Primary Adrenal Lymphoma
Case Analyses
Primary Adrenal Lymphoma - A Rare Entity with Grave Prognosis Chen-Hsun Ho,1,2 Shih-Chieh Chueh,1 Yeong-Shiau Pu,1 Shyh-Chyan Chen,1 Hong-Jeng Yu,1 Kuo-How Huang1 1
Department of Urology, National Taiwan University Hospital, Taipei, Taiwan Division of Urology, Department of Surgery, Buddhist Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan
2
Purpose: Primary adrenal lymphoma is extremely rare. We analyzed our cases to further illustrate the clinical characteristics of this rare disease. Methods: In the past 10 years, there have been three patients diagnosed as primary adrenal lymphoma in our institution. There have been another three patients with secondary adrenal lymphoma, involving not only the adrenal glands but also other organs or lymph nodes. The clinical and pathological characteristics of the six cases were compared and analyzed. Results: The three cases of primary adrenal lymphoma were characterized with old age, male-predominance, bilateral adrenal involvement, adrenal insufficiency, and histological type of diffuse large B-cell lymphoma. All of them received chemotherapy but died within half year of diagnosis: one died of disease progression; the other two died of complications. The three cases of secondary adrenal lymphoma were relatively young. All had unilateral adrenal involvement and no adrenal insufficiency. The pathological examinations revealed diffuse large B-cell lymphoma. The prognosis was better: two of them have been disease-free after treatment; the other died of disease progression. Conclusions: Primary adrenal lymphoma is extremely rare. It predominantly affects the elderly and men, mostly involves the bilateral adrenal glands, and usually causes adrenal insufficiency. The majority of the cases are of diffuse large B-cell lymphoma. The prognosis is poor, and most patients die within one year of diagnosis. With very limited experience, the optimal therapeutic strategy remained unclear and required further studies. It is important to differentiate between primary and secondary adrenal lymphoma since the clinical course is extremely different.(JTUA 20:168-72, 2009) Key words: Adrenal, lymphoma, non-Hodgkin's, diffuse large B-cell.
INTRODUCTION It has been reported that up to 25 percent of nonHodgkin's lymphoma has adrenal glands involvement on autopsy.1 In contrast, primary adrenal lymphoma, defined as malignant neoplastic proliferation of the lymphoid cells exclusively in the adrenal glands, is very rare. To date, there have been only about 100 cases in the literature review.2-15 The hypothesis for the origin of these tumors is hematopoietic tissue rests in the adrenal gland. With very limited experience, we know little about the clinical characteristics of this disease. In the past 10 years, there have been 1,670 patients with non-Hodgkin lymphoma in our institution. Of these Address reprint requests and correspondence to: Kuo-How Huang, M.D. Department of Urology, College of Medicine, National Taiwan University, No. 7, Chung-Shan South Road, Taipei, Taiwan 100 TEL: +886-2-23123456#65952 FAX: +886-2-23219145 Email:
[email protected]
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patients, six patients presented with adrenal tumors initially. Three of them had adrenal glands involvement exclusively and were diagnosed as primary adrenal lymphoma; the other three patients had not only adrenal glands but also other lymph nodes or organs involvement, which were diagnosed as secondary adrenal lymphoma. We illustrated and analyzed the six cases with an effort to clarify the clinical and pathological features of primary adrenal lymphoma.
PATIENTS AND METHODS Between January 1996 and December 2006, a total of 1,670 patients were diagnosed as non-Hodgkin lymphoma and received treatment in our institution. Among them, 846 patients were of diffuse large B-cell lymphoma. The ratio of male to female was 1.3. The mean age was 55 ± 18.7 years. Six patients initially presented with adrenal tumors. Three of the six patients were diagnosed as primary adrenal lymphoma, and the
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other three patients were diagnosed as secondary adrenal lymphoma. The medical records of the six patients were analyzed retrospectively. The age, gender, clinical presentations, pathological characteristics, and prognosis were illustrated and analyzed. The diagnosis of primary adrenal lymphoma was made by pathologically confirmed lymphoma in the adrenal glands without evidence of other organs or lymph nodes involvement. If there was involvement of other lymph nodes or organs, it was classified as secondary adrenal lymphoma.
RESULTS
Primary adrenal lymphoma Between January 1996 and December 2006, a total of three patients were diagnosed with primary adrenal lymphoma in our institution. The clinicopathological characteristics of the three patients (Patient 1, 2, and 3) with primary adrenal lymphoma were listed in Table 1. The age at diagnosis was 79, 60, and 79 respectively. All the three patients were male in gender. The initial presentations included several constitutional symptoms: anorexia, poor appetite, body weight loss, and fever. All of them had involvement of bilateral adrenal glands exclusively. The three patients all had adrenal insufficiency. All the 3 patients had no leukemic pictures in complete blood count or bone marrow. For making a diagnosis, two of them underwent unilateral adrenalectomy (Patient 1 and 2), while the other (Patient 3) one received CT-guided biopsy. On the computed tomography (CT), the lesions were either heterogenous (Patient 1 and 2) or homogenous (Patient 3); all were hypodense. Grossly, the tumors were white-gray and partially necrotic. The pathological examinations revealed malignant lymphoid cells with increased mitosis infiltrated and replaced the adrenal medullary and cortical tissue. Based on the immunostatining, all the three cases were diffuse large B-cell lymphoma. The clinical course of Patient 1 was characterized by persistent disease progression and treatment failure. The chemotherapy regimen included one cycle of COP (cyclophosphamide, vincristine, and prednisolone), two cycles of COP with bleomycin, one cycle of CNOP (cyclophosphamide, mitoxantrone, vincristine, and prednisolone), one cycle of EPOCN (etoposide, prednisolone, vincristine, cyclophosphamide, and mitoxantrone). Rituximab (anti-CD20 monoclonal antibody) was also prescribed after chemotherapy failed. Patient 1 died of disease progression five months after
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the diagnosis. Patient 2 received chemotherapy with two cycles of BOMES (BCNU, vincristine, methotrexate, etoposide, and methylprednisolone). The treatment was complicated by febrile neutropenia, and he died of sepsis three months after the diagnosis. Patient 3 was treated with two cycles of R-COP (rituximab, cyclophosphamide, vincristine, and prednisone). The treatment was also complicated by neutropenic fever, and he died of sepsis two months after the diagnosis.
Secondary adrenal lymphoma During the same period, we had another three patients presenting with retroperitoneal lymphoma with involvement of the adrenal glands (Patient 4, 5, and 6). The clinicopathological characteristics were shown in Table 1. The three patients had distinct clinical courses and outcomes. The ages at diagnosis were 48, 25, and 76 respectively. All the three patients were male in gender. The initial presentations were fever (Patient 4) and abdominal pain (Patient 5). Patient 6 was asymptomatic and was found to have an adrenal tumor incidentally. On CT, the adrenal tumor was homogenous and hypodense in Patient 4; it was heterogenous and hypodense in Patient 5. The angiography of Patient 5 demonstrated a hypervascular tumor. On the magnetic resonance imaging (MRI), the tumor of Patient 6 was of high signalintensity in T2-weighted images and low signal-intensity in T1-weighted images. The diagnostic procedures included adrenalectomy in Patient 4 and 5, and CTguided biopsy without further surgery in Patient 6. All the pathological examinations revealed diffuse large Bcell lymphoma. The pathological findings were similar to the group of primary adrenal lymphoma. The patient 4 had disease at the left adrenal gland and lymph nodes in the mediastinum and the retroperitoneum. He received four cycle of CHOP and another one cycle of ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin). He died of disease progression six months after the diagnosis. The patient 5 had disease involving the right adrenal gland, right kidney, right psoas muscle, and right retroperitoneal lymph nodes. He underwent radical surgery including adrenalectomy, nephrectomy, lymphadenectomy, and excision of the involved psoas muscle 10 years ago. Postoperatively, he received eight courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). He had been disease-free for four years before recurrence at the para-aortic lymph
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nodes. He then received one cycle of ESHAP and two cycles of BOMES. He then received high-dose BEAM chemotherapy (BCNU, etoposide, cytarabine, and melphalan) and autologous PBSCT (peripheral blood
stem cells transplantation). He has been disease-free thereafter and is still alive. Patient 6 had disease involving the right adrenal
Table 1. Clinicopathological characteristics of the six patients with adrenal lymphoma Patient Adrenal Lymphoma Age at diagnosis Gender Adrenal laterality Disease involvement Initial presentations Diagnostic procedures Diagnostic image Image findings
Leukemic pictures Comorbidities Pathology IHC staining
#1
Primary Primary 79 60 M M Bilateral Bilateral Bilateral adrenal Bilateral adrenal glands glands Anorexia, malaise, Fever, anorexia, body weight loss body weight loss Adrenalectomy, Adrenalectomy, left left CT CT Left adrenal gland: Right adrenal mass: 10×8 cm, Right 8×5 cm; adrenal gland: Left adrenal mass: 2×3 cm, 6×5 cm, heterogenous, heterogenous, hypodense hypodense (-) (-) Hypetension, atrial No fibrillation DLBCL DLBCL CD45 (+) CD45 (+) CD20 (+) CD20 (+) CD3 (-) CLA (+) S-100 (-) CD3 (-) cytokeratin (-) NSE (-) NSE (-)
Adrenal Insufficiency Symptoms-to-Diagnosis, months Chemotherapy regimens
Cause of Death Diagnosis-to-Death, months
#2
Yes 12
Yes 3
#3
#4
#5
#6
Primary Secondary Secondary Secondary 79 48 25 76 M M M M Bilateral Left Right Right Bilateral adrenal Left adrenal Right adrenal Right adrenal glands gland, paraaortic gland, right gland, Anorexia, malaise, Fever Abdominal pain Incidental finding body weight loss CT-guided biopsy, Adrenalectomy, Adrenalectomy, CT-guided biopsy, left left right right CT CT CT, angiography MRI Right adrenal mass: Left adrenal mass: Right adrenal mass: Right adrenal 4.8×2.5 cm; 3×3 cm, 5×6 cm, mass: 7×5 cm, Left adrenal mass: homogenous, heterogenous, high signal intensity 5×2.8 cm, hypodense hypodense, in T2W image; homogenous, hypervascular low signal intensity hypodense in T1W image (-) (-) (-) (-) Peptic ulcer Anemia No Peptic ulcer DLBCL CD45 (+) CD20 (+) CD3 (-) CLA(+) CK (-) EBER (-) Yes 1
COP (1) BOMES (2) R-COP (2) COP + bleomycin (2) CNOP (1) EPOCN (1) Rituximab Disease Sepsis (complication Sepsis (complication progression of treatment) of treatment) 5 3 2
DLBCL CD45 (+) CD20 (+) CLA (+) c-kit (+) CD 3(-) S-100 (-) CK (-) No 2
DLBCL CD45 (+) CD20 (+) CD3 (-) S-100 (-) cytokeratin (-) NSE (-)
DLBCL CD45 (+) CD20 (+) S-100 (-) cytokeratin (-) NSE (-)
No 5
No 1
CHOP (4) ESHAP (1)
CHOP (8) ESHAP (1) BOMES (2)
R-CHOP (3)
Disease progression 6
High-dose BEAM and Auto-PBSCT Alive
Alive
120 (alive)
15 (alive)
CLA:Common leukocyte antigen, CK: cytokeratin, EBER: Epstein-Barr virus encoded RNA, NSE: neuron specific enolase; COP (cyclophosphamide, vincristin, and prednisolone), CNOP (cyclophosphamide, mitoxantrone, vincristine, and prednisoloneand), EPOCN (etoposide, prednisolone, vincristine, cyclophospahmide, and mitoxantrone), BOMES (BCNU, vincristine, methotrexate, etoposide, and methylprednisolone), R-COP (rituximab, cyclophosphamide, vincristine, and prednisone), ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin), BEAM (BCNU, etoposide, cytarabine, and melphalan).
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gland and suprarenal lymph nodes. He received three cycles of rituximab and CHOP. He had complete remission and has been alive.
DISCUSSION Primary adrenal lymphoma is an extremely rare disease. The present study is the largest series in a single institute despite of the small patient numbers. To illustrate the distinct clinical presentations and courses of primary adrenal lymphoma, we also compared the primary cases with the secondary cases. The clinical pictures of the three cases of primary adrenal lymphoma generally accords with previously published literature.2-15 Primary adrenal lymphoma predominantly affects the elderly and men.13,14 Wang J et al13 reviewed 55 cases which had been reported in the literature. The median age was 68 and the male to female ratio was 2.2 to 1. Of these patients, 40 (73%) patients had involvement of bilateral adrenal glands; 20 (36%) had adrenal insufficiency. In our series, all the three patients with primary adrenal lymphoma had bilateral involvement and adrenal insufficiency. In the present study, all the three patients with primary adrenal lymphoma had diffuse large B-cell lymphoma, concurring with the report of Wang J et al13, in which 71% of the patients had diffuse large B-cell lymphoma. Other less common histological types included mixed large and small cells, small non-cleaved cells, undifferentiated, and others. The majority of the reported cases were of B cell type with only two cases of T cell type (2/55). Some studies mentioned that poor prognostic factors include advanced age, large tumor, the presence of adrenal insufficiency, and a high plasma LDH level.3,5,8,13,14 In our series, all the patients with primary adrenal lymphoma had a high serum level of LDH, involvement of bilateral adrenal glands, and adrenal insufficiency. The three patients had a distinctly poor prognosis in comparison with the other three patients with secondary adrenal lymphoma. The cause may be due the distinctly special disease entity or other factors including older age, larger size of tumor and adrenal insufficiency, which remained much to be explored in the future. All the six patients, either with primary or secondary adrenal lymphoma, presented with adrenal tumor initially. The differential diagnosis included poorly differentiated adrenal cortical carcinoma, metastatic carcinoma, primary or metastatic malignant melanoma and malignant pheochromocytoma.6,7,10,13 It is difficult to make a diagnosis according to the image study. It requires pathological examinations to make the final
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diagnosis. With very limited experience in the literature, the optimal therapeutic modality is poorly defined. Surgery is more a diagnostic procedure than a therapeutic intention. Long-term survival has been rarely reported with either adrenalectomy followed by chemotherapy or adrenalectomy followed by radiotherapy.13,14 However, the result of either strategy has been disappointing; most patients died of the disease or its complications within one year of diagnosis in the literature review.13 The choices of treatment modalities should be balanced between effects and side effects. The prognosis is grave with the survival period less than 5 months in the group of primary adrenal lymphoma. All the three cases of primary adrenal lymphoma had involvement of the bilateral adrenal glands, and unilateral adrenalectomy simply meant a diagnostic procedure. It is unclear whether a radical surgery (bilateral adrenalectomy) combined with chemotherapy can achieve a better survival. In the three patients with secondary adrenal lymphoma, the outcomes were distinctly better in comparison with the three primary cases. Even with more extensive involvement, Patient 5 and 6 had a long-term survival after surgery and chemotherapy. It remained unclear what causes the extremely different courses between primary and secondary adrenal lymphoma.
CONCLUSIONS Primary adrenal lymphoma is very rare. It predominantly affects the elderly and the men. It tends to involve the bilateral adrenal glands and usually causes adrenal insufficiency. The majority are of diffuse large B-cell type. The outcome is very ominous, and most patients die of disease progression of treatment complications within one year of diagnosis. It is prudent to differentiate between primary and secondary adrenal lymphoma since the clinical course is extremely different. Although the secondary cases have a more extensive disease, the patients have a significantly better outcome. The treatment modalities for primary adrenal lymphoma include surgery, chemotherapy, radiotherapy, or combinations. With very limited experience, the optimal therapeutic strategy remained unclear and required further studies.
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3. Feldberg MA, Hendriks MJ, Klinkhamer AC. Massive bilateral non-Hodgkin's lymphomas of the adrenals. Urol. Radiol 1986;8:85-8. 4. Harris GJ, Tio FO, Von Hoff DD. Primary adrenal lymphoma. Cancer 1989;63:799-803. 5. Lu JY, Chang CC, Chang YL. Adrenal lymphoma and Addison's disease: report of a case. J. Formos. Med. Assoc 2002;101:854-8. 6. Zhang LJ, Yang GF, Shen W, Qi J. Imaging of primary adrenal lymphoma: case report and literature review. Acta Radiol 2006;47:993-7. 7. Varez-Castells A, Pedraza S, Tallada N, Castella E, Gifre L, Torrents C. CT of primary bilateral adrenal lymphoma. J. Comput. Assist. Tomogr 1993;17:408-9. 8. Choi CH, Durishin M, Garbadawala ST, Richard J. NonHodgkin's lymphoma of the adrenal gland. Arch. Pathol. Lab. Med 1990;114:883-5. 9. Curry NS, Chung CJ, Potts W, Bissada N. Isolated lymphoma of genitourinary tract and adrenals. Urology 1993;41:494-8.
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10. Kato H, Itami J, Shiina T et al. MR imaging of primary adrenal lymphoma. Clin. Imaging 1996;20:126-8. 11. Sasagawa I, Sadamori N, Itoyama T et al. Primary adrenal lymphoma with chromosomal abnormalities. Acta Haematol. 1995;94:156-62. 12. Serrano S, Tejedor L, Garcia B, Hallal H, Polo JA, Alguacil G. Addisonian crisis as the presenting feature of bilateral primary adrenal lymphoma. Cancer 1993; 71:4030-3. 13. Wang J, Sun NC, Renslo R et al. Clinically silent primary adrenal lymphoma: a case report and review of the literature. Am. J. Hematol. 1998;58:130-6. 14. 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;78:289-92. 15. Ohsawa M, Tomita Y, Hashimoto M, Yasunaga Y, Kanno H, Aozasa K. Malignant lymphoma of the adrenal gland: its possible correlation with the Epstein-Barr virus. Mod. Pathol 1996;9:534-43.
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