Annals of Diagnostic Pathology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Annals of Diagnostic Pathology
Original Contribution
Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma☆,☆☆ Samih H. Nasr, MD a,⁎, Tait D. Shanafelt, MD b, Curtis A. Hanson, MD c, Mary E. Fidler, MD a, Lynn D. Cornell, MD a, Sanjeev Sethi, MD, PhD a, Kari G. Chaffee, MS d, Joseph Morris, MD e, Nelson Leung, MD b,f a
Division of Anatomic Pathology, Mayo Clinic, Rochester, MN Division of Hematology, Mayo Clinic, Rochester, MN Division of Hematopathology, Mayo Clinic, Rochester, MN d Department of Health Sciences Research, Mayo Clinic, Rochester, MN e Great River Nephrology, West Burlington, IA f Division of Nephrology, Mayo Clinic, Rochester, MN b c
a r t i c l e
i n f o
Available online xxxx Keywords: Granulomatous interstitial nephritis interstitial nephritis chronic lymphocytic leukemia small lymphocytic lymphoma kidney biopsy lymphoma
a b s t r a c t Granulomatous interstitial nephritis (GIN) is an uncommon pathologic lesion encountered in 0.5% to 5.9% of renal biopsies. Drugs, sarcoidosis, and infections are responsible for most cases of GIN. Malignancy is not an established cause of GIN. Here, we report a series of 5 patients with GIN secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients were mostly elderly white males with an established history of CLL/SLL who presented with severe renal impairment (median peak serum creatinine, 7.3 mg/dL), leukocyturia, and mild proteinuria. One had nephromegaly. In 2 patients, the development and relapse of renal insufficiency closely paralleled the level of lymphocytosis. Kidney biopsy in all patients showed GIN concomitant with CLL/ SLL leukemic interstitial infiltration. Granulomas were nonnecrotizing and epithelioid and were associated with giant cells. One biopsy showed granulomatous arteritis. One patient had a granulomatous reaction in lymph nodes and skin. Steroids with/without CLL/SLL–directed chemotherapy led to partial improvement of kidney function in all patients except 1 who had advanced cortical scarring on biopsy. In conclusion, we report an association between CLL/SLL and GIN. Patients typically present with severe renal failure due to both GIN and leukemic interstitial infiltration, which tends to respond to steroids with/without CLL/SLL–directed chemotherapy. The pathogenesis of GIN in this clinical setting is unknown but may represent a local hypersensitivity reaction to the CLL/SLL tumor cells. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Granulomatous interstitial nephritis (GIN) is a distinct morphological variant of interstitial nephritis defined histologically by the presence of interstitial inflammation and 1 or more interstitial granulomas [1,2]. Granulomas are composed of activated macrophages, also called “epithelioid cells,” with or without giant cells. The renal biopsy incidence of GIN ranges from 0.5% to 5.9% [1-5]. In our experience, GIN accounts for 26% of cases of acute interstitial nephritis [6]. Most cases of GIN in the developed countries are due to drugs or sarcoidosis [1,2], whereas infections, particularly by mycobacteria or fungi, are the most common etiology in the developing countries [4]. Antibiotics and nonsteroidal anti-inflammatory drugs are the most frequent classes of drugs to
☆ The authors of this manuscript have no conflicts of interest to disclose. ☆☆ There was no support/funding for this study. ⁎ Corresponding author at: Division of Anatomic Pathology, Mayo Clinic, Hilton 10-20, 200 First St SW, Rochester, MN 55905. E-mail address: [email protected] (S.H. Nasr).
cause GIN [1,2], although there have been many case reports of GIN linked to other therapeutic agents, including analgesics, diuretics, anticoagulants, and others (reviewed in Javaud et al [2]). Chronic lymphocytic leukemia (CLL) is the most common leukemia in developed counties and is characterized by progressive accumulation of functionally incompetent B lymphocytes. Chronic lymphocytic leukemia/small lymphocytic lymphoma (SLL) cells have a characteristic immunophenotype, which is a key for diagnosis: they express B-cell– associated antigens CD19, CD20 (weak), and CD23; CD5, a T-cell– associated antigen; and low-intensity surface immunoglobulins (usually immunoglobulin M) with only 1 immunoglobulin light chain (κ or λ). When CLL cells involve lymph nodes without substantial peripheral blood involvement (B-cell count b5 × 109/L), the disease is referred to as the “SLL” variant [7]. Most patients with CLL/SLL are asymptomatic at diagnosis, but some present with painless lymph node swelling, weight loss, fevers, night sweats, and/or fatigue. Patients with CLL/SLL have dysfunction of their immune system leading to acquired immunodeficiency and development of autoimmune disorders. Important complications of CLL/SLL include infections, anemia, thrombocytopenia, and increased risk of second cancer.
http://dx.doi.org/10.1016/j.anndiagpath.2015.03.003 1092-9134/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Nasr SH, et al, Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.03.003
Rituximab, HD Hypertension, diabetes, BPH Yes
NA
63/M/W 5
IV
4
2 (4 mo prior)
10.2
7
2
Yes (Foley catheter) No 2.2 5.7 6.1 2.4 (2 mo prior) 18 79/M/W 4
I
78/M/W 3
Abbreviations: BPH, benign prostatic hyperplasia; Bx, renal biopsy; CA, carcinoma; ESRD, end-stage kidney disease; F, female; GERD, gastrointestinal reflux disease; HD, hemodialysis; M, male; NA, not available; SCr, serum creatinine; W, white.
Alive (43 mo post-Bx)
Died (49 mo post-Bx)
Partial recovery (S. Cr 2.1) ESRD (never recovered) Steroids, rituximab, HD
Died of cellulitis (2 mo post-Bx) Partial recovery (S. Cr 3.2) Yes No 0.2 6.9 7.3 2.4 (4 mo prior) 8
74/F/W 2
III
4
NA
18
14.9
0.9
No
Yes
Hypertension, chronic urinary tract infection Hypertension, atrial fibrillation BPH
Steroids
Died of breast CA (31 mo post-Bx)
Partial recovery (S. Cr 2.3) Partial recovery (S. Cr 2.1) Steroids, rituximab, cyclophosphamide Steroids, cyclophosphamide, HD GERD No Yes 1 57/M/W 1
0
Baseline SCr (mg/dL) Time from diagnosis of CLL/SLL to GIN in yrs CLL/SLL Rai stage at GIN diagnosis Age/sex/race Case no.
Table 1 Clinical data.
2.1.3. Case 3 A 78-year-old man was admitted for acute on chronic renal failure and severe pruritus in September 2002. He was diagnosed with CLL Rai stage III in 1994 and received intravenous immunoglobulin to treat hypogammaglobulinemia. In May 2002, he was noted to have a serum creatinine of 2.4 mg/dL and a 24-hour urine protein of 242 mg. Afterward, the patient became fatigued and developed rash and severe
Peak SCr SCr at Bx (mg/dL)
2.1.2. Case 2 A 74-year-old woman had a history of CLL Rai stage 0 diagnosed in 1998. She presented in August 2002 with acute renal failure. Two weeks before admission, she began to experience fatigue, nausea, diarrhea, and vomiting. On admission, she had a hemoglobin level of 9.5 g/dL, WBC count of 100.6 × 109/L with 91% lymphocytes, and platelet count of 203 × 109/L (Table 1). Testing for cytoplasmic anti-neutrophil cytoplasmic antibodies (C-ANCA) and perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) was negative. Urinalysis showed less than 1 RBC/ HPF, greater than 100 WBCs/HPF, and occasional hyaline casts. Her admission medications were nitrofurantoin (intermittently for 2 years), spironolactone/hydrochlorothiazide (for many years), and alendronate sodium (for 2 weeks). A renal biopsy was obtained. She was treated with levofloxacin until urine culture was confirmed to be negative. She was also initially treated with high-dose corticosteroid. Despite this, her renal failure progressed, and dialysis was initiated. One dose of intravenous cyclophosphamide was administered, and the WBC count dropped to 26.7 × 10 9/L. Patient became dialysis independent after 2 months. Her CLL/SLL remained stable, but she was diagnosed with breast cancer in 2005 and elected not to undergo any treatment. Patient died in March 2005 of complications of breast cancer.
5.9
Proteinuria Hematuria (g/day)
Leukocyturia Other medical conditions
2.1.1. Case 1 During a routine follow-up visit in December 2007, a 57-year-old man was noted to have renal insufficiency (Table 1). He had a known history of CLL Rai stage I, ZAP70 and CD38 positive, diagnosed in December 2005, which was followed without treatment. His admission medications were cimetidine, ranitidine, and Tums. He took 2 doses of Aleve 2 days before admission but none prior. On examination, there were nontender 2- to 3-cm nodes along anterior cervical chain, bilateral axillary, and inguinal adenopathy. No organomegaly was identified. Laboratory data showed a hemoglobin level of 15.2 g/dL, white blood cell (WBC) count of 29.0 × 10 9/L with 90% lymphocytes, platelet count of 149 × 10 9/L, serum C3 67 and serum C4 23, a total urine protein of 1 g/24 hours, and negative serum and urine protein electrophoresis (Table 1). Urinalysis showed 4 to 10 nondysmorphic red blood cells (RBCs)/high-power field (HPF) without WBCs. A renal biopsy was obtained. Over the next 5 years, patient was treated with multiple courses of chemotherapy, which lead to an improvement in kidney function, but experienced multiple relapses. As shown in Fig. 1, his renal relapses closely paralleled the level of lymphocytosis.
6.7
Treatment
2.1. Clinical histories
1.3 (9 mo prior)
2. Results
2
Renal outcome
Patient outcome
Although leukemic infiltration of the kidney is seen on autopsy in most patients with CLL/SLL [8,9], clinical kidney dysfunction is uncommon [10]. Several glomerular lesions pathogenically related to CLL/SLL have been described, including membranoproliferative glomerulonephritis [11-13], minimal change disease [11], immunotactoid glomerulopathy [10,14], cryoglobulinemic glomerulonephritis [13,15], proliferative glomerulonephritis with monoclonal immunoglobulin G deposits [16], membranous glomerulopathy [13,17], and amyloidosis [18]. Expanding the spectrum of renal lesions associated with CLL/SLL, we report the first series of GIN secondary to CLL/SLL. The clinicopathologic features, outcomes, and possible pathogenetic mechanisms of this underrecognized complication of CLL/SLL are discussed.
Alive (81 mo post-Bx)
S.H. Nasr et al. / Annals of Diagnostic Pathology xxx (2015) xxx–xxx
I
2
Please cite this article as: Nasr SH, et al, Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.03.003
S.H. Nasr et al. / Annals of Diagnostic Pathology xxx (2015) xxx–xxx
3
Fig. 1. Graphical display of patient 1 WBC and serum creatinine (Scr) values. The WBC from December 13, 2007, of 217.7 × 109/L was omitted due to the scale issue. Patient received rituximab, cyclophosphamide, prednisone (RCP) from February 2008 to July 2008 and rituximab, cyclophosphamide, vincristine, prednisone (R-CVP) from May 2010 to September 2010. In August 2011, 2 cycles of rituximab and methylprednisone (R-Mp) were given. Two cycles of alemtuzumab and rituximab (R-Alem) were administered in August 2012. Patient then received ofatumumab (Ofat) from January 2013 to September 2013 for bulky lymphadenopathy.
pruritus with lesions involving his lower extremities and back. Biopsy of the skin lesions revealed granulomas. In September 2002, the patient presented with fever, chills, and left axillary pain. Laboratory data showed a hemoglobin level of 10 g/dL, WBC count of 20.6 × 10 3/mm with 83% lymphocytes, platelet count of 169 × 10 3/mm, negative serum protein electrophoresis, and negative testing for ANCA (Table 1). Angiotensin-converting enzymes were 30 U/L (normal, 7-46). An infectious disease workup and fungal serologies were negative. His admitting medications were diltiazem, digoxin, sennosides A and B, erythropoietin, and intravenous immunoglobulin. A lymph node biopsy was obtained, which showed CLL/SLL and noncaseating granulomatous inflammation. Fungal and acid-fast stains were negative. A renal biopsy was performed. Patient was treated with prednisone 1 mg/kg per day. Serum creatinine improved to 3.2 mg/dL, and he was discharged. Patient died 2 months later of complications of cellulitis and CLL/SLL.
2.1.4. Case 4 A 79-year-old man with a known history of CLL Rai stage I diagnosed in 1988 presented in April 2006 with acute renal failure. Review of systems and physical examination were remarkable for weight loss, anorexia, generalized weakness, and lethargy. There was no peripheral edema or skin rash. Laboratory data showed a 24-hour urine protein of 0.2 g, hemoglobin level of 8.8 g/dL, WBC count of 18.5 × 10 3/mm, and platelet count of 127 × 10 3/mm (Table 1). Bone marrow flow cytometry showed a population of CD19-positive B-cells with a monotypic staining pattern for λ surface immunoglobulin light chain and coexpressed CD20 (dim), CD22, CD5, CD23, and CD38, consistent with B-cell CLL/SLL. Urinalysis revealed leukocyturia, and urine culture revealed bacterial urinary tract infection. Renal scan showed mild hydronephrosis with minimal obstruction. On abdominal computed tomography, there was extensive abdominal and pelvic lymphadenopathy without organomegaly. Medications at the time of admission were pantoprazole and tamsulosin hydrochloride. Kidney function did not improve on rehydration, antibiotics, and stenting; therefore, a kidney biopsy was performed, which showed both GIN and CLL/SLL infiltration.
Granulomatous interstitial nephritis was treated with hemodialysis, steroids, and rituximab. Four months later, he came off dialysis with a serum creatinine declining to 2.1 mg/dL and WBC count declining to 9.1 × 103/mm. In 2009, he developed acute on chronic kidney injury and increasing WBC count, which responded to prednisone. In 2010, he was admitted with pneumonia and worsening serum creatinine to 3.9 mg/dL. He refused further therapy, was transferred to hospice care, and died. 2.1.5. Case 5 A 63-year-old man was admitted in April 2006 for severe acute kidney injury. He was diagnosed with stage IV low-grade non-Hodgkin lymphoma at an outside institution in 2004. He received chemotherapy (data not available) initially at diagnosis and 2 years later for disease recurrence and had been on maintenance rituximab every 3 months. Physical examination showed submandibular, cervical, and supraclavicular adenopathy. There was no organomegaly, edema, or skin rash. Abdominal ultrasound showed bilateral kidney enlargement and retroperitoneal and periaortic lymphadenopathy. Laboratory investigation revealed a random urine protein/creatinine ratio of 2 g, hemoglobin level of 8.7 g/dL, WBC count of 7.6 × 10 3/mm, platelet count of 127 × 10 9/L, negative ANCA, hepatitis B surface antigen, and hepatitis C antibody, and normal C3 and C4 complement levels (Table 1). Urinalysis revealed 100 mg/dL of protein, trace blood, 3 RBCs/HPF, and 12 WBCs/HPF with many WBC clumps. Medications at the time of admission were lisinopril (for many years, which was discontinued without improvement in kidney function), tamsulosin hydrochloride, amlodipine, and Humulin. Hemodialysis was started, and a kidney biopsy was performed. Over the next 5 years of follow-up, he continued on his maintenance rituximab. He never had a complete response to chemotherapy, but there was no evidence of significant progression of his lymphoma. He remained dialysis dependent. 2.2. Renal biopsy findings All five cases showed GIN and leukemic interstitial infiltration (Table 2). GIN interstitial inflammation was composed predominantly of lymphocytes and monocytes and was diffuse in 4 cases and patchy
Please cite this article as: Nasr SH, et al, Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.03.003
4
S.H. Nasr et al. / Annals of Diagnostic Pathology xxx (2015) xxx–xxx
Table 2 Pathologic findings. Case no. No. of % global Degree of Tubulitis Degree of glomeruli glomerulosclerosis reactive tubular atrophy interstitial and interstitial inflammation fibrosis
Acute Degree of CLL/ tubular SLL interstitial injury involvement
Morphology of granulomas
Arteriosclerosis Concurrent glomerular disease
1
6
17
Diffuse
Yes
Mild
Yes
Focal (20%)
Mild
No
2
4
0
Diffuse
Yes
Mild
Yes
Focal (30%)
Mild
No
3
11
0
Patchy
Yes
Moderate
Yes
Focal (10%)
Moderate
Focal segmental glomerulosclerosis
4
16
38
Diffuse
Yes
Moderate
No
Focal (20%)
Mild
No
5
11
27
Diffuse
Yes
Severe
No
Diffuse (80%)
Nonnecrotizing, small, ill defined, with giant cells Nonnecrotizing, large, well defined, with giant cells Nonnecrotizing, large, well defined, also involving interlobular arteries, with giant cells Nonnecrotizing, small to large, ill defined, with giant cells Nonnecrotizing, large, well defined, with giant cells
Mild
No
in 1 (Figs. 2 and 4). The lymphocytes were mostly reactive CD3 and CD5-positive T-lymphocytes with only rare CD20-positive Blymphocytes (Figs. 2 and 3). Interstitial eosinophils were increased in only 1 case. T-cell lymphocytic tubulitis was present in all cases (Figs. 3 and 4). Scattered nonnecrotizing epithelioid granulomas with multinucleated giant cells were seen in all cases (Figs. 2, 3, 4, and 6). In 4 cases, granulomas were large and well circumscribed (sarcoid like) (Fig. 3), whereas in the remaining 1 case, they ranged from small to large and were ill defined (Fig. 4). The granulomas lacked staining for CD20 (Fig. 3) or CD23. Three cases showed focal acute tubular injury. The degree of tubular atrophy and interstitial fibrosis ranged from mild in 2 cases, to moderate in 2, to severe in 1. Granulomatous arteritis was noted in 1 case (Fig. 5). Grocott's methenamine silver stain for fungi and Ziehl-Neelsen stain for mycobacteria were negative in all cases. The morphology and immunoperoxidase stains on the kidney biopsy in all 5 cases were consistent with interstitial involvement by CLL/SLL (Figs. 2, 4, and 6), which affected approximately 10% to 30% of the cortex in 4 cases and 80% of the cortex in the remaining case. Chronic
lymphocytic leukemia/SLL cells were small, round, relatively monotonous (Fig. 6C), and tended to form dense rounded aggregates in the cortex and/or medulla (Figs. 2, 4, and 6). Chronic lymphocytic leukemia/SLL cells stained positive for CD20 and CD23; negative for CD3; and, with the exception of case 4 (in which CLL/SLL cells were positive for CD5 on bone marrow and peripheral blood flow cytometry), positive for CD5 (Figs. 2 and 3). No glomerular or tubulointerstitial immune complex type deposits were detected by immunofluorescence (performed on all cases) or electron microscopy (performed in 4 cases). Case 3 showed concurrent secondary focal segmental glomerulosclerosis, which was likely due to hypertensive arterionephrosclerosis. 3. Discussion In this study, we report a series of 5 patients who developed GIN that we believe is secondary to CLL/SLL. During the study period, 66 renal biopsies accessioned in our laboratory had CLL/SLL interstitial infiltration, indicating a 7% GIN incidence in biopsies with CLL/SLL infiltration. In line
Fig. 2. Renal biopsy findings from case 1. Low-power view shows diffuse interstitial infiltration by inflammatory cells. A large epithelioid granuloma is present on the bottom (arrow) (hematoxylin and eosin, ×40). Lymphocytes diffusely infiltrating the interstitium were mostly reactive CD3-positive T-cells (×100). The CD20-positive CLL/SLL B-cells form dense aggregates in the cortex and perirenal fat (×100).
Please cite this article as: Nasr SH, et al, Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.03.003
S.H. Nasr et al. / Annals of Diagnostic Pathology xxx (2015) xxx–xxx
5
Fig. 3. Renal biopsy findings from case 5. A high-power field depicts a large, well-circumscribed noncaseating epithelioid granuloma (hematoxylin and eosin, ×200). The top right image shows diffuse interstitial infiltration and tubulitis by reactive CD3-positive T-cells. T-cells are also seen within a large well-circumscribed interstitial granuloma (arrow) (×100). The lower right image of the same field shows multifocal interstitial infiltration by CD20-positive leukemic B-cells, which spare the granuloma and tubules (×100).
with CLL/SLL patients' demographics in general [19], our cohort consisted mostly of elderly white males. All patients had an established history of CLL/SLL before presentation with renal insufficiency with a median time from CLL/SLL diagnosis to GIN diagnosis of 4 years (range, 2-18 years). Three patients (60%) had CLL/SLL Rai stage 0 or I at renal presentation, suggesting that GIN may develop even with early stages of disease. All patients presented with severe renal impairment (median peak serum creatinine, 7.3 mg/dL), and 1 had nephromegaly, both of which are likely due to concomitant GIN and CLL/SLL interstitial infiltration. In 2 patients (1 and 4), the development and relapse of renal insufficiency closely paralleled the level of lymphocytosis, which strongly suggests CLL/SLL as the cause of GIN. The association between CLL/SLL and GIN that we show in this small cohort was not recognized when we initially published the case report on patient 2 and were advised to attribute the GIN to a medication [20]. None of these patients had other conditions known to be associated with GIN, such as sarcoidosis, tubulointerstitial nephritis and uveitis syndrome, granulomatosis with polyangiitis, and fungal or mycobacterial infection.
Fig. 4. Renal biopsy findings from case 4. The image shows reactive diffuse interstitial inflammation on the right with associated prominent lymphocytic tubulitis on the top. A large epithelioid granuloma is seen on the bottom (arrow), and a dense aggregate of small monotonous leukemia cells is present on the left (black star) (periodic acidSchiff, ×100).
Patient 2 was receiving nitrofurantoin, and patient 5 was on lisinopril medications that were described in rare case reports to cause GIN [21,22]. However, the 2 patients had been on these medications for many years without side effects; therefore, it is unlikely that they were responsible for GIN. Two additional patients with CLL/SLL causing GIN have been reported previously [23,24]. Chronic lymphocytic leukemia/SLL was diagnosed concomitantly with GIN in 1 and 1.5 years prior in the other patient. Both patients presented with severe renal impairment requiring renal replacement therapy. Kidney biopsy in all 5 patients reported here and the 2 patients reported previously showed leukemic interstitial infiltration concomitant with GIN [23,24]. Granulomatous interstitial nephritis is likely a bigger contributor to renal failure than CLL/SLL infiltration because it was generally more extensive and was accompanied by tubulitis. It is crucial not to overlook reactive interstitial nephritis in CLL/SLL patients, as kidney function tends to improve on steroids with/without CLL/SLL–directed chemotherapy. Kidney function improvement on therapy occurred in
Fig. 5. Renal biopsy findings from case 3. This interlobular artery shows medial and adventitial infiltration by epithelioid histiocytes and rupture of its elastica externa, consistent with granulomatous arteritis. No fibrinoid necrosis is seen. An interstitial giant cell is seen below (methenamine silver stain, ×100).
Please cite this article as: Nasr SH, et al, Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.03.003
6
S.H. Nasr et al. / Annals of Diagnostic Pathology xxx (2015) xxx–xxx
Fig. 6. Renal biopsy findings from case 2. Low-power field shows a large dense aggregate of CLL/SLL lymphocytes (hematoxylin and eosin, ×100) (A). A different field reveals a dense aggregate of CLL/SLL cells in the middle with 2 large epithelioid granulomas on the sides (arrows) (hematoxylin and eosin, ×100) (B). At high magnification, SLL/SLL cells appear small, round to oval, and monotonous (hematoxylin and eosin, ×600) (C).
4 patients in our cohort. The single patient who did not recover kidney function had irreversible severe tubular atrophy and interstitial fibrosis at diagnostic biopsy. In CLL/SLL patients in whom kidney biopsy shows interstitial lymphocytic infiltration, we recommend performing immunohistochemical staining for CD3, CD20, CD5, and CD23 to confirm or exclude CLL/SLL infiltration and to exclude concurrent interstitial nephritis. Likewise, the finding of interstitial epithelioid granulomas in biopsies showing CLL/SLL infiltration should alert the pathologist to the possibility of concurrent reactive interstitial nephritis. Special stains for fungi and mycobacteria and molecular studies for mycobacteria are advised in biopsies showing necrotizing granulomas to exclude infectious interstitial nephritis. The development of reactive noncaseating, sarcoid-like, epithelioid granulomas is a well-documented phenomenon in a variety of carcinomas and lymphoproliferative malignancies [25]. Among lymphoproliferative malignancies, they are most commonly seen in Hodgkin lymphoma, encountered in approximately 14% of cases [25-27], and may also develop in non-Hodgkin lymphomas, including CLL/SLL [28], Burkitt lymphoma [29,30], peripheral T-cell lymphoma [31], and diffuse large B-cell lymphoma [32]. They may occur in lymph nodes, spleen, and/or liver, with or without concomitant lymphoma in the same biopsy [25]. These granulomas are thought to represent a nonspecific host response to the tumor and have been shown in Hodgkin lymphoma and Burkitt lymphoma to confer a favorable prognosis [27,29,33]. Necrotizing granulomas are much less common than nonnecrotizing granulomas in lymphoma patients and usually occur in the setting of mycobacterial infection [28,34]. The pathogenesis of GIN in patients with CLL/SLL is unknown. There is ample evidence that B-cell CLL/SLL patients have T-cell dysfunction, which may contribute to pathogenesis, infectious and autoimmune complications, and prognosis of the disease [35-39]. The fact that every case of GIN was accompanied by CLL/SLL interstitial infiltration suggests that GIN is perhaps a local hypersensitivity reaction to tumor-derived antigens, which may stimulate antigenpresenting cells to produce cytokines known to be involved in granulomatous inflammation, such as interleukin (IL) 12, IL-18, and/or IL27 [25,28,29]. These cytokines are capable of triggering proliferation of T-helper cells and their production of lymphokines (such as interferon γ and IL-2) that attract and activate monocytes to undergo maturation into epithelioid cells [25,28,40]. None of our patients had evidence by immunofluorescence or electron microscopy of monoclonal protein or immune-complex–type deposits, providing evidence against paraprotein-mediated or immune-complex– mediated interstitial nephritis, respectively.
In summary, we report an association between CLL/SLL and GIN. Patients present with severe renal failure with/without nephromegaly. Kidney biopsy typically reveals GIN concomitant with leukemic interstitial infiltration. In most patients, kidney function improves on steroids with/without CLL/SLL–directed chemotherapy, but relapse of renal failure may occur in association with CLL/SLL relapse. Granulomatous interstitial nephritis should be considered in the differential diagnosis in CLL/ SLL patients who present with severe renal impairment associated with leukocyturia in the absence of nephrotic-range proteinuria. Kidney biopsy is recommended to confirm the diagnosis and direct appropriate therapy. Larger clinicopathologic studies are needed to determine the incidence and risk factors of GIN in patients with CLL/SLL.
References [1] Bijol V, Mendez GP, Nose V, Rennke HG. Granulomatous interstitial nephritis: a clinicopathologic study of 46 cases from a single institution. Int J Surg Pathol 2006;14: 57–63. [2] Javaud N, Belenfant X, Stirnemann J, Laederich J, Ziol M, Callard P, et al. Renal granulomatoses: a retrospective study of 40 cases and review of the literature. Medicine (Baltimore) 2007;86:170–80. [3] Muriithi AK, Leung N, Valeri AM, Cornell LD, Sethi S, Fidler ME, et al. Clinical characteristics, causes and outcomes of acute interstitial nephritis in the elderly. Kidney Int 2015;87:458–64. [4] Naidu GD, Ram R, Swarnalatha G, Uppin M, Prayaga AK, Dakshinamurty KV. Granulomatous interstitial nephritis: Our experience of 14 patients. Indian J Nephrol 2013; 23:415–8. [5] Viero RM, Cavallo T. Granulomatous interstitial nephritis. Hum Pathol 1995;26: 1347–53. [6] Muriithi AK, Leung N, Valeri AM, Cornell LD, Sethi S, Fidler ME, et al. Biopsy-proven acute interstitial nephritis, 1993-2011: a case series. Am J Kidney Dis 2014;64: 558–66. [7] Swerdlow SH, Campo E, Harris NL, editors. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008. [8] Barcos M, Lane W, Gomez GA, Han T, Freeman A, Preisler H, et al. An autopsy study of 1206 acute and chronic leukemias (1958 to 1982). Cancer 1987;60:827–37. [9] Schwartz JB, Shamsuddin AM. The effects of leukemic infiltrates in various organs in chronic lymphocytic leukemia. Hum Pathol 1981;12:432–40. [10] Da'as N, Polliack A, Cohen Y, Amir G, Darmon D, Kleinman Y, et al. Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic leukemia: a retrospective study in 700 patients. Eur J Haematol 2001;67:158–64. [11] Kowalewska J, Nicosia RF, Smith KD, Kats A, Alpers CE. Patterns of glomerular injury in kidneys infiltrated by lymphoplasmacytic neoplasms. Hum Pathol 2011;42: 896–903. [12] Li SJ, Chen HP, Chen YH, Zhang LH, Tu YM, Liu ZH. Renal involvement in non-Hodgkin lymphoma: proven by renal biopsy. PLoS One 2014;9:e95190. [13] Moulin B, Ronco PM, Mougenot B, Francois A, Fillastre JP, Mignon F. Glomerulonephritis in chronic lymphocytic leukemia and related B-cell lymphomas. Kidney Int 1992;42:127–35. [14] Nasr SH, Fidler ME, Cornell LD, Leung N, Cosio FG, Sheikh SS, et al. Immunotactoid glomerulopathy: clinicopathologic and proteomic study. Nephrol Dial Transplant 2012;27:4137–46.
Please cite this article as: Nasr SH, et al, Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.03.003
S.H. Nasr et al. / Annals of Diagnostic Pathology xxx (2015) xxx–xxx [15] Nasr SH, Snyder RW, Bhagat G, Markowitz GS. Chronic lymphocytic leukemia and cryoglobulinemic glomerulonephritis. Kidney Int 2007;71:93. [16] Barbour SJ, Beaulieu MC, Zalunardo NY, Magil AB. Proliferative glomerulonephritis with monoclonal IgG deposits secondary to chronic lymphocytic leukemia. Report of two cases. Nephrol Dial Transplant 2011;26:2712–4. [17] Butty H, Asfoura J, Cortese F, Doyle M, Rutecki G. Chronic lymphocytic leukemiaassociated membranous glomerulopathy: remission with fludarabine. Am J Kidney Dis 1999;33:E8. [18] Kourelis TV, Gertz M, Zent C, Lacy M, Kyle R, Kapoor P, et al. Systemic amyloidosis associated with chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Hematol 2013;88:375–8. [19] Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9–29. [20] Pena de la Vega L, Fervenza FC, Lager D, Habermann T, Leung N. Acute granulomatous interstitial nephritis secondary to bisphosphonate alendronate sodium. Ren Fail 2005;27:485–9. [21] Korzets Z, Elis A, Bernheim J. Acute granulomatous interstitial nephritis due to nitrofurantoin. Nephrol Dial Transplant 1994;9:713–5. [22] Nadri Q, Althaf MM. Granulomatous tubulointerstitial nephritis secondary to omeprazole. BMJ Case Rep 2014;2014. [23] Inoue T, Sato T, Okada H, Kayano H, Watanabe Y, Kikuta T, et al. Granulomatous interstitial nephritis in chronic lymphocytic leukaemia. Nephrol Dial Transplant 2010; 25:4107–9. [24] Kamat AV, Goldsmith D, O'Donnell P, van der Walt J, Carr R. Renal failure with granulomatous interstitial nephritis and diffuse leukemic renal infiltration in chronic lymphocytic leukemia. Ren Fail 2007;29:763–5. [25] Brincker H. Sarcoid reactions in malignant tumours. Cancer Treat Rev 1986;13: 147–56. [26] O'Carroll DI, McKenna RW, Brunning RD. Bone marrow manifestations of Hodgkin's disease. Cancer 1976;38:1717–28. [27] Sacks EL, Donaldson SS, Gordon J, Dorfman RF. Epithelioid granulomas associated with Hodgkin's disease: clinical correlations in 55 previously untreated patients. Cancer 1978;41:562–7. [28] Brunner A, Kantner J, Tzankov A. Granulomatous reactions cause symptoms or clinically imitate treatment resistance in small lymphocytic lymphoma/chronic lymphocytic leukaemia more frequently than in other non-Hodgkin lymphomas. J Clin Pathol 2005;58:815–9.
7
[29] Hollingsworth HC, Longo DL, Jaffe ES. Small noncleaved cell lymphoma associated with florid epithelioid granulomatous response. A clinicopathologic study of seven patients. Am J Surg Pathol 1993;17:51–9. [30] Haralambieva E, Rosati S, van Noesel C, Boers E, van Marwijk Kooy M, et al. Florid granulomatous reaction in Epstein-Barr virus-positive nonendemic Burkitt lymphomas: report of four cases. Am J Surg Pathol 2004;28:379–83. [31] Pujol RM, Gallardo F, Servitje O, Marti RM, Bordes R, Garcia-Muret MP, et al. Peripheral T-cell lymphoma with secondary epithelioid granulomatous cutaneous involvement: a clinicopathologic study of four cases. J Dermatol 2005;32:541–8. [32] Kornacker M, Kraemer A, Leo E, Ho AD. Occurrence of sarcoidosis subsequent to chemotherapy for non-Hodgkin's lymphoma: report of two cases. Ann Hematol 2002; 81:103–5. [33] O'Connell MJ, Schimpff SC, Kirschner RH, Abt AB, Wiernik PH. Epithelioid granulomas in Hodgkin disease. A favorable prognostic sign? Jama 1975;233:886–9. [34] Blanco M, Ratzan J, Cabello-Inchausti B, Fernandes L. Necrotizing granulomas in B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma. Ann Diagn Pathol 2002;6:216–21. [35] Callery RT, Strelkauskas AJ, Yanovich S, Marks S, Rosenthal D, Schlossman SF. Functional abnormalities associated with T lymphocytes from patients with chronic lymphocytic leukemia. Clin Immunol Immunopathol 1980;17:451–8. [36] Herrmann F, Lochner A, Philippen H, Jauer B, Ruhl H. Imbalance of T cell subpopulations in patients with chronic lymphocytic leukaemia of the B cell type. Clin Exp Immunol 1982;49:157–62. [37] Kay NE, Johnson JD, Stanek R, Douglas SD. T-cell subpopulations in chronic lymphocytic leukemia: abnormalities in distribtuion and in in vitro receptor maturation. Blood 1979;54:540–4. [38] Ramsay AG, Johnson AJ, Lee AM, Gorgun G, Le Dieu R, Blum W, et al. Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J Clin Invest 2008;118: 2427–37. [39] Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood 2013;121:1612–21. [40] Larousserie F, Pflanz S, Coulomb-L'Hermine A, Brousse N, Kastelein R, Devergne O. Expression of IL-27 in human Th1-associated granulomatous diseases. J Pathol 2004;202:164–71.
Please cite this article as: Nasr SH, et al, Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.03.003
Contents lists available at ScienceDirect
Annals of Diagnostic Pathology
Original Contribution
Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma☆,☆☆ Samih H. Nasr, MD a,⁎, Tait D. Shanafelt, MD b, Curtis A. Hanson, MD c, Mary E. Fidler, MD a, Lynn D. Cornell, MD a, Sanjeev Sethi, MD, PhD a, Kari G. Chaffee, MS d, Joseph Morris, MD e, Nelson Leung, MD b,f a
Division of Anatomic Pathology, Mayo Clinic, Rochester, MN Division of Hematology, Mayo Clinic, Rochester, MN Division of Hematopathology, Mayo Clinic, Rochester, MN d Department of Health Sciences Research, Mayo Clinic, Rochester, MN e Great River Nephrology, West Burlington, IA f Division of Nephrology, Mayo Clinic, Rochester, MN b c
a r t i c l e
i n f o
Available online xxxx Keywords: Granulomatous interstitial nephritis interstitial nephritis chronic lymphocytic leukemia small lymphocytic lymphoma kidney biopsy lymphoma
a b s t r a c t Granulomatous interstitial nephritis (GIN) is an uncommon pathologic lesion encountered in 0.5% to 5.9% of renal biopsies. Drugs, sarcoidosis, and infections are responsible for most cases of GIN. Malignancy is not an established cause of GIN. Here, we report a series of 5 patients with GIN secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients were mostly elderly white males with an established history of CLL/SLL who presented with severe renal impairment (median peak serum creatinine, 7.3 mg/dL), leukocyturia, and mild proteinuria. One had nephromegaly. In 2 patients, the development and relapse of renal insufficiency closely paralleled the level of lymphocytosis. Kidney biopsy in all patients showed GIN concomitant with CLL/ SLL leukemic interstitial infiltration. Granulomas were nonnecrotizing and epithelioid and were associated with giant cells. One biopsy showed granulomatous arteritis. One patient had a granulomatous reaction in lymph nodes and skin. Steroids with/without CLL/SLL–directed chemotherapy led to partial improvement of kidney function in all patients except 1 who had advanced cortical scarring on biopsy. In conclusion, we report an association between CLL/SLL and GIN. Patients typically present with severe renal failure due to both GIN and leukemic interstitial infiltration, which tends to respond to steroids with/without CLL/SLL–directed chemotherapy. The pathogenesis of GIN in this clinical setting is unknown but may represent a local hypersensitivity reaction to the CLL/SLL tumor cells. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Granulomatous interstitial nephritis (GIN) is a distinct morphological variant of interstitial nephritis defined histologically by the presence of interstitial inflammation and 1 or more interstitial granulomas [1,2]. Granulomas are composed of activated macrophages, also called “epithelioid cells,” with or without giant cells. The renal biopsy incidence of GIN ranges from 0.5% to 5.9% [1-5]. In our experience, GIN accounts for 26% of cases of acute interstitial nephritis [6]. Most cases of GIN in the developed countries are due to drugs or sarcoidosis [1,2], whereas infections, particularly by mycobacteria or fungi, are the most common etiology in the developing countries [4]. Antibiotics and nonsteroidal anti-inflammatory drugs are the most frequent classes of drugs to
☆ The authors of this manuscript have no conflicts of interest to disclose. ☆☆ There was no support/funding for this study. ⁎ Corresponding author at: Division of Anatomic Pathology, Mayo Clinic, Hilton 10-20, 200 First St SW, Rochester, MN 55905. E-mail address: [email protected] (S.H. Nasr).
cause GIN [1,2], although there have been many case reports of GIN linked to other therapeutic agents, including analgesics, diuretics, anticoagulants, and others (reviewed in Javaud et al [2]). Chronic lymphocytic leukemia (CLL) is the most common leukemia in developed counties and is characterized by progressive accumulation of functionally incompetent B lymphocytes. Chronic lymphocytic leukemia/small lymphocytic lymphoma (SLL) cells have a characteristic immunophenotype, which is a key for diagnosis: they express B-cell– associated antigens CD19, CD20 (weak), and CD23; CD5, a T-cell– associated antigen; and low-intensity surface immunoglobulins (usually immunoglobulin M) with only 1 immunoglobulin light chain (κ or λ). When CLL cells involve lymph nodes without substantial peripheral blood involvement (B-cell count b5 × 109/L), the disease is referred to as the “SLL” variant [7]. Most patients with CLL/SLL are asymptomatic at diagnosis, but some present with painless lymph node swelling, weight loss, fevers, night sweats, and/or fatigue. Patients with CLL/SLL have dysfunction of their immune system leading to acquired immunodeficiency and development of autoimmune disorders. Important complications of CLL/SLL include infections, anemia, thrombocytopenia, and increased risk of second cancer.
http://dx.doi.org/10.1016/j.anndiagpath.2015.03.003 1092-9134/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Nasr SH, et al, Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.03.003
Rituximab, HD Hypertension, diabetes, BPH Yes
NA
63/M/W 5
IV
4
2 (4 mo prior)
10.2
7
2
Yes (Foley catheter) No 2.2 5.7 6.1 2.4 (2 mo prior) 18 79/M/W 4
I
78/M/W 3
Abbreviations: BPH, benign prostatic hyperplasia; Bx, renal biopsy; CA, carcinoma; ESRD, end-stage kidney disease; F, female; GERD, gastrointestinal reflux disease; HD, hemodialysis; M, male; NA, not available; SCr, serum creatinine; W, white.
Alive (43 mo post-Bx)
Died (49 mo post-Bx)
Partial recovery (S. Cr 2.1) ESRD (never recovered) Steroids, rituximab, HD
Died of cellulitis (2 mo post-Bx) Partial recovery (S. Cr 3.2) Yes No 0.2 6.9 7.3 2.4 (4 mo prior) 8
74/F/W 2
III
4
NA
18
14.9
0.9
No
Yes
Hypertension, chronic urinary tract infection Hypertension, atrial fibrillation BPH
Steroids
Died of breast CA (31 mo post-Bx)
Partial recovery (S. Cr 2.3) Partial recovery (S. Cr 2.1) Steroids, rituximab, cyclophosphamide Steroids, cyclophosphamide, HD GERD No Yes 1 57/M/W 1
0
Baseline SCr (mg/dL) Time from diagnosis of CLL/SLL to GIN in yrs CLL/SLL Rai stage at GIN diagnosis Age/sex/race Case no.
Table 1 Clinical data.
2.1.3. Case 3 A 78-year-old man was admitted for acute on chronic renal failure and severe pruritus in September 2002. He was diagnosed with CLL Rai stage III in 1994 and received intravenous immunoglobulin to treat hypogammaglobulinemia. In May 2002, he was noted to have a serum creatinine of 2.4 mg/dL and a 24-hour urine protein of 242 mg. Afterward, the patient became fatigued and developed rash and severe
Peak SCr SCr at Bx (mg/dL)
2.1.2. Case 2 A 74-year-old woman had a history of CLL Rai stage 0 diagnosed in 1998. She presented in August 2002 with acute renal failure. Two weeks before admission, she began to experience fatigue, nausea, diarrhea, and vomiting. On admission, she had a hemoglobin level of 9.5 g/dL, WBC count of 100.6 × 109/L with 91% lymphocytes, and platelet count of 203 × 109/L (Table 1). Testing for cytoplasmic anti-neutrophil cytoplasmic antibodies (C-ANCA) and perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) was negative. Urinalysis showed less than 1 RBC/ HPF, greater than 100 WBCs/HPF, and occasional hyaline casts. Her admission medications were nitrofurantoin (intermittently for 2 years), spironolactone/hydrochlorothiazide (for many years), and alendronate sodium (for 2 weeks). A renal biopsy was obtained. She was treated with levofloxacin until urine culture was confirmed to be negative. She was also initially treated with high-dose corticosteroid. Despite this, her renal failure progressed, and dialysis was initiated. One dose of intravenous cyclophosphamide was administered, and the WBC count dropped to 26.7 × 10 9/L. Patient became dialysis independent after 2 months. Her CLL/SLL remained stable, but she was diagnosed with breast cancer in 2005 and elected not to undergo any treatment. Patient died in March 2005 of complications of breast cancer.
5.9
Proteinuria Hematuria (g/day)
Leukocyturia Other medical conditions
2.1.1. Case 1 During a routine follow-up visit in December 2007, a 57-year-old man was noted to have renal insufficiency (Table 1). He had a known history of CLL Rai stage I, ZAP70 and CD38 positive, diagnosed in December 2005, which was followed without treatment. His admission medications were cimetidine, ranitidine, and Tums. He took 2 doses of Aleve 2 days before admission but none prior. On examination, there were nontender 2- to 3-cm nodes along anterior cervical chain, bilateral axillary, and inguinal adenopathy. No organomegaly was identified. Laboratory data showed a hemoglobin level of 15.2 g/dL, white blood cell (WBC) count of 29.0 × 10 9/L with 90% lymphocytes, platelet count of 149 × 10 9/L, serum C3 67 and serum C4 23, a total urine protein of 1 g/24 hours, and negative serum and urine protein electrophoresis (Table 1). Urinalysis showed 4 to 10 nondysmorphic red blood cells (RBCs)/high-power field (HPF) without WBCs. A renal biopsy was obtained. Over the next 5 years, patient was treated with multiple courses of chemotherapy, which lead to an improvement in kidney function, but experienced multiple relapses. As shown in Fig. 1, his renal relapses closely paralleled the level of lymphocytosis.
6.7
Treatment
2.1. Clinical histories
1.3 (9 mo prior)
2. Results
2
Renal outcome
Patient outcome
Although leukemic infiltration of the kidney is seen on autopsy in most patients with CLL/SLL [8,9], clinical kidney dysfunction is uncommon [10]. Several glomerular lesions pathogenically related to CLL/SLL have been described, including membranoproliferative glomerulonephritis [11-13], minimal change disease [11], immunotactoid glomerulopathy [10,14], cryoglobulinemic glomerulonephritis [13,15], proliferative glomerulonephritis with monoclonal immunoglobulin G deposits [16], membranous glomerulopathy [13,17], and amyloidosis [18]. Expanding the spectrum of renal lesions associated with CLL/SLL, we report the first series of GIN secondary to CLL/SLL. The clinicopathologic features, outcomes, and possible pathogenetic mechanisms of this underrecognized complication of CLL/SLL are discussed.
Alive (81 mo post-Bx)
S.H. Nasr et al. / Annals of Diagnostic Pathology xxx (2015) xxx–xxx
I
2
Please cite this article as: Nasr SH, et al, Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.03.003
S.H. Nasr et al. / Annals of Diagnostic Pathology xxx (2015) xxx–xxx
3
Fig. 1. Graphical display of patient 1 WBC and serum creatinine (Scr) values. The WBC from December 13, 2007, of 217.7 × 109/L was omitted due to the scale issue. Patient received rituximab, cyclophosphamide, prednisone (RCP) from February 2008 to July 2008 and rituximab, cyclophosphamide, vincristine, prednisone (R-CVP) from May 2010 to September 2010. In August 2011, 2 cycles of rituximab and methylprednisone (R-Mp) were given. Two cycles of alemtuzumab and rituximab (R-Alem) were administered in August 2012. Patient then received ofatumumab (Ofat) from January 2013 to September 2013 for bulky lymphadenopathy.
pruritus with lesions involving his lower extremities and back. Biopsy of the skin lesions revealed granulomas. In September 2002, the patient presented with fever, chills, and left axillary pain. Laboratory data showed a hemoglobin level of 10 g/dL, WBC count of 20.6 × 10 3/mm with 83% lymphocytes, platelet count of 169 × 10 3/mm, negative serum protein electrophoresis, and negative testing for ANCA (Table 1). Angiotensin-converting enzymes were 30 U/L (normal, 7-46). An infectious disease workup and fungal serologies were negative. His admitting medications were diltiazem, digoxin, sennosides A and B, erythropoietin, and intravenous immunoglobulin. A lymph node biopsy was obtained, which showed CLL/SLL and noncaseating granulomatous inflammation. Fungal and acid-fast stains were negative. A renal biopsy was performed. Patient was treated with prednisone 1 mg/kg per day. Serum creatinine improved to 3.2 mg/dL, and he was discharged. Patient died 2 months later of complications of cellulitis and CLL/SLL.
2.1.4. Case 4 A 79-year-old man with a known history of CLL Rai stage I diagnosed in 1988 presented in April 2006 with acute renal failure. Review of systems and physical examination were remarkable for weight loss, anorexia, generalized weakness, and lethargy. There was no peripheral edema or skin rash. Laboratory data showed a 24-hour urine protein of 0.2 g, hemoglobin level of 8.8 g/dL, WBC count of 18.5 × 10 3/mm, and platelet count of 127 × 10 3/mm (Table 1). Bone marrow flow cytometry showed a population of CD19-positive B-cells with a monotypic staining pattern for λ surface immunoglobulin light chain and coexpressed CD20 (dim), CD22, CD5, CD23, and CD38, consistent with B-cell CLL/SLL. Urinalysis revealed leukocyturia, and urine culture revealed bacterial urinary tract infection. Renal scan showed mild hydronephrosis with minimal obstruction. On abdominal computed tomography, there was extensive abdominal and pelvic lymphadenopathy without organomegaly. Medications at the time of admission were pantoprazole and tamsulosin hydrochloride. Kidney function did not improve on rehydration, antibiotics, and stenting; therefore, a kidney biopsy was performed, which showed both GIN and CLL/SLL infiltration.
Granulomatous interstitial nephritis was treated with hemodialysis, steroids, and rituximab. Four months later, he came off dialysis with a serum creatinine declining to 2.1 mg/dL and WBC count declining to 9.1 × 103/mm. In 2009, he developed acute on chronic kidney injury and increasing WBC count, which responded to prednisone. In 2010, he was admitted with pneumonia and worsening serum creatinine to 3.9 mg/dL. He refused further therapy, was transferred to hospice care, and died. 2.1.5. Case 5 A 63-year-old man was admitted in April 2006 for severe acute kidney injury. He was diagnosed with stage IV low-grade non-Hodgkin lymphoma at an outside institution in 2004. He received chemotherapy (data not available) initially at diagnosis and 2 years later for disease recurrence and had been on maintenance rituximab every 3 months. Physical examination showed submandibular, cervical, and supraclavicular adenopathy. There was no organomegaly, edema, or skin rash. Abdominal ultrasound showed bilateral kidney enlargement and retroperitoneal and periaortic lymphadenopathy. Laboratory investigation revealed a random urine protein/creatinine ratio of 2 g, hemoglobin level of 8.7 g/dL, WBC count of 7.6 × 10 3/mm, platelet count of 127 × 10 9/L, negative ANCA, hepatitis B surface antigen, and hepatitis C antibody, and normal C3 and C4 complement levels (Table 1). Urinalysis revealed 100 mg/dL of protein, trace blood, 3 RBCs/HPF, and 12 WBCs/HPF with many WBC clumps. Medications at the time of admission were lisinopril (for many years, which was discontinued without improvement in kidney function), tamsulosin hydrochloride, amlodipine, and Humulin. Hemodialysis was started, and a kidney biopsy was performed. Over the next 5 years of follow-up, he continued on his maintenance rituximab. He never had a complete response to chemotherapy, but there was no evidence of significant progression of his lymphoma. He remained dialysis dependent. 2.2. Renal biopsy findings All five cases showed GIN and leukemic interstitial infiltration (Table 2). GIN interstitial inflammation was composed predominantly of lymphocytes and monocytes and was diffuse in 4 cases and patchy
Please cite this article as: Nasr SH, et al, Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.03.003
4
S.H. Nasr et al. / Annals of Diagnostic Pathology xxx (2015) xxx–xxx
Table 2 Pathologic findings. Case no. No. of % global Degree of Tubulitis Degree of glomeruli glomerulosclerosis reactive tubular atrophy interstitial and interstitial inflammation fibrosis
Acute Degree of CLL/ tubular SLL interstitial injury involvement
Morphology of granulomas
Arteriosclerosis Concurrent glomerular disease
1
6
17
Diffuse
Yes
Mild
Yes
Focal (20%)
Mild
No
2
4
0
Diffuse
Yes
Mild
Yes
Focal (30%)
Mild
No
3
11
0
Patchy
Yes
Moderate
Yes
Focal (10%)
Moderate
Focal segmental glomerulosclerosis
4
16
38
Diffuse
Yes
Moderate
No
Focal (20%)
Mild
No
5
11
27
Diffuse
Yes
Severe
No
Diffuse (80%)
Nonnecrotizing, small, ill defined, with giant cells Nonnecrotizing, large, well defined, with giant cells Nonnecrotizing, large, well defined, also involving interlobular arteries, with giant cells Nonnecrotizing, small to large, ill defined, with giant cells Nonnecrotizing, large, well defined, with giant cells
Mild
No
in 1 (Figs. 2 and 4). The lymphocytes were mostly reactive CD3 and CD5-positive T-lymphocytes with only rare CD20-positive Blymphocytes (Figs. 2 and 3). Interstitial eosinophils were increased in only 1 case. T-cell lymphocytic tubulitis was present in all cases (Figs. 3 and 4). Scattered nonnecrotizing epithelioid granulomas with multinucleated giant cells were seen in all cases (Figs. 2, 3, 4, and 6). In 4 cases, granulomas were large and well circumscribed (sarcoid like) (Fig. 3), whereas in the remaining 1 case, they ranged from small to large and were ill defined (Fig. 4). The granulomas lacked staining for CD20 (Fig. 3) or CD23. Three cases showed focal acute tubular injury. The degree of tubular atrophy and interstitial fibrosis ranged from mild in 2 cases, to moderate in 2, to severe in 1. Granulomatous arteritis was noted in 1 case (Fig. 5). Grocott's methenamine silver stain for fungi and Ziehl-Neelsen stain for mycobacteria were negative in all cases. The morphology and immunoperoxidase stains on the kidney biopsy in all 5 cases were consistent with interstitial involvement by CLL/SLL (Figs. 2, 4, and 6), which affected approximately 10% to 30% of the cortex in 4 cases and 80% of the cortex in the remaining case. Chronic
lymphocytic leukemia/SLL cells were small, round, relatively monotonous (Fig. 6C), and tended to form dense rounded aggregates in the cortex and/or medulla (Figs. 2, 4, and 6). Chronic lymphocytic leukemia/SLL cells stained positive for CD20 and CD23; negative for CD3; and, with the exception of case 4 (in which CLL/SLL cells were positive for CD5 on bone marrow and peripheral blood flow cytometry), positive for CD5 (Figs. 2 and 3). No glomerular or tubulointerstitial immune complex type deposits were detected by immunofluorescence (performed on all cases) or electron microscopy (performed in 4 cases). Case 3 showed concurrent secondary focal segmental glomerulosclerosis, which was likely due to hypertensive arterionephrosclerosis. 3. Discussion In this study, we report a series of 5 patients who developed GIN that we believe is secondary to CLL/SLL. During the study period, 66 renal biopsies accessioned in our laboratory had CLL/SLL interstitial infiltration, indicating a 7% GIN incidence in biopsies with CLL/SLL infiltration. In line
Fig. 2. Renal biopsy findings from case 1. Low-power view shows diffuse interstitial infiltration by inflammatory cells. A large epithelioid granuloma is present on the bottom (arrow) (hematoxylin and eosin, ×40). Lymphocytes diffusely infiltrating the interstitium were mostly reactive CD3-positive T-cells (×100). The CD20-positive CLL/SLL B-cells form dense aggregates in the cortex and perirenal fat (×100).
Please cite this article as: Nasr SH, et al, Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.03.003
S.H. Nasr et al. / Annals of Diagnostic Pathology xxx (2015) xxx–xxx
5
Fig. 3. Renal biopsy findings from case 5. A high-power field depicts a large, well-circumscribed noncaseating epithelioid granuloma (hematoxylin and eosin, ×200). The top right image shows diffuse interstitial infiltration and tubulitis by reactive CD3-positive T-cells. T-cells are also seen within a large well-circumscribed interstitial granuloma (arrow) (×100). The lower right image of the same field shows multifocal interstitial infiltration by CD20-positive leukemic B-cells, which spare the granuloma and tubules (×100).
with CLL/SLL patients' demographics in general [19], our cohort consisted mostly of elderly white males. All patients had an established history of CLL/SLL before presentation with renal insufficiency with a median time from CLL/SLL diagnosis to GIN diagnosis of 4 years (range, 2-18 years). Three patients (60%) had CLL/SLL Rai stage 0 or I at renal presentation, suggesting that GIN may develop even with early stages of disease. All patients presented with severe renal impairment (median peak serum creatinine, 7.3 mg/dL), and 1 had nephromegaly, both of which are likely due to concomitant GIN and CLL/SLL interstitial infiltration. In 2 patients (1 and 4), the development and relapse of renal insufficiency closely paralleled the level of lymphocytosis, which strongly suggests CLL/SLL as the cause of GIN. The association between CLL/SLL and GIN that we show in this small cohort was not recognized when we initially published the case report on patient 2 and were advised to attribute the GIN to a medication [20]. None of these patients had other conditions known to be associated with GIN, such as sarcoidosis, tubulointerstitial nephritis and uveitis syndrome, granulomatosis with polyangiitis, and fungal or mycobacterial infection.
Fig. 4. Renal biopsy findings from case 4. The image shows reactive diffuse interstitial inflammation on the right with associated prominent lymphocytic tubulitis on the top. A large epithelioid granuloma is seen on the bottom (arrow), and a dense aggregate of small monotonous leukemia cells is present on the left (black star) (periodic acidSchiff, ×100).
Patient 2 was receiving nitrofurantoin, and patient 5 was on lisinopril medications that were described in rare case reports to cause GIN [21,22]. However, the 2 patients had been on these medications for many years without side effects; therefore, it is unlikely that they were responsible for GIN. Two additional patients with CLL/SLL causing GIN have been reported previously [23,24]. Chronic lymphocytic leukemia/SLL was diagnosed concomitantly with GIN in 1 and 1.5 years prior in the other patient. Both patients presented with severe renal impairment requiring renal replacement therapy. Kidney biopsy in all 5 patients reported here and the 2 patients reported previously showed leukemic interstitial infiltration concomitant with GIN [23,24]. Granulomatous interstitial nephritis is likely a bigger contributor to renal failure than CLL/SLL infiltration because it was generally more extensive and was accompanied by tubulitis. It is crucial not to overlook reactive interstitial nephritis in CLL/SLL patients, as kidney function tends to improve on steroids with/without CLL/SLL–directed chemotherapy. Kidney function improvement on therapy occurred in
Fig. 5. Renal biopsy findings from case 3. This interlobular artery shows medial and adventitial infiltration by epithelioid histiocytes and rupture of its elastica externa, consistent with granulomatous arteritis. No fibrinoid necrosis is seen. An interstitial giant cell is seen below (methenamine silver stain, ×100).
Please cite this article as: Nasr SH, et al, Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.03.003
6
S.H. Nasr et al. / Annals of Diagnostic Pathology xxx (2015) xxx–xxx
Fig. 6. Renal biopsy findings from case 2. Low-power field shows a large dense aggregate of CLL/SLL lymphocytes (hematoxylin and eosin, ×100) (A). A different field reveals a dense aggregate of CLL/SLL cells in the middle with 2 large epithelioid granulomas on the sides (arrows) (hematoxylin and eosin, ×100) (B). At high magnification, SLL/SLL cells appear small, round to oval, and monotonous (hematoxylin and eosin, ×600) (C).
4 patients in our cohort. The single patient who did not recover kidney function had irreversible severe tubular atrophy and interstitial fibrosis at diagnostic biopsy. In CLL/SLL patients in whom kidney biopsy shows interstitial lymphocytic infiltration, we recommend performing immunohistochemical staining for CD3, CD20, CD5, and CD23 to confirm or exclude CLL/SLL infiltration and to exclude concurrent interstitial nephritis. Likewise, the finding of interstitial epithelioid granulomas in biopsies showing CLL/SLL infiltration should alert the pathologist to the possibility of concurrent reactive interstitial nephritis. Special stains for fungi and mycobacteria and molecular studies for mycobacteria are advised in biopsies showing necrotizing granulomas to exclude infectious interstitial nephritis. The development of reactive noncaseating, sarcoid-like, epithelioid granulomas is a well-documented phenomenon in a variety of carcinomas and lymphoproliferative malignancies [25]. Among lymphoproliferative malignancies, they are most commonly seen in Hodgkin lymphoma, encountered in approximately 14% of cases [25-27], and may also develop in non-Hodgkin lymphomas, including CLL/SLL [28], Burkitt lymphoma [29,30], peripheral T-cell lymphoma [31], and diffuse large B-cell lymphoma [32]. They may occur in lymph nodes, spleen, and/or liver, with or without concomitant lymphoma in the same biopsy [25]. These granulomas are thought to represent a nonspecific host response to the tumor and have been shown in Hodgkin lymphoma and Burkitt lymphoma to confer a favorable prognosis [27,29,33]. Necrotizing granulomas are much less common than nonnecrotizing granulomas in lymphoma patients and usually occur in the setting of mycobacterial infection [28,34]. The pathogenesis of GIN in patients with CLL/SLL is unknown. There is ample evidence that B-cell CLL/SLL patients have T-cell dysfunction, which may contribute to pathogenesis, infectious and autoimmune complications, and prognosis of the disease [35-39]. The fact that every case of GIN was accompanied by CLL/SLL interstitial infiltration suggests that GIN is perhaps a local hypersensitivity reaction to tumor-derived antigens, which may stimulate antigenpresenting cells to produce cytokines known to be involved in granulomatous inflammation, such as interleukin (IL) 12, IL-18, and/or IL27 [25,28,29]. These cytokines are capable of triggering proliferation of T-helper cells and their production of lymphokines (such as interferon γ and IL-2) that attract and activate monocytes to undergo maturation into epithelioid cells [25,28,40]. None of our patients had evidence by immunofluorescence or electron microscopy of monoclonal protein or immune-complex–type deposits, providing evidence against paraprotein-mediated or immune-complex– mediated interstitial nephritis, respectively.
In summary, we report an association between CLL/SLL and GIN. Patients present with severe renal failure with/without nephromegaly. Kidney biopsy typically reveals GIN concomitant with leukemic interstitial infiltration. In most patients, kidney function improves on steroids with/without CLL/SLL–directed chemotherapy, but relapse of renal failure may occur in association with CLL/SLL relapse. Granulomatous interstitial nephritis should be considered in the differential diagnosis in CLL/ SLL patients who present with severe renal impairment associated with leukocyturia in the absence of nephrotic-range proteinuria. Kidney biopsy is recommended to confirm the diagnosis and direct appropriate therapy. Larger clinicopathologic studies are needed to determine the incidence and risk factors of GIN in patients with CLL/SLL.
References [1] Bijol V, Mendez GP, Nose V, Rennke HG. Granulomatous interstitial nephritis: a clinicopathologic study of 46 cases from a single institution. Int J Surg Pathol 2006;14: 57–63. [2] Javaud N, Belenfant X, Stirnemann J, Laederich J, Ziol M, Callard P, et al. Renal granulomatoses: a retrospective study of 40 cases and review of the literature. Medicine (Baltimore) 2007;86:170–80. [3] Muriithi AK, Leung N, Valeri AM, Cornell LD, Sethi S, Fidler ME, et al. Clinical characteristics, causes and outcomes of acute interstitial nephritis in the elderly. Kidney Int 2015;87:458–64. [4] Naidu GD, Ram R, Swarnalatha G, Uppin M, Prayaga AK, Dakshinamurty KV. Granulomatous interstitial nephritis: Our experience of 14 patients. Indian J Nephrol 2013; 23:415–8. [5] Viero RM, Cavallo T. Granulomatous interstitial nephritis. Hum Pathol 1995;26: 1347–53. [6] Muriithi AK, Leung N, Valeri AM, Cornell LD, Sethi S, Fidler ME, et al. Biopsy-proven acute interstitial nephritis, 1993-2011: a case series. Am J Kidney Dis 2014;64: 558–66. [7] Swerdlow SH, Campo E, Harris NL, editors. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008. [8] Barcos M, Lane W, Gomez GA, Han T, Freeman A, Preisler H, et al. An autopsy study of 1206 acute and chronic leukemias (1958 to 1982). Cancer 1987;60:827–37. [9] Schwartz JB, Shamsuddin AM. The effects of leukemic infiltrates in various organs in chronic lymphocytic leukemia. Hum Pathol 1981;12:432–40. [10] Da'as N, Polliack A, Cohen Y, Amir G, Darmon D, Kleinman Y, et al. Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic leukemia: a retrospective study in 700 patients. Eur J Haematol 2001;67:158–64. [11] Kowalewska J, Nicosia RF, Smith KD, Kats A, Alpers CE. Patterns of glomerular injury in kidneys infiltrated by lymphoplasmacytic neoplasms. Hum Pathol 2011;42: 896–903. [12] Li SJ, Chen HP, Chen YH, Zhang LH, Tu YM, Liu ZH. Renal involvement in non-Hodgkin lymphoma: proven by renal biopsy. PLoS One 2014;9:e95190. [13] Moulin B, Ronco PM, Mougenot B, Francois A, Fillastre JP, Mignon F. Glomerulonephritis in chronic lymphocytic leukemia and related B-cell lymphomas. Kidney Int 1992;42:127–35. [14] Nasr SH, Fidler ME, Cornell LD, Leung N, Cosio FG, Sheikh SS, et al. Immunotactoid glomerulopathy: clinicopathologic and proteomic study. Nephrol Dial Transplant 2012;27:4137–46.
Please cite this article as: Nasr SH, et al, Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.03.003
S.H. Nasr et al. / Annals of Diagnostic Pathology xxx (2015) xxx–xxx [15] Nasr SH, Snyder RW, Bhagat G, Markowitz GS. Chronic lymphocytic leukemia and cryoglobulinemic glomerulonephritis. Kidney Int 2007;71:93. [16] Barbour SJ, Beaulieu MC, Zalunardo NY, Magil AB. Proliferative glomerulonephritis with monoclonal IgG deposits secondary to chronic lymphocytic leukemia. Report of two cases. Nephrol Dial Transplant 2011;26:2712–4. [17] Butty H, Asfoura J, Cortese F, Doyle M, Rutecki G. Chronic lymphocytic leukemiaassociated membranous glomerulopathy: remission with fludarabine. Am J Kidney Dis 1999;33:E8. [18] Kourelis TV, Gertz M, Zent C, Lacy M, Kyle R, Kapoor P, et al. Systemic amyloidosis associated with chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Hematol 2013;88:375–8. [19] Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9–29. [20] Pena de la Vega L, Fervenza FC, Lager D, Habermann T, Leung N. Acute granulomatous interstitial nephritis secondary to bisphosphonate alendronate sodium. Ren Fail 2005;27:485–9. [21] Korzets Z, Elis A, Bernheim J. Acute granulomatous interstitial nephritis due to nitrofurantoin. Nephrol Dial Transplant 1994;9:713–5. [22] Nadri Q, Althaf MM. Granulomatous tubulointerstitial nephritis secondary to omeprazole. BMJ Case Rep 2014;2014. [23] Inoue T, Sato T, Okada H, Kayano H, Watanabe Y, Kikuta T, et al. Granulomatous interstitial nephritis in chronic lymphocytic leukaemia. Nephrol Dial Transplant 2010; 25:4107–9. [24] Kamat AV, Goldsmith D, O'Donnell P, van der Walt J, Carr R. Renal failure with granulomatous interstitial nephritis and diffuse leukemic renal infiltration in chronic lymphocytic leukemia. Ren Fail 2007;29:763–5. [25] Brincker H. Sarcoid reactions in malignant tumours. Cancer Treat Rev 1986;13: 147–56. [26] O'Carroll DI, McKenna RW, Brunning RD. Bone marrow manifestations of Hodgkin's disease. Cancer 1976;38:1717–28. [27] Sacks EL, Donaldson SS, Gordon J, Dorfman RF. Epithelioid granulomas associated with Hodgkin's disease: clinical correlations in 55 previously untreated patients. Cancer 1978;41:562–7. [28] Brunner A, Kantner J, Tzankov A. Granulomatous reactions cause symptoms or clinically imitate treatment resistance in small lymphocytic lymphoma/chronic lymphocytic leukaemia more frequently than in other non-Hodgkin lymphomas. J Clin Pathol 2005;58:815–9.
7
[29] Hollingsworth HC, Longo DL, Jaffe ES. Small noncleaved cell lymphoma associated with florid epithelioid granulomatous response. A clinicopathologic study of seven patients. Am J Surg Pathol 1993;17:51–9. [30] Haralambieva E, Rosati S, van Noesel C, Boers E, van Marwijk Kooy M, et al. Florid granulomatous reaction in Epstein-Barr virus-positive nonendemic Burkitt lymphomas: report of four cases. Am J Surg Pathol 2004;28:379–83. [31] Pujol RM, Gallardo F, Servitje O, Marti RM, Bordes R, Garcia-Muret MP, et al. Peripheral T-cell lymphoma with secondary epithelioid granulomatous cutaneous involvement: a clinicopathologic study of four cases. J Dermatol 2005;32:541–8. [32] Kornacker M, Kraemer A, Leo E, Ho AD. Occurrence of sarcoidosis subsequent to chemotherapy for non-Hodgkin's lymphoma: report of two cases. Ann Hematol 2002; 81:103–5. [33] O'Connell MJ, Schimpff SC, Kirschner RH, Abt AB, Wiernik PH. Epithelioid granulomas in Hodgkin disease. A favorable prognostic sign? Jama 1975;233:886–9. [34] Blanco M, Ratzan J, Cabello-Inchausti B, Fernandes L. Necrotizing granulomas in B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma. Ann Diagn Pathol 2002;6:216–21. [35] Callery RT, Strelkauskas AJ, Yanovich S, Marks S, Rosenthal D, Schlossman SF. Functional abnormalities associated with T lymphocytes from patients with chronic lymphocytic leukemia. Clin Immunol Immunopathol 1980;17:451–8. [36] Herrmann F, Lochner A, Philippen H, Jauer B, Ruhl H. Imbalance of T cell subpopulations in patients with chronic lymphocytic leukaemia of the B cell type. Clin Exp Immunol 1982;49:157–62. [37] Kay NE, Johnson JD, Stanek R, Douglas SD. T-cell subpopulations in chronic lymphocytic leukemia: abnormalities in distribtuion and in in vitro receptor maturation. Blood 1979;54:540–4. [38] Ramsay AG, Johnson AJ, Lee AM, Gorgun G, Le Dieu R, Blum W, et al. Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J Clin Invest 2008;118: 2427–37. [39] Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood 2013;121:1612–21. [40] Larousserie F, Pflanz S, Coulomb-L'Hermine A, Brousse N, Kastelein R, Devergne O. Expression of IL-27 in human Th1-associated granulomatous diseases. J Pathol 2004;202:164–71.
Please cite this article as: Nasr SH, et al, Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma, Ann Diagn Pathol (2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.03.003
