Primary adrenal lymphoma as a cause of adrenal insufficiency, a report of two cases

Background

Primary adrenal insufficiency is characterized by low or subnormal serum cortisol and elevated levels of adrenocorticotropic hormone (ACTH). Patients also have low aldosterone and elevated plasma renin. Elevated ACTH and low aldosterone distinguish primary adrenal insufficiency from secondary adrenal insufficiency, where cortisol is low with low ACTH and normal aldosterone. Other biochemical disturbances in primary adrenal insufficiency are hyponatremia (84–88%), hyperkalemia (36–64%) and elevated TSH (50%) (1). Clinically, fatigue and weight loss is reported in 100%, anorexia and nausea/vomiting in 80–90%, hyperpigmentation in >90% and low blood pressure in 90% (2). ACTH stimulation test confirms the diagnosis. The condition may progress to adrenal crisis and death. Causes of adrenal insufficiency include autoimmune adrenalitis, infections, infiltrative disorders and malignancy. We hereby report two patients presenting with adrenal insufficiency with negative 21-hydroxylase antibodies and bilateral adrenal lesions.

Case presentations

Investigations

Biochemistry showed acute kidney failure (creatinine 265 µmol/L) and hyponatremia (131 mmol/L). During the next 3 days, plasma sodium decreased to 120 mmol/L despite treatment with i.v. isotonic sodium chloride. Urinary sodium was 26 at presentation, increasing to 68 during treatment. Urine osmolality was 392 mosm/kg measured at the same time as the second urinary sodium. The first urine sodium could be explained by hypovolemia. Increasing urinary sodium content with falling plasma sodium raised suspicion of SIADH. Further assessment revealed low serum cortisol at 37 nmol/L (112–502 nmol/L) and grossly elevated ACTH at 87.7 pmol/L (1.4–14 pmol/L). Synacthen test (250 µg i.v.) confirmed primary adrenal insufficiency (Table 1). On reconsideration, this explained hyponatremia with high urinary sodium. Because of negative 21-hydroxylase antibodies, a CT scan was undertaken, revealing bilateral adrenal masses (Fig. 1A). The right lesion consisted of two parts: a ventral lesion with diameter 1.8 cm and precontrast density 25 Hounsfield Units (HU) and a dorsal part measuring 1.6 cm with precontrast density 30 HU. Washout was 74% for the ventral lesion and 55% for the dorsal lesion. On the left side, the mass measured 4.2 x 2.1 cm with precontrast density 32 HU and washout 32% (Fig. 1B). High precontrast density and modest washout of the right dorsal lesion and the left mass was suggestive of metastases. There were no other signs of malignancy. Normal plasma metanephrines excluded pheochromocytoma.

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Contrast-enhanced computed tomography (CT) of the adrenals in patient 2 showing bilateral masses (arrows). Right-sided lesion consisting of two parts with ventral diameter measuring 1.8 cm and dorsal diameter measuring 1.6 cm. The left lesion measures 4.2 × 2.1 cm.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2020, 1; 10.1530/EDM-19-0131

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Table 1

Baseline laboratory values and synacthen test.

	Patient 1	Patient 2	Reference
S-cortisol, nmol/L
0	193	37	112–502
30 min	175	46
60 min	173	40	>500
ACTH, pmol/L
0	191	87
30 min	81.6
60 min	93.1		1.4–14
S-sodium, mmol/L	133	131	137–145
S-potassium, mmol/L	5.5	6.0	3.5–5.0
Aldosterone, pmol/L	<69	97	<653*
Renin, mIU/L	4.8	27.8	2.8–39.9*

*Laying down.

Treatment and follow-up

Recovery was rapid after stabilization with i.v. hydrocortisone 100 mg intravenously three times during the first 24 h followed by oral replacement therapy with cortisone acetate 25 mg x 3 with gradual reduction to 25 + 12.5 mg and fludrocortisone 0.1 mg daily. MRI after 4 weeks confirmed bilateral adrenal lesions with characteristics pointing toward malignancy. He was planned for a CT-guided biopsy. Due to the Easter vacation and a mistake concerning the appointment, it took almost 1.5 months from the MRI (2.5 months from first presentation) until biopsy was scheduled. By then, the malignant-looking masses had almost disappeared. The right ventral lesion was unchanged, whereas the right dorsal lesion was undetectable and the left measured 8 mm (Fig. 2). Biopsy was not performed. On reconsideration, the lesions were thought to represent hemorrhage or infection with spontaneous recovery. The patient was in good condition on replacement therapy with regular follow-up at the endocrinology outpatient clinic.

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Adrenal CT 2 months later. Almost total regress of the right dorsal lesion and the left lesion. The right ventral lesion is still present (adenoma according to wash-out analyses).

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2020, 1; 10.1530/EDM-19-0131

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Six months later he presented acutely with fever, tachycardia and hypotension without focal infection signs. Prior to admission, he had a 3 months history of abdominal discomfort, nausea and 10 kg weight reduction with a positive test for occult fecal bleeding. Gastrointestinal pathology had been excluded by endoscopic examinations. Subsequent abdominal CT had revealed a large mass in relation to the right adrenal. This finding was not yet evaluated. On acute admission, he had progressive systemic inflammatory response syndrome despite therapy with i.v. fluids, hydrocortisone and broad spectrum antibiotics. No infection was identified on urinary analyses and pulmonary X-ray. Abdominal CT confirmed a heterogenous tumor of the right adrenal measuring 6.0 x 7.0 x 12.0 cm (Fig. 3A), growing into liver parenchyma and infiltering adjacent lymph nodes. The left adrenal was atropic (Fig. 3B). A biopsy was performed, showing aggressive diffuse large B-cell lymphoma with high proliferation index (Ki67 of 100%). Standard treatment with six courses of rituximab, cyclophosphamide, vincristine, doxorubicine and prednisolone (R-CHOP) followed by radiation therapy was initiated. Therapy was successful without signs of tumor recurrence at last follow-up, 2 years after treatment. The patient still takes replacement therapy for adrenal insufficiency and is seen by endocrinologist regularly.

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Adrenal CT 7 months after spontaneous regress. Heterogenous tumor of the right adrenal measuring 6 × 7 × 12 cm (A). Atropic left adrenal without mass (B).

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2020, 1; 10.1530/EDM-19-0131

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Discussion

Primary adrenal lymphoma (PAL) is uncommon. In a systematic review by Rashidi & Fisher (3), it is defined as histologically proven lymphoma involving one or both adrenal glands, with no prior history of lymphoma elsewhere and adrenal lesions dominating over lymph nodes or other organs involved. PAL is bilateral in about 70% of cases. Radiologically, the lesions tend to show low density and slight to moderate contrast enhancement on CT. On MRI, the tumors tend to be iso-/hypo-intense in T1 and hyperintense in T2 (3). In Rashidi & Fisher’s material, all masses studied with PET and Gallium scans showed increased uptake demonstrating high metabolic activity. Angiographic studies showed low vascularity. A definitive diagnosis is made histologically and requires biopsy. The most common subtypes are diffuse large B-cell lymphoma (DLBCL) accounting for 78% and peripheral T-cell lymphoma (PTCL) – 7%. Tumor behavior is aggressive with B-symptoms in 68% and adrenal insufficiency in 61%. Other manifestations include pain (42%) and fatigue (36%). Only 1% are found incidentally. Demographic studies show male predominance (1, 8:1) with mean age 62 ± 14 years. Causes of bilaterality is not fully understood. According to Rashidi & Fisher, ‘field effect’ with simultaneous cancers of an anatomic ‘field’ (like an organ or gland) with genetically altered cells is one possible mechanism. Organotropism (affinity of tumour cells for certain tissues) is also suggested. As the adrenal parenchyma lacks lymphatic vessels, lymphomagenesis outside the organs before ‘homing’ to the adrenals is proposed. Chemokine- and microRNA-driven organotropism in CNS and testicular lymphoma is under investigation, and similar mechanisms could exist in the pathophysiology of primary adrenal lymphoma (3). The authors pinpoint that more research is needed to explain the pathophysiology and bilaterality of primary adrenal lymphoma. B-symptoms are associated with bilaterality, thought to reflect greater systemic cytokine-effects from lymphomas with larger tumour burden and greater access to blood and lymphoid vessels. There was a significant association between bilaterality and adrenal insufficiency. No concrete example of unilaterality and adrenal insufficiency was mentioned. On the other hand, even small primary adrenal lymphomas have been associated with adrenal insufficiency. This observation has led to a suggestion that the correlation between tumor size and adrenal insufficiency may be weak or absent (3). The percentage of patients with adrenal failure is considerably higher than in bilateral adrenal metastases from carcinoma (3–8%) (4). Cytokine-driven paracrine effects of lymphoma cells on adrenal gland microenvironment is suggested. The exact mechanisms are uncertain. Adrenal insufficiency in metastatic carcinoma is thought to reflect tumor replacement of functional tissue and interruption of vascular supply rather than cytochemical effects.

We present two cases of primary adrenal lymphoma manifesting as adrenal insufficiency with bilateral adrenal masses. One of the patients experienced almost total regression of the masses on treatment with standard replacement therapy alone, before subsequent aggressive regrowth. The other was biopsied during primary evaluation and responded to a combination of cytostatic therapy and radiation. Both patients presented with adrenal failure at an older age than expected for autoimmune adrenalitis. Negative 21-hydroxylase antibodies raised suspicion of an uncommon cause, and both had adrenal lesions pointing toward malignant disease. Adrenal lesions may have several causes, and biopsy should be taken when pheochromocytoma is biochemically excluded. The possible tumor-reducing effect of replacement therapy in one of our cases confused and delayed the diagnostics. Glucocorticoids are part of the standard regimen for several lymphoid cancers, due to steroid sensitivity of tumor cells that seems to be more pronounced for immature lymphoid cells (4). Glucocorticoids have direct actions on gene transcription through glucocorticoid response elements (GREs) and indirect actions through interaction with transcription factors. Effects on immune cells include inhibition of nuclear factor kappa B (NF-κB) and AP-1 (5, 6). NF-κB is a transcription factor for cytokines and genes involved in lymphocyte development, inflammatory response and apoptosis. AP-1 is also a proinflammatory transcription factor (6). In our case number two, tumor regress was seen shortly after starting cortisone replacement therapy. Because of the strong correlation in time between treatment initiation and tumor shrinking, steroid sensitivity rather than spontaneous recovery seems to explain the regression. Obviously, this postulation will never be confirmed. Supporting our theory, there are no previous reports describing spontaneous regression of primary adrenal lymphoma. Initial recovery might be explained by primary indolent tumor histology transforming into a more aggressive type. In lack of biopsy, this hypothesis will remain unconfirmed. Diffuse large B-cell lymphoma has a reported 3-, 6- and 12-month survival of 67, 46 and 20%, respectively (3). As described in the section on 'Case presentations', one of our patients died of CNS-lymphoma 9 years after first presentation. The other one had no clinical signs of recurrence at the last follow-up at the haematology outpatient clinic. It is now nearly 3 years after first presentation and about 2 years after diagnosis of diffuse large-cell B-cell lymphoma and initiation of chemotherapy.

Conclusions

Primary adrenal failure with negative 21-hydroxylase antibodies should be evaluated radiologically. As outlined in the European guidelines on adrenal nodules (7), patients with adrenal lesions should be discussed in a multidisciplinary team if imaging is not consistent with benign etiology. In general, biopsy is not recommended as part of diagnostic work-up unless there is a history of extra-adrenal malignancy. Lymphoma and infiltrative/infectious processes are mentioned as potential differential diagnoses where biopsy has a role in evaluation. Adrenalectomy is considered a better option than biopsy in most cases. Bilateral adrenal masses should be evaluated in the same way as unilateral lesions with separate characterization of each lesion. Given the high proportion of bilaterality and adrenal insufficiency in primary adrenal lymphoma, we find it reasonable to perform biopsy in patients with both characteristics when pheochromocytoma is excluded biochemically. Biopsy should be performed quickly to avoid potential steroid influences.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Patient consent

The authors confirm that they have obtained written informed consent from the patients for publication of this article and accompanying images.

Author contribution statement

K G wrote the first draft of the manuscript and did the review of the patient 1 and the literature search. E S H and K L did the review of the case 2. B D K is responsible for the x-rays. The other authors listed have actively contributed to the manuscript and approved the submission of this version of the manuscript.