Y
Y
Y
Y
N
N
Y
Y
Duratio n of sympto ms (weeks)
P. ACTH (pg/ml)
S. Cortisol (μg/dl)
24
1089
2.5
12
24
145
108
31
21
18
F-FDG PET CT (SUVmax )
Histologic al subtype
Treatment
Outcome
Lateralisation and Size
Enhancement pattern on contrast CT
Bilateral Rt:5.9*4.4 cm Lt :6.5*3.2 cm
Homogenous , and mild enhancement
Baseline: NA
DLBCL
Six cycles of REPOCH + EBRT
Alive after 8 months of completing the chemotherapy
Bilateral Rt :7.4*6.4cm Lt : Bulky
Heterogeneous and mild to moderate
DLBCL
Six cycles of REPOCH + EBRT
Alive after 6 months of completing the chemotherapy
DLBCL
Six cycles of CHOP f/b ICE, awaiting local radiotherapy
Alive after 8 months with partial remission ,
Unilateral Rt:13.2*10.3 cm
Heterogeneous with extensive necrosis with patchy areas of good enhancement
Post Rx scan : Complete metabolic and morphological response Base line: Rt: 32 Lt : 15 Para aortic LN: 30 Post RX scan: complete metabolic and partial morphological response Baseline scan: NA Post Rx scan: Partial metabolic (SUvmax:5) And morphologic (6.0*3*7)
Table 1: Clinical, biochemical, imaging characteristics and treatment outcome of seven patients of PALs *BS: B symptoms, A I: Adrenal insufficiency, AP: Abdominal pain.
A
B
C
D
Fig 1. A,B) 18 F- FDG PET/CT showing large left adrenal mass with SUV max of 32 & single lymph node with SUV max of 15 C,D) Post Chemottherapy 18 F-FDG PET/CT showing complete metabolic response & partial morphological respo onse(arrow)
Original Article
EP14471.OR PRIMARY ADRENAL LYMPHOMA: A SINGLE CENTER EXPERIENCE
Rajeev kasaliwal DM1; Manjunath Goroshi MD1; Kranti Khadilkar MD1; Ganesh Bakshi Mch2 , Venkatesh Rangarajan MD2 , Gaurav Malhotra MD3 , Anurag Lila DM1, Tushar Bandgar DM1 , Nalini S Shah DM1 From: 1Dept. of Endocrinology KEM Hospital Mumbai, 2TATA Memorial Hospital Mumbai, 3 Radiation Medicine Centre Mumbai
Running Title: PAL single centre experience
Name of Corresponding author: Dr. Rajeev Kasaliwal MD Department of Endocrinology Seth G S Medical College KEM Hospital, Parel Mumbai-400012, INDIA Email: [email protected]
DOI:10.4158/EP14471.OR © 2015 AACE.
Key words: Primary adrenal lymphoma, Adrenal insufficiency, Chemotherapy
Word count: 1500 On behalf of all the contributors, I will act and guarantor and will correspond with the journal from this point onward. Prior publication: Nil Disclosure summary: There is nothing to disclose
Abstract: Objective: To describe the clinical presentation, biochemistry, imaging features and treatment outcome of patients with primary adrenal lymphomas (PAL) presented to a single tertiary care centre Methods: We performed a retrospective analysis of case records of seven patients diagnosed with PAL between January 2011 and May 2014 at our institution in Mumbai, India. DOI:10.4158/EP14471.OR © 2015 AACE.
Results: Median age of presentation in our series was 48 years (range: 41-60) with male to female ratio of 6:1. Bilateral adrenal involvement was seen in 4/7 patients (58%). Adrenal insufficiency (AI) was seen in 3/4 patients with bilateral involvement (75%). Computerised tomography showed slight to moderate contrast enhancement of adrenal masses 4/5 patients (80%). Diffuse large B cell lymphoma (DLBCL) was the most common immmunophenotype (85%). One patient died due to rapid disease progression even before starting of chemotherapy. Six patients were treated with chemotherapy ± external beam radiotherapy. After one year, two more patients were dead while four patients were in remission. Conclusion: PAL should always be considered in differential diagnosis of bilateral adrenal mass with AI. DLBCL is the most common histological subtype of PAL. Despite treatment, long term prognosis of PAL remains poor. Abbreviations: AI = Adrenal Insufficiency; DLBCL = Diffuse Large B Cell Lymphoma; EBRT = External Beam Radiotherapy; PAL = Primary Adrenal Lymphoma; PTCL = Peripheral T Cell Lymphoma.
Introduction:
DOI:10.4158/EP14471.OR © 2015 AACE.
Secondary adrenal gland involvement has been described radiologically in up to 5 % of cases. Non-Hodgkin’s lymphomas (NHL) which increases up to 25 % with inclusion of autopsy series. (1, 2, 3)
However, primary adrenal lymphoma (PAL) is a rare entity with less than 200 cases
described worldwide till date.
(4)
Although there has been no consensus on definition of PAL,
most experts define PAL as histologically proven lymphomas that involve one or both adrenal glands with two additional criteria: (1) there is no prior history of lymphoma elsewhere; (2) if lymph nodes or other organs are involved, adrenal lesions are unequivocally dominant. (4)PAL has been described to predominantly affect elderly males. Bilateral adrenal involvement has been described in about 70 % of cases of PAL. (5, 6) Non-germinal center type diffuse large B cell lymphoma (DLBCL) is the most common histological subtype (70 %) of PAL. (7, 8, 9) Indian data on PAL is sparse with one case series and three case reports published till date (total eight cases only).
(10, 11, 12, 13, 14)
We report here the clinical features, biochemistry, imaging
characteristics and treatment outcome of seven cases of PAL presented to our center. Material and methods: Between January 2011 to May 2014, seven cases of PAL were treated at single tertiary care center in Mumbai, western India. We retrospectively reviewed the medical charts of these patients for the current study after approval from institutional review board. The diagnosis of adrenal insufficiency (AI) was based on the 8 am cortisol value less than 5 µg/dl. Synacthen stimulation test was not done to diagnose AI due to its poor availability in our country.
DOI:10.4158/EP14471.OR © 2015 AACE.
Results: Presenting features, imaging characteristics and treatment outcomes of seven patients of PAL are described in detail in Table1& figure 1, 2. Presenting features: Median age of presentation was 48 years (range: 41-60) with male to female ratio of 6:1. Mean duration of symptoms was 13±8 weeks. All patients of PAL presented with localised abdominal pain (sometimes disproportionately severe) and B symptoms (weight loss, low grade fever) with or without features of adrenal insufficiency (nausea, vomiting, anorexia, hyper pigmentation, altered neurological status, electrolyte imbalance) depending on the extent of adrenal involvement Imaging features: Non contrast and contrast enhanced computerised tomography was available in seven and five patients respectively. Bilateral adrenal gland involvement was seen in 4/7 patients (58 %).In patient with unilateral disease, right and left adrenal involvement was seen in two and one patient respectively. Average maximum diameter of adrenal masse was 7.5 ± 3 cm on CT. Five out of six patients had slight to moderate contrast enhancement on CT (80%). Wherever available,
18
F-FDG PET CT showed intense metabolic activity in adrenal masses as
well as involvement of few regional lymph nodes. Follow up
18
F-FDG PET CT was used to
assess the metabolic as well as morphological response to treatment. Histology and other associations: Final diagnosis of PAL was based on histopathological examination and immunohistochemistry of adrenal tissue obtained by biopsy. Plasma free metanephrines were done in patients who did not have AI at presentation prior to adrenal biopsy. DLBCL and T/NK immuno-phenotype was seen in six and one patients respectively in our series. One patient was detected to have human immmuno deficiency virus (HIV) infection
DOI:10.4158/EP14471.OR © 2015 AACE.
during evaluation. None of the patients with PAL had any prior history of auto immune diseases in our series. Treatment: Six patients were treated with chemotherapy. Fourpatients with B cell variant received etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin along with rituximab (EPOCH-R regimen). Another patient with B cell variant received cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP regimen) initiallyand ifosfamide, carboplatin, etoposide (ICE regimen) as a salvage treatment for residual disease. Patient with T/NK cell variant was treated with dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide (SMILE regimen). One patient died even before starting the chemotherapy due to rapid disease progression. Five out of six patients had partial remission whileone patient had complete metabolic and morphological remission following chemotherapy. One patientdied after two cycle of chemotherapy due to disease progression despite showing good clinical response initially. Three patients with partial remission received EBRT for residual disease while one patient is awaiting EBRT
Discussion: We discussed here clinical presentation and treatment outcome of seven cases of PAL presented to our center during last three and half years. To our best knowledge, this is the largest case series of PAL reported from India.
DOI:10.4158/EP14471.OR © 2015 AACE.
Males were predominantly affected with male to female ratio of 6:1, much higher than earlier reports. In addition, our patients were comparatively younger than reported in world literature (mean age of presentation 48±8 Vs 62 ±12 years).(4)Patients with U/L adrenal involvement presented with B symptoms and localised abdominal pain (sometimes disproportionately severe) while presentation of patients with B/L PAL was dominated by symptoms of AI in our series. B/L adrenal involvement was seen in 4/7 (58 %) cases and AI was present in 3/4 (75%) cases of B/L PAL. PAL has been described to occur in association with autoimmune diseases in 20 % cases.
(4)
However, none of the patient in our series had any prior history of underlying
autoimmune disease. Adrenal insufficiency has been described to be more common in B/L PAL (61 %) compared to B/L adrenal metastasis (AM) (20-30 %).
(4, 15, 16)
In AM, cytochemically “inert” metastatic cell
leads to AI mostly by compressing or replacing the normally functioning adrenal parenchyma or by compromising the regional vascular supply to the gland, resulting in parenchymal hemorrhage, necrosis, or infarction. This requires destruction of around 90% of adrenal parenchyma to cause AI due very large adrenal reserve. In PAL, lymphoma cells, in addition to local mass effect, also produces cytokine mediated paracrine effect on adrenal cell microenvironment to cause AI. (4) This can also explain the presence of AI even in patients of PAL with smaller adrenal masses. NHL arises primarily in an endocrine organ in less than 3% case and the thyroid gland is the most commonly affected endocrine organ of origin.
(17, 18)
Various hypotheses have been
proposed in the past to explain the development of PAL. It can arise either from mesenchymal DOI:10.4158/EP14471.OR © 2015 AACE.
cells that exist as a part of the reticular framework in the adrenal or from hematopoietic tissue rests in the adrenal like adrenal myelo-lipoma.
(19)
Another interesting hypotheses suggest that
PAL may arise from background of autoimmune adrenalitis just like primary thyroid lymphoma developing on a background of autoimmune thyroiditis. This may also explain the unexpectedly high rate of adrenal insufficiency in PAL. (14, 20) However, we did not have any patient with prior history of autoimmune adrenal disease in our series. A large review recently also did not find a single case of PAL associated with prior history of autoimmune adrenal disease. (4) PALs have been described to present as homogeneous or heterogeneous adrenal masses with hypodense more common than hyperdense appearance on non-contrast CT. Another useful feature is frequent preservation of their normal “adeniform” shape in PAL, especially when they are smaller in size. PALs have been described to shows slight to moderate contrast enhancement. (14)
This is unlike other adrenal neoplastic lesion like pheochromocytoma which generally shows
good contrast enhancement. Four out of five patients (80%) in our series had shown slight to moderate contrast enhancement of adrenal masses. The data on the FDG PET CT in the PAL is scarce & limited to the case reports (13, 21, 22). In our series, 18F-FDG PET scan showed intense metabolic activity in adrenal mass lesions in PAL. Mean SUV of adrenal mass lesion was 32± 20 gm/ml on
18
F-FDG PET scan. In addition, it helps in ascertaining the involvement of regional
lymph nodes, leading to better mapping of disease. Post treatment 18F-FDG PET CT scan can be used to assess the tumor response to chemotherapy. These classical imaging characteristics, if present, can increase probability of adrenal mass being a lymphoma. However, final diagnosis of PAL can only be made by adrenal biopsy. DOI:10.4158/EP14471.OR © 2015 AACE.
DLBCL was the most common subtype of PALs in our series (6/7, 85%) followed by T/NK cell variant (1/7, 15 %). B cell subgroup has been much more commonly described than T cell subgroup in PAL. Most common B cell subtype is DLBCL, accounting for 75 % of the cases of PAL. Most common T cell subtype is PTCL followed by extra nodal NK/T cell lymphoma, nasal type, accounting for 10 % cases of PAL. (4) PAL is a high grade lymphoma; despite a good initial response, durable remission after chemotherapy is rare. Complete remission and partial remission to chemotherapy was seen in 17 % and 83 % respectively in our series. Three patients with partial remission were treated with EBRT for residual disease in our series. A recent review showed poor prognosis for PAL with 3-, 6-, and 12-month survival rates being only 67, 46, and 20 %, respectively. (4) Only chemotherapy and AI were shown to significantly predict the outcome in this review. (4) Another study reported 2-year overall and progression-free survival rates of 68% and 51%, respectively when treated with R-CHOP regimen. Out come in this study was better than earlier reported studies, suggesting the benefit of addition of rituximab.
(23)
Two out seven patients died within six
months of diagnosisin our study, with six months survival rate of 70%. In addition to chemotherapy, treatment of AI requires careful attention to decrease the mortality in these patients. Conclusion: All patients with adrenal mass, particularly those with bilateral involvement, preservation of “adeniform” shape and adrenal insufficiency, should raise the suspicion of PAL. PAL is an aggressive neoplasm with relatively poor prognosis and requires better chemotherapeutic regimen to improve the outcome. DOI:10.4158/EP14471.OR © 2015 AACE.
References: 1. Paling MR, Williamson BR. Adrenal involvement in non-Hodgkin lymphoma. AJR Am J Roentgenol. 1983;141:303–5. 2. Rosenberg SA, Diamond HD, Jaslowitz B, Craver LF. Lymphosarcoma: a review of 1269 cases. Medicine (Baltimore). 1961;40:31-84. 3. Straus DJ, Filippa DA, Lieberman PH, Koziner B, Thaler HT, Clarkson BD. The nonHodgkin’s lymphomas. I. A retrospective clinical and pathologic analysis of 499 cases diagnosed between 1958 and 1969. Cancer. 1983;51:101–9. 4. Rashidi A, Fisher SI. Primary adrenal lymphoma: A systematic review. Annals of Hematology. 2013. p. 1583–93 5. Wang J, Sun NCJ, Renslo R, Chuang CC, Tabbarah HJ, Barajas L, et al. Clinically silent primary adrenal lymphoma: A case report and review of the literature. Am J Hematol. 1998;58:130–6.
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6. Wu HC, Shih LY, Chen TC, Chu SH, Tsai CC. A patient with bilateral primary adrenal lymphoma, presenting with fever of unknown origin and achieving long-term disease-free survival after resection and chemotherapy. Ann Hematol.1999;78:289–292 7. Al-Fiar FZ, Pantalony D, Shepherd F. Primary bilateral adrenal lymphoma. Leukemia & lymphoma. 1997. p. 543–9. 8. Grigg AP, Connors JM. Primary adrenal lymphoma.Clin Lymphoma. 2003;4:154-60. 9. Ozimek A, Diebold J, Linke R, Heyn J, Hallfeldt K, Mussack T. Bilateral primary adrenal non-Hodgkin’s lymphoma and primary adrenocortical carcinoma--review of the literature preoperative differentiation of adrenal tumors. Endocrine Journal. 2008. p. 625–38. 10. Singh D, Kumar L, Sharma A, Vijayaraghavan M, Thulkar S, Tandon N. Adrenal involvement in non-Hodgkin’s lymphoma: four cases and review of literature. Leukemia & lymphoma. 2004. p. 789–94. 11. Panchani R, Goyal A, Varma T, Gupta N, Tripathi S, Kumar S. Adrenal incidentalomas: A collection of six interesting cases and brief review of literature. Indian J Endocrinol Metab [Internet]. 2012;16(Suppl 2):S378–81. 12. Aziz SA, Laway BA, Rangreze I, Lone MI, Ahmad SN. Primary adrenal lymphoma: Differential involvement with varying adrenal function. Indian J Endocrinol Metab. 2011;15:220–3. 13. Santhosh S, Mittal BR, Shankar P, Kashyap R, Bhattacharya A, Singh B, Das A, Bhansali. A. (18) F-FDG PET/CT in bilateral primary adrenal T-cell lymphoma. Hell J Nucl Med. 2011;14:166-7.
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14. Reddy SV, Prabhudesai S, Gnanasekaran B. Origin of primary adrenal lymphoma and predisposing factors for primary adrenal insufficiency in primary adrenal lymphoma.Indian J Endocrinol Metab. 2011;15:350-1. 15. Redman BG, Pazdur R, Zingas AP, Loredo R. Prospective evaluation of adrenal insufficiency in patients with adrenal metastasis. Cancer. 1987;60:103–7. 16. Seidenwurm DJ, Elmer EB, Kaplan LM, Williams EK, Morris DG, Hoffman AR. Metastases to the adrenal glands and the development of Addison’s disease. Cancer. 1984. p. 552–7. 17. Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer. 1972;29:252–60. 18. López-Guillermo A1, Colomo L, Jiménez M, Bosch F, Villamor N, Arenillas L et al.Diffuse large B-cell lymphoma: clinical and biological characterization and outcome according to the nodal or extranodal primary origin.J Clin Oncol. 2005 Apr 20;23:2797-804. 19. Dutta P, Bhansali A, Venkatesan R, Mittal BR, Kumar V. Primary adrenal lymphoma. Endocrinologist 2005;15-340-2. 20. Osei K, Falko JM, Pacht E, Wall R, Goldberg RF. Primary adrenal insufficiency manifesting as malignant lymphoma. Archives of internal medicine. 1983;1791–2 21. Kumar R, Xiu Y, Mavi A, El-Haddad G, Zhuang H, Alavi A. FDG-PET imaging in primary bilateral adrenal lymphoma: a case report and review of the literature. Clin Nucl Med. 2005;30:222–30. 22. Wu H-B, Wang Q-S, Wang M-F, Li H-S, Zhou W-L, Ye X-H, et al. Utility of 18F-FDG PET/CT for staging NK/T-cell lymphomas. Nucl Med Commun. 2010;31:195–200. DOI:10.4158/EP14471.OR © 2015 AACE.
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DOI:10.4158/EP14471.OR © 2015 AACE.
Table 1: Clinical, biochemical, imaging characteristics and treatment outcome of seven patients of PALs
Age/ sex
Clinical Presentation
Duratio n of sympto ms (weeks)
P. ACTH (pg/ml)
S. Cortisol (μg/dl)
Lateralisation and Size
Enhancement pattern on contrast CT
18
F-FDG PET CT (SUVmax )
Histologic al subtype
Treatment
Outcome
Died due to disease progression one year after treatment completion Initial response after two cycles then relapse and died due to disease progression Died before starting of chemotherapy due to rapid disease progression
BS
AI
AP
44/F
N
N
Y
4
44
14
Unilateral Lt: 10*8cm
Heterogeneous and mild to moderate
NA
DLBCL
Six cycles of REPOCH+ EBRT
60/M
Y
Y
Y
2
>1200
0.5
Bilateral Rt: 4.4*4cm Lt :7.8*7.3 cm
NA
NA
DLBCL
Two cycles of R-EPOCH
42/M
Y
Y
Y
16
245
4.5
Bilateral Rt : 6.9*6.3cm Lt : 9.0*7.9 cm
Heterogeneous and moderate
Baseline: Lt: 15.9 Rt: 15.1 Para aortic LN: 24
DLBCL
Only symptomatic treatment
41/M
Y
N
Y
12
43
17
Unilateral Lt :8.*6.9 cm
Heterogeneous and mild to moderate
Baseline: Lt: 63gm/ml Periportal LN: 19 Post Rx scan: Complete metabolic and partial morphological response
NK/T cell type
Six cycles of SMILE +EBRT
Alive after 6months of completing the chemotherapy
Table 1: Clinical, biochemical, imaging characteristics and treatment outcome of seven patients of PALs
Age/ sex
54/M
48/M
60/M
Clinical Presentation BS
AI
AP
Y
Y
Y
Y
Y
N
N
Y
Y
Duratio n of sympto ms (weeks)
P. ACTH (pg/ml)
S. Cortisol (μg/dl)
24
1089
2.5
12
24
145
108
31
21
18
F-FDG PET CT (SUVmax )
Histologic al subtype
Treatment
Outcome
Lateralisation and Size
Enhancement pattern on contrast CT
Bilateral Rt:5.9*4.4 cm Lt :6.5*3.2 cm
Homogenous , and mild enhancement
Baseline: NA
DLBCL
Six cycles of REPOCH + EBRT
Alive after 8 months of completing the chemotherapy
Bilateral Rt :7.4*6.4cm Lt : Bulky
Heterogeneous and mild to moderate
DLBCL
Six cycles of REPOCH + EBRT
Alive after 6 months of completing the chemotherapy
DLBCL
Six cycles of CHOP f/b ICE, awaiting local radiotherapy
Alive after 8 months with partial remission ,
Unilateral Rt:13.2*10.3 cm
Heterogeneous with extensive necrosis with patchy areas of good enhancement
Post Rx scan : Complete metabolic and morphological response Base line: Rt: 32 Lt : 15 Para aortic LN: 30 Post RX scan: complete metabolic and partial morphological response Baseline scan: NA Post Rx scan: Partial metabolic (SUvmax:5) And morphologic (6.0*3*7)
Table 1: Clinical, biochemical, imaging characteristics and treatment outcome of seven patients of PALs *BS: B symptoms, A I: Adrenal insufficiency, AP: Abdominal pain.
A
B
C
D
Fig 1. A,B) 18 F- FDG PET/CT showing large left adrenal mass with SUV max of 32 & single lymph node with SUV max of 15 C,D) Post Chemottherapy 18 F-FDG PET/CT showing complete metabolic response & partial morphological respo onse(arrow)
