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Journal of Clinical Oncology, Vol 25, No 16 (June 1), 2007: pp. 2322-2324 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.8159
Addison's Disease From Non-Hodgkin's Lymphoma With Normal-Size Adrenal GlandsDepartment of Internal Medicine, Franklin Square Hospital Center, Washington, DC
Department of Hematology and Oncology, St Agnes Hospital, Baltimore, MD
Department of Endocrinology, St Agnes Hospital, Baltimore, MD In 1995, a 60-year-old woman presented with a 2-month history of left flank pain, 20-pound weight loss, fatigue, and fever. An abdominal computed tomography (CT) scan showed a 10-cm mass in the region of the lesser sac involving the spleen and pancreas. Exploratory laparotomy revealed an unresectable mass and enlarged celiac lymph nodes. Fine needle aspiration of the mass showed a poorly differentiated neoplasm; however, one celiac lymph node revealed a non-Hodgkin's (NHL) diffuse large B-cell lymphoma (DLBCL; Fig 1). The patient had stage IVb DLBCL. The patient received six cycles of EPOCH (etoposide, vincristine, adriamycin, cyclophosphamide, prednisone) and radiation therapy. There was no evidence of disease at 9-year follow-up. In 2005, the patient presented with weakness, 30-pound weight loss, back pain, hyperpigmentation, and orthostatic hypotension. Pertinent laboratory data revealed a serum sodium of 118 mEq/L and potassium of 5 mEq/L. Adrenal failure was diagnosed based on low basal cortisol levels of 5.0 µg/dL. Cortisol levels remained low after synthetic adrenocorticotropic stimulation ranging from 5.0 to 5.9 µg/dL. Clinically, the patient improved with hydrocortisone and fludracortisone supplementation, though her adrenocorticotropic hormone levels remained elevated at 153 pg/mL (normal, < 52 pg/mL). Other laboratory examinations, including adrenal autoantibodies, thyroid autoantibodies, and tuberculin skin test were unremarkable. CT of the abdomen was reported as showing "normal" adrenal glands, though the right adrenal gland may have been slightly enlarged (Fig 2). There was also evidence of retroperitoneal lymphadenopathy, with the largest lymph node measuring 1.2 cm. Six months later, the patient presented with sharp, right-sided flank pain, a tender palpable abdominal mass and anemia (hematocrit of 22%). Lactate dehydrogenase was elevated at 4,873 U/L (normal, 313 to 618 U/L). An abdominal CT scan showed a mass in the region of the right adrenal gland (9.8 x 5.7 cm; Fig 3). The left adrenal gland was slightly enlarged (3.6 x 4.1 cm), and there was retroperitoneal lymphadenopathy (the largest lymph node measuring 1.7 cm). A positron emission tomography scan showed extensive mediastinal and abdominal lymphadenopathy, as well as a metabolically active neoplasm in the right and left adrenal glands (Fig 4). The CT scan from 6 months ago was re-evaluated by several radiologists, and there was disagreement as to whether the right adrenal gland was normal or slightly enlarged; however, all radiologists agreed that the left adrenal gland was within normal limits. CT-guided fine needle aspiration of the adrenal mass disclosed a DLBCL similar to the pathology from 10 years ago (Fig 5). The patient also had pleural effusions and underwent a paracentesis. The pleural fluid was positive for CD20, a B-lymphocyte marker (Fig 6). The patient refused treatment and died approximately 1 month after diagnosis. No autopsy was performed. The first case of adrenal insufficiency was described by Thomas Addison in 1855.1 Today, the most common cause of primary adrenal insufficiency worldwide is due to infectious disease such as tuberculosis, fungal infections, cytomegalovirus, and HIV. In the United States, autoimmune disease accounts for more than 70% of all cases of Addison's disease. However, in these cases, the adrenal glands are usually atrophic.2,3 Other causes of Addison's disease are rare, but may include hemorrhage, septicemia, and malignancy. The adrenal glands are commonly involved by metastatic disease from other neoplasms, such as lung and breast primaries.4 In NHL, secondary adrenal involvement occurs in 4% of cases assessed by CT5 and in 24% at postmortem examination.6 However, clinical and biochemical evidence of adrenal insufficiency is rare, as more than 90% of the gland must be destroyed. A study7 suggested that adrenal insufficiency may be underestimated in patients with NHL. A review of the literature in 1991 found only seven cases of adrenal insufficiency in patients with NHL. However, the study found that eight out of 127 patients (3%) with NHL had adrenal gland enlargement. Half of these patients had bilateral adrenal enlargement, all of which had adrenal insufficiency.7 Disease originating from the adrenal gland is rare and is termed primary adrenal lymphoma. There have been approximately 100 cases reported in the literature, most of which are single-case reports. With the use of advanced imaging techniques, there has been an increase in the incidence of adrenal lymphomas.8 Most of the patients are older than 60 years, have bilateral adrenal masses, are diffuse large cell by histology, and are likely to have clinical adrenal insufficiency.9 Adrenal insufficiency has been the presenting symptom in several case reports, all of which were accompanied by adrenal enlargement by CT scans.10-14 These patients usually present with advanced disease and rarely survive more than 1 year after diagnosis.11 Early diagnosis is difficult as there are no pathognomonic symptoms.10
Our patient had clinical and biochemical evidence of Addison's disease 6 months before presenting with enlarged bilateral adrenal glands. At the time of initial presentation, CT imaging suggested normal adrenal glands. In retrospect, the right gland may have been slightly enlarged, though this is debatable. However it is unusual that our patient would have adrenal insufficiency in the presence of even slight enlargement of one adrenal gland. To our knowledge, there has been only one other case report of adrenal insufficiency with slight enlargement of one adrenal gland.15 All other cases of adrenal lymphomas associated with adrenal insufficiency, whether primary or secondary, have had massive enlargement of one or both adrenal glands. It is unclear if this is a relapse of NHL or a new primary lesion, as the patient remained disease free for 10 years. As the pathology is the same, this is probably a recurrence of NHL. There is one other report of a patient that remained disease free for 7 years and then presented with acute adrenal insufficiency as a manifestation of his relapse.16 The work-up revealed a large mass in the retroperitoneal space that wrapped around the abdominal aorta, inferior vena cava, destroyed both adrenals, and also extended into the right lobe of the liver. The report also speculated that it may be a relapse from local recurrence of disease or a new primary that originated in the adrenal glands.16 As the presenting symptoms of patients with cancer are similar to those of patients with adrenal insufficiency (weakness, weight loss, abdominal pain, and electrolyte abnormalities), it is important to include stimulation tests to evaluate hormonal function if there is suspected clinical adrenal insufficiency. The first group to report complete remission of a patient with primary adrenal lymphoma associated with adrenal insufficiency addressed the adrenal insufficiency with normal replacement prior to a standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen. This patient had compete remission for 50 months.17 Thus, early diagnosis and management of adrenal insufficiency before chemotherapy may improve outcomes. Our patient demonstrates that Addison's disease may be an early manifestation of adrenal lymphoma or relapse of prior lymphoma, despite the presence of normal or slightly enlarged adrenal glands. In patients with a prior history of lymphoma that present with adrenal insufficiency, clinicians should consider malignant lymphoma of the adrenal gland as part of the differential diagnosis. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest.
REFERENCES 1. Addison T: On the Constitutional and Local Effects of Disease of the Supra-Renal Capsules (special ed). London, United Kingdom, Highley, 1855, p 9 2. Larsen PR: Williams Textbook of Endocrinology (ed 10). W.B. Saunders Co, Philadelphia, PA, 2003 3. Carey RM: The changing clinical spectrum of adrenal insufficiency. Ann Intern Med 127:1103-1105, 1997 4. Redman BG, Pazdur R, Zingas AP, et al: Prospective evaluation of adrenal insufficiency in patients with adrenal metastasis. Cancer 60:103-107, 1987[CrossRef][Medline] 5. Paling MR, Williamson BRJ: Adrenal involvement in non-Hodgkin's lymphoma. Am J Roentgenol 141:303-305, 1983 6. Shea TC, Spark R, Kane B, et al: Non-Hodgkin's lymphoma limited to the adrenal gland with adrenal insufficiency. Am J Med 78:711-714, 1985[CrossRef][Medline] 7. Gamelin E, Beldent V, Rousselet M, et al: Non-Hodgkin's lymphoma presenting with primary adrenal insufficiency. Cancer 69:2333-2336, 1992[CrossRef][Medline] 8. Salvatore JR, Ross RS: Primary bilateral adrenal lymphoma. Leuk Lymphoma 34:111-117, 1999[Medline] 9. Al-Fiar FZ, Pantalongy D, Shepherd F: Primary bilateral adrenal lymphoma. Leuk Lymphoma 27:543-549, 1997[Medline] 10. Diamante-Kandarakis E, Chatzismalis P, Economou F, et al: Primary adrenal lymphoma presented with adrenal insufficiency. Hormones 3:68-73, 2004[Medline] 11. Hsu CW, Ho CL, Sheu WHH, et al: Adrenal insufficiency caused by primary aggressive non- Hodgkin's lymphoma of bilateral adrenal glands: A report of a case and literature review. Ann Hematol 78:151-154, 1999[CrossRef][Medline] 12. Miyamura T, Obama K, Takahira H, et al: A case of primary non-Hodgkin lymphoma of the adrenal gland presenting with Addison's disease. Rinsho Ketsueki 34:882-884, 1993[Medline] 13. Serrano S, Tejedor L, Garcia B, et al: Addisonian crisis as the presenting feature of bilateral primary adrenal lymphoma. Cancer 71:4030-4033, 1993[CrossRef][Medline] 14. Huminer D, Garty M, Lapidot M, et al: Lymphoma presenting with adrenal insufficiency: Adrenal enlargment on computed tomographic scanning as a clue to diagnosis. Am J Med 84:169-172, 1988[CrossRef][Medline] 15. Lu JY, Chang CC, Chang YL: Adrenal lymphoma and Addison's disease: A report of a case. J Formos Med Assoc 101:854-858, 2002[Medline] 16. Chung HT, Wong KL, Liang RHS, et al: Non-Hodgkin's lymphoma as a cause of hypoadrenalism. Aust NZ J Med 17:605-607, 1987[Medline] 17. Kuyama A, Takeuchi M, Munemasa M, et al: Successful Treatment of Primary Adrenal Non-Hodgkin's Lymphoma Associated with Adrenal Insufficiency. Leuk Lymphoma 38:203-205, 2000[Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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