Hemophagocytic syndrome with histiocytic glomerulopathy associated with ovarian serous carcinoma

Abstract

Histiocytic glomerulopathy, an entity characterized by glomerular infiltration by foamy histiocytes with endothelial injury, has recently been reported as a manifestation of hemophagocytic syndrome. We report a case of histiocytic glomerulopathy in a woman receiving chemotherapy for ovarian serous carcinoma with proteinuria in whom hemophagocytic syndrome was not clinically suspected.

Hemophagocytic syndrome (HPS), which includes hemophagocytic lymphohistiocytosis and macrophage activation syndrome, is caused by inappropriate activation of the immune system with hypersecretion of cytokines and widespread activation and proliferation of macrophages. While primary HPS results from mutations related to cytotoxic pathways, secondary HPS is associated with a number of conditions including infection, autoimmune disease, and malignancy. Many patients develop acute kidney injury, although glomerular involvement is rare. Recently, infiltration of glomeruli by foamy histiocytes with evidence of glomerular endothelial injury, termed histiocytic glomerulopathy, has been reported in patients with HPS,^1,2 representing an additional histopathologic manifestation of this disease.

CASE PRESENTATION

A 45-year-old woman receiving carboplatin/paclitaxel for stage IV ovarian serous carcinoma was admitted with severe hypertension (blood pressure 200/120 mm Hg). The patient reportedly had a headache. Her heart rate, respiratory rate, and temperature were normal, and physical examination was unremarkable. Initial laboratory studies revealed leukocytosis with thrombocytopenia and mild anemia (Table 1). Her serum creatinine was 0.98 mg/dL, and renal ultrasound was unremarkable. Her blood pressure subsequently improved, and she was discharged on metoprolol, losartan, and nifedipine. Follow-up over the next few months showed an increased serum creatinine with persistent nephrotic-range proteinuria (urine protein-to-creatinine ratio 4.2–10.5 g/g). Renal biopsy showed numerous CD68-positive histiocytes within glomerular capillary loops with segmental contour duplication of glomerular basement membranes and endothelial swelling (Figure 1). There were no fibrin thrombi, and arterioles and arteries showed no evidence of microangiopathic injury. Immunofluorescence studies were negative. By electron microscopy, glomerular capillary lumens were occluded by infiltrating histiocytes and swollen endothelial cells. There was evidence of endothelial injury with significant (60%–70%) foot process effacement (Figure 2). The final diagnosis was reported to be consistent with histiocytic glomerulopathy associated with glomerular features of thrombotic microangiopathy. Additional laboratory studies following the biopsy showed elevated C-reactive protein, lactate dehydrogenase, and ferritin (Table 1). The patient continued to receive chemotherapy for her ovarian carcinoma and was maintained on losartan. Renal function subsequently improved, and further studies were deferred with close clinical follow-up.

Table 1.

Serum laboratory parameters before and after renal biopsy

Laboratory test	Reference range	Initial presentation	Before biopsy	After biopsy
White blood cells (K/mm3)	3.8–10.8	13	6.6	8.4
Red blood cells (M/mm3)	3.80–5.10	4.5	3.97	3.34
Hemoglobin (g/dL)	11.7–15.5	10.4	10	7.9
Hematocrit (%)	35%–45%	32.4	30	24.5
Platelets (K/mm3)	140–400	90	198	285
Absolute neutrophils (K/mm3)	1.5–7.8	10	5.4	6.9
Blood urea nitrogen (mg/dL)	7–25	16	17	27
Creatinine (mg/dL)	0.5–1.1	0.98	1.9	1.14
Albumin (g/dL)	3.6–5.1		3.1	3.0
Protein/creatinine ratio	0.021–0.161		10.5	2.769
Myeloperoxidase Ab			<1.0
Proteinase-3 Ab			<1.0
ESR (mm/h)	0–20		82
Antinuclear antibody			Negative
C3 (mg/dL)	90–180		223
C4 (mg/dL)	16–47		59
Anti-PLA2R antibody			Negative
Lactate dehydrogenase (U/L)	100–200			280
Triglycerides (mg/dL)	<150			112
Fibrinogen activity (mg/dL)	175–425			708
High-sensitivity CRP (mg/L)	<10			>10
Ferritin (ng/mL)	16–232			2230

CRP indicates C-reactive protein; ESR, erythrocyte sedimentation rate.

Figure 1.

Light microscopy. (a) Hematoxylin and eosin staining showing segmental occlusion of glomerular capillary loops with endocapillary foam cells and endothelial cell swelling. (b, c) Jones methenamine silver and periodic acid–Schiff stains showing foam cells with contour duplication of glomerular basement membranes. (d) Immunohistochemical stain for CD68 showing histiocytes infiltrating glomeruli (×400).

Figure 2.

Electron microscopy. (a) Capillary lumina occluded by infiltrating foam cells. (b) Glomerular basement membranes show features of endothelial injury with endothelial cell swelling and loss of fenestrations, as well as segmental widening of subendothelial spaces by electron lucent material (original magnification ×2900).

DISCUSSION

HPS occurs when a defect in the perforin pathway leads to overactivation of natural killer and cytotoxic T cells, resulting in proliferation of antigen-presenting cells and hypersecretion of cytokines.^3,4 The clinical presentation of HPS is variable, though patients most commonly present with fever, lymphadenopathy, and hepatosplenomegaly. Laboratory studies typically show cytopenias, abnormal liver function tests, elevated acute-phase reactants, and acute kidney injury.^5–7 Due to the relatively nonspecific presentation, diagnostic guidelines were first proposed in 1991 by the Histiocyte Society and revised in 2004⁸ (Table 2). Although now widely used in the diagnosis of HPS, these guidelines were based predominantly on pediatric cases and were not validated in adult patients with HPS.

Table 2.

Diagnostic criteria for hemophagocytic lymphohistiocytosis, 2004^*

Option	Criteria
1	Molecular diagnosis of mutation known to cause hemophagocytic lymphohistiocytosis
2	Meets at least five of the following eight criteria: Fever Splenomegaly Cytopenias of at least two lineages in peripheral blood: Hemoglobin <90 g/L Platelets <100 × 109/L Neutrophils <1.0 × 109/L Hypertriglyceridemia and/or hypofibrinogenemia Fasting triglycerides ≥3.0 mmol/L Fibrinogen ≤1.5 g/L Hemophagocytosis in bone marrow, spleen, or lymph nodes Low or absent natural killer cell activity Ferritin >500 ng/mL Soluble CD25 (IL-2 receptor) >2400 U/mL

^*From Henter et al, 2007.⁸

HPS in children is frequently hereditary, while in adults it is typically secondary to an underlying stimulus.^3,6,9,10 Viral infection is the most common etiology and often occurs in immunosuppressed patients. Patients with hematologic malignancies are particularly at risk for the development of HPS,^5,10 although it may also occur in patients with solid organ malignancies. To the best of our knowledge, no cases of HPS have been reported in association with ovarian serous carcinoma. While no viral studies were performed for our patient, in the setting of immunosuppression and a relatively mild clinical presentation, viral infection remains the most probable inciting etiology.

Glomerular involvement in HPS is relatively rare, but collapsing glomerulopathy, minimal change disease, and thrombotic microangiopathy (TMA) have all been reported.^11–14 More recently, marked glomerular infiltration by foamy histiocytes with evidence of glomerular endothelial injury, termed histiocytic glomerulopathy, has been described. Histiocytic glomerulopathy has only been reported with HPS, although glomerular foam cells may be seen to a lesser degree in a number of other conditions.¹⁵ There is some morphologic overlap with TMA; however, histiocytic glomerulopathy does not show fibrin thrombi or mesangiolysis and does not involve arterioles or arteries. Of note, our patient was receiving carboplatin/paclitaxel, which has rarely been associated with TMA.¹⁶ While there was evidence of glomerular endothelial injury, there were no fibrin thrombi or vascular changes, and the distribution of foam cells was greater than that seen with TMA. Furthermore, the patient showed clinical improvement with continuation of her chemotherapeutic regimen, arguing against a chemotherapy-induced TMA.

In conclusion, we present a case of histiocytic glomerulopathy in a patient with ovarian serous carcinoma and renal dysfunction in which HPS was not clinically suspected. Although our patient did not meet strict diagnostic criteria, HPS is a diagnostically challenging and likely underrecognized entity due to its heterogeneous presentation. Increased recognition of the various morphologic manifestations of HPS is critical in order to initiate prompt evaluation and treatment of this potentially fatal disease.