A case report of syndrome of inappropriate antidiuretic hormone secretion with Castleman’s disease and lymphoma

Background Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia in hospitalized patients and is often described in patients with small-cell carcinoma of the lung. In this report, we described both Castleman’s disease and lymphoma coexisting in one patient with SIADH. Case presentation A 70-year-old Chinese woman with a history of diabetes mellitus and insulin therapy had severe hyponatremia and gastrointestinal symptoms. Through a series of examinations, common causes such as pulmonary carcinoma were excluded. An abdominal mass was detected by computed tomography. Although the peripheral lymph node biopsy showed the pathological result as Castleman’s disease, the pathology of the abdominal lymph node revealed diffuse large B-cell lymphoma. After chemotherapy, the hyponatremia was treated during a period of follow-up. Conclusion This patient presented with the rare clinical condition of inappropriate antidiuretic hormone secretion alongside Castleman’s disease and lymphoma. Asymptomatic hyponatremia may persist for some time suggesting that clinical physicians should pay attention to the mild cases of hyponatremia. We also hypothesized that Castleman’s disease is a condition of pre-lymphoma with both having the ability to cause SIADH. The possibility of lymphoma as well as Castleman’s disease triggering the development of SIADH should also be taken into consideration for conducting recurrent biopsies.


Background
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is caused by the excessive release of antidiuretic hormone (ADH, also known as vasopressin) from the posterior pituitary gland [1,2] and can cause hyponatremia in hospitalized patients with an incidence as high as 30% [3]. SIADH is generally seen in patients diagnosed with small-cell lung cancer (SCLC) which was first described by Schwartz et al. in two patients with lung cancer [4].
SIADH is not difficult to diagnose in clinic. It can be secondary to a variety of disorders, such as medications, malignancies, surgery, and HIV infection or be idiopathic [1,2]. While SCLC is the primary malignancy causing SIADH, lymphoma can also induce this condition [5,6]. In this report, the diagnosis of Castleman's disease was established before we suspected SIADH was caused by a malignancy. After extensive examinations, we made the final diagnosis of diffuse large B-cell lymphoma. Chemotherapy treatment was recommended for the patient and significantly ameliorated the SIADH symptoms.

Case presentation
In October 2011, a 70-year-old Han Chinese woman with Type 2 diabetes (T2D) was admitted to Department of Endocrinology at the Tianjin Medical University General Hospital for uncontrolled hyperglycemia. The patient had a history of T2D for 21 years and received continuous long-term insulin treatment with a dosage of about fifty units per day. On the seventh day after admission, the patient developed symptoms of nausea and vomiting accompanied by left leg radiating pain without diarrhea and fever. She did not present with headache, dizziness, disturbance of consciousness, melana or hematemesis. The medications used in the hospital are listed in Table 1. The patient had no recent history of using diuretic agents. Serum sodium levels decreased to 112 mmol/l and chloride levels to 81 mmol/l with an effective osmolality at 267 mOsm/kg.H 2 O (normal range: 280-310 mOsm/kg. H 2 O). Urinary sodium increased to 85 mmol/l and chloride to 86 mmol/l with an osmolality of 257 mOsm/kg. H 2 O indicating hypotonicity during normal dietary salt intake. She was clinically normovolemic with no signs of fluid retention. Her hepatic and renal functions were normal with a serum creatinine of 68 (normal range: 44-115) umol/L. Fractional sodium excretion was calculated as 1.56%. Thyroid and adrenal function were measured with ACTH = 59.8 pg/mL(normal range: 0-46), cortisol = 25.6 ug/dL(normal range: 5-25), 24-hour cortisol in urine = 64.4 ug(normal range: 30-110), FT3 = 3.04 pmol/L(normal range: 3.5-6.5), FT4 = 19.76 pmol/L (normal range: 11.5-23.5), TSH = 3.657 uIU/mL(normal range: 0.3-5.0) and rT3 = 1.76 nmol/l (normal range: 0.43-1.15). The magnetic resonance imaging (MRI) of her pituitary gland showed herniation of the suprasellar cistern. Based on the MRI result, our first diagnosis was hypopituitarism, which was treated with intravenous hydrocortisone at 50 mg/day. Both the serum sodium and serum chloride increased from 112 to 116 mmol/l and from 81 to 84 mmol/l, respectively, on the following day.
After further inquiry, the patient informed us of a past history of Mucosal-associated lymphoid tissue lymphoma (MALT) which had not received further treatment. We also discovered that she was last hospitalized on March 2011 for uncontrolled hyperglycemia without symptoms of nausea and vomiting. Nevertheless, hyponatremia had been noticed with serum sodium of 131 mmol/L and serum chloride of 95 mmol/l. Urinary investigation showed increased levels of sodium (90 mmol/l) and chloride (83 mmol/l) without corresponding osmolality data. Her renal function was normal with a serum creatinine of 63 umol/L. This information led us to believe that SIADH caused the patient's hyponatremia. Three days after restricting fluid intake to 1000 ml/day, the serum sodium rose to 128 mmol/L from 116 mmol/L. Ten days later, the patient's serum sodium levels increased to 142 mmol/l, and the symptoms of nausea and vomiting disappeared.
Since the patient had a past history of MALT, we performed a gastric endoscopy, which indicated the absence of lymphoma. Additionally, the serology result was negative for purified protein derivative (PPD), and the serum and urine protein electrophoresis were also negative for monoclonal gammopathy. Additional laboratory findings were listed in Table 2. A negative chest computed tomography (CT) scan excluded the possibility of SCLC as the cause of SIADH in this patient. However, we noticed that the patient had obvious pain in the left leg, abdominal distension, and skin itching on a clinical exam and further discovered that her abdomen circumference had increased significantly in the last six months. An abdominal CT scan showed that a mass measuring approximately 49 mm*70 mm*90 mm was located on front lumbar vertebra 1-4 and the surrounding abdominal aorta. A subsequent abdominal enhancement CT revealed that the mass might be lymphoma ( Figure 1). As the pathological result was critical for her diagnosis, we conducted a left inguinal lymph node puncture showing no abnormal lymphocytes. Consequently, a whole left inguinal (2 × 1 × 0.5 cm) lymph node was resected. The pathological morphology revealed that the lymph node structure was replaced with substantial amounts of lymphoid tissue and fibrosis. Thus, the diagnosis of Castleman's disease was established according to the pathological exam ( Figure 2A, B, C).
Although hyponatremia was corrected, her hemoglobulin levels decreased from 109 g/L to 96 g/L. With her consent, we conducted a biopsy of the enlarged abdominal lymph node by using a celioscope. The pathological exam disclosed diffuse large B-cell lymphoma with an anaplastic subtype ( Figure 3A, B).
After the diagnosis of lymphoma was established, the patient was transferred to the Department of Hematology for further treatment. For the etiology treatment of B-cell lymphoma, the chemotherapy of cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP) with rituximab (a monoclonal antibody against the protein CD20) was administered. The patient's serum sodium level stabilized without fluid restriction.

Discussion
In this case, the hyponatremia had existed for a long time and failed to gain proper attention until serious clinical manifestations developed. Her past history of MALT as well as the success of fluid restriction and failure of hydrocortisone infusion suggested the possibility of hyponatremia caused by SIADH. One limitation of our investigation was the failure to measure urine uric acid and urea levels. Fractional uric acid excretion (FE-UA) has been demonstrated as a useful criterion in the diagnosis of SIADH particularly when attempting to differentiate between SIADH and hypovolaemic hyponatremia [7]. The main therapeutic issue in SIADH is fluid excess, and hyponatremia is dilutional in essence. Fluid restriction is the primary treatment option for SIADH. The vasopressin V2 receptor antagonist is effective for assisting the SIADH treatment [8]. Urea administration could be used in patients with chronic SIADH but also in acute SIADH like in critically ill patients [9].
Once a diagnosis of SIADH is established, determining its cause is most important. Castleman's disease is characterized by non-cancerous growths that may develop in the lymph node tissue throughout the body [10]. Lesions often occur in the chest, abdomen, or neck, where the abnormal enlargement of lymph nodes could usually be found. Although SIADH is reported to be associated with Castleman's disease [11], the possibility of general lymphoma in this case could not be excluded. Several major points supported this conclusion including: (1) past history of MALT; (2) occurrence of itching (characteristic symptom of lymphoma); (3) CT scan findings suggested lymphoma; and (4) the manifestation of progressive anemia. Moreover, the patient had a long history of T2D treated with insulin. Recent studies suggest that insulin treatment may be associated with an higher risk of the developing certain types cancers including lymphoma [12].
Although Castleman's disease is inherently a nonneoplastic process, an association with concurrent or subsequent lymphoma has been well described [13]. The hyaline-vascular type of Castleman's disease which contains numerous lymphoid follicles should be differentiated from Hodgkin lymphoma and low-grade B-cell lymphomas [14]. Several B-cell lymphomas with prominent atrophic germinal centers and hyaline vascular penetration including follicular lymphoma, mantle cell lymphoma, and  nodal marginal zone lymphoma tend to be misdiagnosed as Castleman's disease due to the similar clinicopathologic features [15]. Furthermore, multicentric Castleman's disease could show similar FDG PET/CT appearance mimicking lymphoma, which reveals that Castleman's disease and lymphoma exhibit similar functions [16]. After consulting the literaure and examining the presentation of SIADH caused by both diseases, we hypothesized that Castleman's disease can develop into lymphoma, and a variety of pathological lymphomas may result in the  development of SIADH [6,17]. One possible mechanism is the effect of hypercytokinemia. Some cytokines, such as interleukin (IL)-2, IL-6, IL-1β, and tumor necrosis factor (TNF)-α, have been reported to stimulate parvicellular and magnocellular neurons to secrete more ADH thus causing SIADH [18,19]. In our case, three separate biopsies showed differing results suggesting that this procedure is so imperative for certain conditions that several biopsies may be needed for a final diagnosis.

Conclusion
This report describes a rare case, in which an older woman had both Castleman's disease and lymphoma coexisting with SIADH. We wish to highlight the following key points: First, lymphoma as well as Castleman's disease, though uncommon, is an important cause of SIADH, and mild hyponatemia should get proper attention by clinical endocrinologists. Second, repeated lymph node biopsy may be crucial for the etiological diagnosis of SIADH.

Consent
Written informed consent was obtained from the patient for publication of this case report and the accompanying images. A copy of the written consent is available upon request for review by the Journal Editor.