Primary adrenal lymphoma presenting as Addison’s disease: case report and review of the literature
Primary adrenal lymphoma (PAL) is an extremely rare entity and adrenal insufficiency is a common complication. Bilateral enlargement of adrenal glands should raise the suspicion of lymphoma, especially in patients with clinical or laboratory features of adrenal insufficiency. Most of these cases are highly aggressive tumors and should be treated with multiagent chemotherapy. The role of bilateral adrenalectomy and/or radiotherapy cannot be estimated. Our patient with PAL was an 80-year-old man who presented with clinical and laboratory features of adrenal insufficiency. Combination chemotherapy plus rituximab was unsuccessful and our patient died from progressive disease.
KeywordsAdrenal lymphoma Addison’s disease Extranodal lymphoma
Primary extranodal lymphomas account for approximately one-third of all lymphomas and can affect almost any organ. Skin and stomach are the most common sites involved, followed by Waldeyer’s ring, thyroid, bone, orbit, lung, brain, and testis. Primary extranodal lymphomas present frequently with localized disease and have the potential to be cured with appropriate treatment. The propensity for bilateral involvement is characteristic for extranodal lymphomas arising in paired organs .
The adrenal gland is the site of metastatic involvement from primary carcinoma of lung, breast, kidney, bladder, pancreas, and melanoma . Several autopsy series have shown that 20–25% of patients with non-Hodgkin’s lymphoma (NHL) have adrenal gland involvement at some time during the course of their disease, usually in association with advanced disease . Instead, primary adrenal lymphoma (PAL) is an extremely rare entity.
Some of the patients with bilateral PAL show clinical or laboratory signs of adrenal insufficiency, which is not usually seen in unilateral adrenal NHL. Very few cases of PAL have been reported in the literature over the previous years. In this article, we describe a PAL patient who presented with adrenal insufficiency.
An 80-year-old man was admitted to our clinic for evaluation of fever, easy fatigue, nausea, emesis, and constipation of 1-week duration. His past history was unremarkable except hypertension for which he was receiving calcium channel blockers.
On clinical examination, nothing was found except mild abdominal distention. Organomegaly or lymphadenopathy was absent. Laboratory evaluation: full blood count (FBC) revealed hematocrit (Hct) 44%, hemoglobin (Hb) 14.4 g/dl, WBC 4.6×103/μl, platelets (PLT) 156×103/μl, differential (neutrophils 46%, lymphocytes 30%, monocytes 24%), urea 100 mg/dl (normal range: 10–45), creatinine 2.2 mg/dl (normal range: 0.5–1.2), serum Na 125 mEq/l (normal range: 130–140), serum K 5.4 mEq/l (normal range: 3.5–5.1), glucose 65 mg/dl (normal range: 70–110), and lactic dehydrogenase (LDH)=240 IU/l (normal range: 90–190). The rest of the biochemical work-up was normal.
Diagnostic work-up for confirmation of the suspected adrenal insufficiency was performed. Serum cortisol at 8 a.m. was 7.5 μg/dl and at 4 p.m. was 4.5 μg/dl (normal range: 5–25) and corticotropin (ACTH) 79.4 pg/ml (normal range: 5–46). An overnight suppression test with 1 mg dexamethasone and cosyntropin-stimulation test were suggestive of adrenal insufficiency. Urine vanillymandelic acid was 17.2 mg/day (normal range: 1–11). Serum aldosterone in supine position was 14 pg/ml (normal range: 10–160) and renin (supine position) 1.9 ng/ml (normal range: 0.2–2.8).
Further examinations including blood cultures for evaluation of fever were all negative. The patient was treated with hormone replacement and hopefully, he had an excellent response with complete disappearance of all clinical signs of adrenal insufficiency.
The patient was treated with the chemotherapeutic combination CNOP (cyclophosphamide, mitoxantrone, vincristine, and prednisolone) plus the anti-CD20 monoclonal antibody rituximab (a more specific regimen was not chosen because of his age). He received three cycles of chemotherapy, but unfortunately he experienced progression of his lymphoma. The patient died 2 months after his first admission from hepatic failure and secondary central nervous system involvement.
No. of patients with relevant data
64.5 years (31–87)
Disease-free survival for at least 6 months
PAL shows a predilection for old males with a mean age at presentation of 65 years and a male-to-female ratio of 2:1. A significant percentage of patients presented with symptoms and signs of adrenal insufficiency, while other common symptoms include abdominal or back pain, fever of unknown origin (FUO), anorexia, weight loss, malaise, etc. More than two-thirds of all patients had bilateral enlargement of the adrenal glands. Although lymphoma involvement of other anatomical sites outside the adrenals was a rare event at presentation, PAL exhibits a propensity for generalized involvement of multiple extranodal regions such as liver, stomach, and CNS during the course of the disease. Almost two-thirds of the patients with bilateral involvement had laboratory and/or clinical features of adrenal insufficiency. Since an Addisonian crisis leads to severe life-threatening consequences, immediate replacement therapy must be considered if adrenal insufficiency is suspected.
Primary adrenal lymphoma can be confused with metastatic carcinoma. Ultrasound, CT scans, and magnetic resonance imaging (MRI) are useful for the detection of adrenal gland enlargement. The increasing use of these imaging techniques allows this disease to be diagnosed more frequently premortem in the last few years. Several imaging features have been described to differentiate adrenal malignancy from benign disorders. PAL appears to have a predilection for necrosis and hemorrhage while calcification is quite common . CT-guided needle biopsy or surgical biopsy through laparoscopy or laparotomy is required for definite histopathological diagnosis. Destruction of more than 90% of the adrenal cortex is necessary before adrenal insufficiency becomes apparent. For this reason, although solid tumor metastases to the adrenal glands are common, clinically apparent adrenal insufficiency is a late feature of disseminated neoplasm and often masked by other signs and symptoms of advanced malignancy .
Almost 90% of these lymphomas were of B-cell origin, while the vast majority of them were high-grade malignancies. Although it is very difficult to be certain of the correct histopathological diagnosis according to the new classification systems, it seems that almost 70% of PAL cases are of diffuse large B-cell lymphoma (DLBCL) type. There were only a few cases of low-grade histology, while there were two cases of anaplastic (CD30+), two cases of angiotropic large cell, and three cases of small non-cleaved cell histology, respectively.
Different modalities were used for the treatment of these patients such as bilateral adrenalectomy, multiagent chemotherapy, radiotherapy, or a combination of them. The patients with adrenal insufficiency received hormone replacement therapy as well. Although in previous reviews PAL seemed to be an entity with very poor prognosis, we consider that it is not possible to make safe conclusions because of the limited data. PAL is in fact an aggressive disease as all patients given only palliative treatment had a rapidly fatal course. Slightly less than half of the patients who have been treated with a curative intent achieved complete remission of their disease, but many of them relapsed usually during the first few months of observation. It is interesting to note that PAL exhibits a propensity for late CNS relapses. Our patient had leptomeningeal involvement during the progression of his disease. This observation raises the possibility that it will be useful in future clinical trials to add CNS prophylaxis in the treatment of PAL patients.
Overall 34% of the treated patients survived disease free for at least 6 months. Although there are long-term survivors, it is not possible to calculate parameters such as overall survival or disease-free survival because of the limited follow-up period in most of these case reports. For the same reason, it is not possible to estimate the efficacy of the different treatment modalities.
PAL is a very rare but interesting disease entity. Bilateral enlargement of adrenal glands should raise the suspicion of lymphoma, especially in patients with clinical or laboratory features of adrenal insufficiency. Most of these cases are highly aggressive tumors and should be treated with multiagent chemotherapy. The role of bilateral adrenalectomy and/or radiotherapy cannot be estimated. Hormone replacement therapy is mandatory. Collection of clinical data from case reports will be useful for the future design of management of these patients, as prospective clinical trials should never be performed because of the rarity of PAL.
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