PMC5548679_01
The pathology of the NK-cell neoplasm with lymphoma-associated hemophagocytic syndrome from a resected lymph node. There are an increased number of atypical lymphoid cells with hemophagocytosis (arrow) on Hematoxylin and Eosin (HE) staining (a, x40 of objective lens magnification). Immunohistochemical assay showed the immunophenotypes of the neoplasm: CD3+(b, x40), CD4+, CD8-, CD20-, CD30+, and CD56+. The Ki-67 index was >90% (c, x40). The neoplastic cells contained granzyme B (d, x40). Immunohistochemical analysis of the stored biopsy samples also revealed expression of TNF-alpha+ (e, x40) and TGF-beta1+ (f, x40), using TNFalpha (52B83) antibody (1:100 dilution; sc-52746; Santa Cruz Biotechnology, Dallas, USA), and TGFbeta1 (V) antibody (1:200 dilution; sc-146; Santa Cruz Biotechnology), respectively (13, 14). Hybrid fluorescence imaging of immunostaining and Epstein-Barr virus-encoded small RNA (EBER)in situ hybridization precisely confirmed the immunophenotypes: green indicates EBER; red indicates CD56 (g, x60) and TNF-alpha (1: 100 dilution; sc-52746; h, x60) in each image; blue indicates DAPI-stained DNA. The component fluorescence images were taken with a fluorescence microscope BZ-8100 (Keyence, Osaka, Japan) by the second author.
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Analysis of a subcutaneous brachial lymph node biopsy specimen revealed an NK-cell neoplasm with lymphoma-associated hemophagocytic syndrome (Fig. 1). The neoplasm expressed tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1 (Fig. 1).
Clinical course and laboratory findings in this case. The results of the lymph node biopsy (*) after methylprednisolone pulse therapy supported the use of chemotherapy for steroid-resistant high fever. The CHOP-like chemotherapies (down arrows) on hospital days 17 and 37 (vertical dashed lines) induced persistent polyuria and natriuresis after transient lactate dehydrogenase (LDH) surges in conjunction with the elevation of serum ferritin levels, with administration of corticosteroids with physiological mineralocorticoid potency. Negative fluid balance, negative sodium (Na) balance and body weight loss indicated volume depletion and salt wasting along with the polyuria. The low serum uric acid (UA) levels persisted even after recovery from the hyponatremia. Potassium (K) levels were managed with intravenous supplementation. The decreasing of granzyme B level on hospital days 28 reflected tumor burden; the simultaneous (as shown by vertical dotted lines) increase in CD365 levels indicated renal tubular damage. Fractional excretion of sodium (FENa) exceeded adequate FENa during polyuria, except during fever after the transient hypovolemic shock ( ). This excess also suggested tubular dysfunction rather than tubular adaptation (16). Urine volume and urinary sodium excretion were independent of creatinine clearance (Ccr) levels, apart from sole spike of Ccr on hospital day 22. The administered steroid doses are shown to be equivalent to glucocorticoid and mineralocorticoid potencies of prednisolone by the following conversion coefficients: hydrocortisone, x0.25 in glucocorticoid potency (dashed line), x1.25 in mineralocorticoid potency (solid line); prednisolone, x1.0, x1.0; methylprednisolone, x1.25, x0.625; betamethasone, x6.25, x0.0 (17-19). Fluid intake includes oral fluids (negligible since hospital day 34), infused solutions, and transfusions. Sodium intake includes dietary salt (negligible since hospital day 24) and infused sodium. These were calculated from his dietary intake and infused dose, respectively, on the observation chart recorded during nursing. The urinary sodium excretion [mEq/day] was estimated by urine volume [mL/day] x urinary sodium concentration [mEq/mL] (sampled from pooled urine in a collection bag, but not 24-hour pooled urine). The Ccr [mL/min per body surface area 1.73 m2] was estimated by the following formula: urine creatinine concentration [mg/dL] (same samples as for urinary sodium excretion) x urine volume [mL/min] x1.73/(serum creatinine concentration [mg/dL] x a constant value of patient's body surface area [m2]). The FENa [%] was calculated by the following formula: 100x urinary sodium concentration [mEq/L] x serum creatinine concentration [mg/dL]/(serum sodium concentration [mEq/L] x urinary creatinine concentration [mg/dL]). The adequate FENa [%] was calculated by the following formula (16): sodium intake [mEq/day] / (0.0144x Ccr [mL/min] x serum sodium concentration [mEq/L]). The dagger ( ) represents the patient's death. The black triangle ( ) represents amikacin (AMK) and the open inverted triangle ( ) represents vancomycin (VCM). This figure was drawn using the ggplot2 software package, version 2.0.0 in R, version 3.2.2.
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Despite only one injection of furosemide (t1/2 <0.5 hour) on the day chemotherapy was initiated, polyuria with natriuresis continued for longer than 1 week after that (Fig. 2). A negative fluid balance (urine volume exceeding fluid intake) and negative sodium balance (urinary sodium excretion exceeding sodium intake) indicated volume depletion and salt wasting (Fig. 2), with a detectable vasopressin level in a hypoosmotic state (0.9 pg/mL in estimated 275 mOsm/L on hospital day 20). CSWS rather than SIADH. Creatinine clearance levels were not elevated along with the polyuria until a sole peak on hospital day 22 (Fig. 2). The patient lost weight (8.5 kg over 13 days) despite total parenteral nutrition (Fig. 2). A virus cellular receptor 1, HAVCR1; recently defined as CD365), which has been shown to correlate with renal tubular damage, was continuously elevated in the patient's samples (>0.078 ng/mL, the upper limit of normal reported in healthy controls), quantified using human TIM-1 (HAVCR1) ELISA kit (EHHAVCR1, ThermoFisher Scientific, Waltham, USA). Therefore, the elevated CD365 levels, which were independent of the granzyme B levels, demonstrated renal tubular damage, even though CD365 has been reported to be expressed not only on proximal tubular epithelial cells, but also on NK-cells and lymphoma cells (Fig. 2). An analysis of stored samples was conducted based on informed consent signed while the patient was alive, in accordance with the Helsinki Declaration, and with the approval of the hospital ethics committee.