An Unusual Finding in the Renal Medulla

KIDNEY BIOPSY TEACHING CASE

An Unusual Finding in the Renal Medulla Lawrence Tsao, MD, David S. Siegel, MD, PhD, Susan Zeveloff, MD, Govind Bhagat, MD, Vivette D. D’Agati, MD, and Glen S. Markowitz, MD INDEX WORDS: Multiple myeloma; myeloma cast nephropathy; extramedullary hematopoiesis.

CASE REPORT

A

64-year-old white woman presented with acute renal failure, anemia, and a 3-month history of progressive fatigue and back pain, for which she had been treated with valdecoxib. On presentation, the patient had a serum creatinine of 15.6 mg/dL (1,379 ␮mol/L; normal, 0.6 to 1.5 mg/dL [53 to 133 ␮mol/L]), increased from a baseline creatinine level of 1.0 mg/dL (88 ␮mol/L) 5 months prior. Past medical history was significant for long-standing hypertension, smoking (40 pack-years), and eczema. There was no history of diabetes. Physical examination showed blood pressure of 140/80 mm Hg and the absence of edema, hepatosplenomegaly, or cutaneous manifestations. Laboratory evaluation showed the following values: 24-hour urine protein, 2.7 g/d (normal, 0 to 150 mg/d); albumin, 4.3 g/dL (43 g/L; normal, 3.5 to 5.5 g/dL [35 to 55 g/L]); calcium, 10.8 mg/dL (2.69 mmol/L; normal, 8.5 to 10.4 mg/dL [2.12 to 2.59 mmol/L]); hemoglobin, 5.9 g/dL (59 g/L; normal, 11.7 to 15.5 g/dL [117 to 155 g/L]); white blood cell count, 8.1 ⫻ 103/␮L (8.1 ⫻ 109/L; normal, 3.8 to 10.8 ⫻ 103/␮L [⫻ 109/L]); and platelet count, 189 ⫻ 103/␮L (189 ⫻ 109/L; normal, 140 to 400 ⫻ 103/␮L [⫻109/L]). Urinalysis showed 2⫹ protein with few white blood cells and no red blood cells. Serological evaluation showed normal C3 and C4 complement levels and negative results for antinuclear antibody, cryoglobulins, antineutrophil cytoplasmic antibody, and anti– glomerular basement membrane antibody. The kidneys measured 12.2 and 12.8 cm in length by ultrasound, without evidence of hydronephrosis or a mass lesion. A renal biopsy was performed.

Kidney Biopsy Findings Light microscopic evaluation showed 2 long cores of renal medulla, 1 of which contained a minute segment of

From the Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, NY; Department of Medicine, Hackensack University Medical Center, Hackensack, NJ; and the Department of Medicine, Pascack Valley Hospital, Westwood, NJ. Received March 18, 2005; accepted as submitted April 13, 2005. Originally published online as doi:10.1053/j.ajkd.2005.04.038 on September 7, 2005. Address reprint requests to Glen Markowitz, MD, Department of Pathology, Columbia University, College of Physicians & Surgeons, 630 West 168th St, VC14-224, New York, NY 10032. E-mail: [email protected] © 2005 by the National Kidney Foundation, Inc. 0272-6386/05/4604-0027$30.00/0 doi:10.1053/j.ajkd.2005.04.038 780

cortex. Findings in the medulla were of particular interest. The medulla contained multiple geographically distinct interstitial cellular aggregates (Fig 1A). At low power, the densely cellular foci contained many atypical cells with a high nuclear-cytoplasmic ratio, raising the possibility of a lymphoproliferative disorder. On closer inspection, the cellular aggregates contained cells of 3 distinct lineages, including immature and maturing myeloid cells (Fig 1C and D), erythroid precursors (including many normoblasts; Fig 1E and F), and rare megakaryocytes (Fig 1G), confirmed by immunohistochemical staining for myeloperoxidase, glycophorin, and von Willebrand factor, respectively. Rare T (CD3⫹) and B cells (CD20⫹ and CD79A⫹) were identified. No plasma cells were seen. The scant sampling of renal cortex contained 2 glomeruli that appeared histologically unremarkable. Proximal and distal tubules showed diffuse degenerative changes characterized by luminal ectasia, cytoplasmic simplification, dropout of tubular epithelial cells, loss of brush border, and vacuolization. Atypical intraluminal fractured casts accompanied the tubular degenerative changes (Fig 1B). The casts appeared strongly eosinophilic with hematoxylin and eosin stain, pale with periodic acid–Schiff stain, and polychromatic with trichrome stain. Tubular casts were seen in distal tubules within the cortex and medulla and were surrounded by adherent monocytes and focal multinucleated giant cells. Mild interstitial inflammation and edema also were seen. Sampling for immunofluorescence was limited to the medulla. Within the medulla, there were multiple tubular casts that stained 3⫹ for ␭ light chain, but negative for ␬ light chain. Sampling for electron microscopy also was limited to medulla. Tubules showed degenerative changes and contained intraluminal electron-dense casts. Sampling for electron microscopy also included immature myeloid and erythroid cells.

Pathological Diagnosis Sampling for light microscopy consisted mainly of medulla. Although medulla usually is inadequate to determine the cause of renal disease, in this case the medullary findings were unusual and diagnostically challenging. The medulla contained multiple distinct aggregates of cells undergoing trilineage hematopoiesis, diagnostic of extramedullary hematopoiesis (EMH). Throughout the renal cortex and medulla, there were diffuse tubular degenerative changes and atypical fractured tubular casts with adherent monocytes, typical of myeloma cast nephropathy. The diagnosis of myeloma cast nephropathy, ␭ type, subsequently was confirmed by immunofluorescence and bone marrow biopsy. The combination of findings raised the question: What is the diagnostic and prognostic significance of EMH in the setting of myeloma cast nephropathy?

American Journal of Kidney Diseases, Vol 46, No 4 (October), 2005: pp 780-786

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Fig 1. (A) Low-power view shows a dense cellular infiltrate within the renal medulla. (B) Tubules within the medulla contain atypical, markedly eosinophilic, fractured casts. The casts are associated with adherent monocytes and a focal multinucleated giant cell (bottom left). The appearance of the casts is typical of myeloma cast nephropathy. (continued)

Clinical Follow-Up The patient began hemodialysis therapy and was referred for oncological evaluation. Bone marrow biopsy showed hypercellular marrow (90% cellularity), with 80% plasma cells. Plasma cells stained diffusely positive for ␭ light chain and negative for ␬ light chain, confirming the diagnosis of multiple myeloma. An increase in marrow fibrosis was noted. Urine immunoelectrophoresis showed ␭ Bence-Jones protein. Serum protein electrophoresis showed abundant free ␭ light chains. Initial treatment consisted of 3 cycles of pulse dexamethasone and thalidomide. The patient had a rapid response and hemodialysis therapy was discontinued. Serum creatinine decreased to 3.4 mg/dL (301 ␮mol/L) at 1

month after renal biopsy and 1.6 mg/dL (141 ␮mol/L) at 3 months after biopsy. The patient subsequently was treated with cyclophosphamide, dexamethasone, etoposide, and cisplatinum; underwent peripheral-blood stem cell collection; and then underwent high-dose melphalan (200 mg/ m2) peripheral-blood stem cell transplantation at 8 months after renal biopsy. At 12 months after renal biopsy, the patient had a serum creatinine level of 1.9 mg/dL (168.0 ␮mol/L), 24-hour urine protein excretion of 378 mg/d, and hematocrit of 42.1%. At 18 months after renal biopsy, the patient has a creatinine level of 2.0 mg/dL (177 ␮mol/L). Urine immunoelectrophoresis continues to show a faint ␭ band.

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Fig 1. (continued) (C) A cluster of maturing myeloid cells with angulated nuclei and pink granular cytoplasm. (D) Myeloid lineage is confirmed by immunohistochemical staining for myeloperoxidase. (continued)

DISCUSSION

EMH is defined as the development of hematopoietic tissue outside the bone marrow. EMH normally is seen in many organs during embryonic and fetal life. Beyond this period, EMH is an abnormal finding most often associated with chronic idiopathic myelofibrosis (also known as agnogenic myeloid metaplasia or myelofibrosis with myeloid metaplasia).1 Other diseases associated less commonly with EMH include thalassemia, hereditary spherocytosis, sickle cell ane-

mia, congenital dyserythropoietic anemia, immune thrombocytopenic purpura, chronic myeloid leukemia, polycythemia vera, myelodysplastic syndrome, Paget disease, osteopetrosis, Gaucher disease, and iatrogenic myeloid growth factor effect.1 EMH is proposed to arise from migration of pluripotent stem cells from the bone marrow to other sites as a compensatory mechanism for chronic hematopoietic deficiency. Supporting this theory are studies showing increased circulating

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Fig 1. (continued) (E) A cluster of erythroid precursors (ie, normoblasts) with uniform, round, hyperchromatic nuclei and scant cytoplasm. (F) Erythroid lineage is confirmed by immunohistochemical staining for glycophorin. (continued)

stem cells in animal models of saponin-induced bone marrow fibrosis.2 However, bone marrow fibrosis and anemia are not always present in patients with EMH, which raises the possibility that circulating stem cells are induced by unknown factors (ie, cytokines) to differentiate into cells of hematopoietic lineage, with or without myelofibrosis.1 The most common sites of EMH in adults are liver and spleen, which are the predominant sites of EMH during the fetal period. Less common

sites of presentation of EMH in adults include the vertebral column (ie, as a paravertebral mass) and lymph nodes.1 Rare cases of EMH have been reported at virtually all anatomic sites, including but not limited to, the central nervous system, middle ear, lungs, pleura, heart, pericardium, retroperitoneum, skin, pharynx, endometrium, breast, and kidney.1 EMH can present as an incidental finding or with symptoms specific to the site of involvement, including pleural effusion, ascites, neurological deficit, cardiac tampon-

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Fig 1. (continued) (G) A megakaryocyte is present within a cluster of maturing myeloid cells. ([A-C, E, G] Hematoxylin and eosin; original magnification: [A] ⴛ200; [B-D] ⴛ400; [E-G] ⴛ600.)

ade, renal failure, respiratory failure, proptosis, and subglottic stenosis.1 Histologically, EMH appears as cellular aggregates of hematopoietic cells. The most common pattern is isolated erythroid cells, followed by erythroid precursors with megakaryocytes and trilineage hematopoiesis (myeloid, erythroid, and megakaryocytic lineages). When only a single lineage is seen, EMH may resemble leukemic infiltration, ie, granulocytic sarcoma.1 However, unlike leukemic infiltrates, EMH infiltrates do not disrupt the normal underlying architecture and show a normal spectrum of hematopoietic maturation. Phenotyping with immunohistochemistry often is helpful to show the presence of cells from multiple hematopoietic lineages. Immature hematopoietic cells also may be found in the outer medulla of patients with acute tubular necrosis, where they typically are confined to the lumen of dilated vasa recta and do not infiltrate the interstitium. The clinical significance of EMH is determined mainly by the underlying condition. In one study of EMH, patients with chronic idiopathic myelofibrosis had a median survival of 13 months compared with 21 months in patients with EMH unrelated to chronic idiopathic myelofibrosis.1 Treatment for EMH generally is unnecessary unless it interferes with organ function. Successful treatment of EMH has been reported with red blood cell transfusion, surgical interven-

tion, chemotherapy with hydroxyurea, and lowdose radiation. EMH is exquisitely sensitive to radiotherapy, which currently is the treatment of choice.1,3 There are 15 detailed reports of renal EMH in the English literature4-17 (Table 1). Thirteen of 15 cases occurred in adults, with an age range of 22 to 75 years (mean, 49.5 years). The remaining 2 cases occurred in female siblings with “infantile” myelofibrosis with myeloid metaplasia.8 The underlying condition leading to EMH was chronic idiopathic myelofibrosis in 10 of 15 patients (66.7%). Clinical presentations included a single mass or multiple bilateral renal masses in 4 and 2 patients, respectively. The 2 infants presented with bilateral kidney enlargement, without discrete mass formation. Five patients presented with acute renal failure, which was associated with bilateral renal enlargement in 2 patients and bilateral obstruction of the renal pelvis in 1 case. The final 2 patients presented with nephrotic syndrome and renal biopsy findings of mesangial proliferative glomerulonephritis and membranous glomerulopathy, in addition to EMH. Information on treatment and outcome was provided in only 7 cases. Two patients had a beneficial response to hydroxyurea and 2 patients appeared to benefit from radiation therapy. An additional report describes 5 cases of EMH of the kidney in the setting of chronic idiopathic myelofibrosis, but provides limited clinical infor-

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Table 1. Reported Cases of EMH in the Kidney Age (y)

Sex

Woodward et al4 Tamiolakis et al5 Perazella and Buller6 Oesterling et al7

58 y

M

58 y

M

65 y

M

44 y

M

Fernbach and Feinstein8 Fernbach and Feinstein8 Moskovitz et al9

3 mo 5 mo 63 y

F

F

Kopecky et al10

22 y

M

Schnuelle et al11 Pamuk et al12

75 y

F

49 y

M

Holt et al13

55 y

M

Kwak and Lee14 Sharma15

59 y

F

38 y

F

Saisorn et al16 Bane et al17

35 y 72 y

F M

Reference

F

Condition

Renal Symptoms

Treatment/Outcome

Chronic idiopathic myelofibrosis Sickle cell anemia

Acute renal failure (normal size kidneys) Mass

Chemotherapy/normal renal function Not available

Chronic idiopathic myelofibrosis Chronic idiopathic myelofibrosis

Nephrotic syndrome*

Not available

Bilateral obstruction/acute renal failure

Infantile chronic idiopathic myelofibrosis Infantile chronic idiopathic myelofibrosis Chronic idiopathic myelofibrosis Acute lymphocytic leukemia Chronic idiopathic myelofibrosis Chronic idiopathic myelofibrosis Chronic idiopathic myelofibrosis Chronic idiopathic myelofibrosis Idiopathic thrombocytopenic purpura Thalassemia Chronic myelomonocytic leukemia

Enlarged kidneys

Radiation and bilateral nephrostomy tubes/resolution of acute renal failure Not available

Enlarged kidneys

Not available

Mass Multiple small masses

Hydroxyurea/no change in size of mass over 24 mo Spontaneous resolution

Acute renal failure/enlarged kidneys Nephrotic syndrome†

Hydroxyurea/discontinuation of hemodialysis (death at 7 mo) Not available

Acute renal failure/enlarged kidneys Bilateral renal masses

Radiation and busulfan/normal renal function Not available

Mass

Not available

Mass Hematuria, acute renal failure‡

Not available None/death at 7 mo

*Renal biopsy showed mesangial proliferative glomerulonephritis and EMH. †Renal biopsy showed membranous glomerulopathy and EMH. ‡Renal biopsy showed leukemic infiltrates and EMH.

mation. All 5 patients had enlarged kidneys, 2 patients had discrete masses, and 2 patients had renal insufficiency.18 In summary, we report the first case of EMH of the kidney occurring in the setting of multiple myeloma. The patient presented with acute renal failure, undoubtedly caused by myeloma cast nephropathy. EMH apparently was an incidental finding. After an excellent response to chemotherapy, the patient was able to discontinue dialysis therapy and has maintained stable renal function at 18 months after biopsy. EMH is an extremely rare finding in patients with multiple myeloma. In this patient, the finding of EMH likely represents a compensatory response to chronic hematopoietic insufficiency secondary to replacement of the bone marrow by neoplastic

plasma cells. This unusual renal finding must be differentiated from renal infiltration by hematologic malignancy. Although the finding of EMH may predict a poor prognosis, this has not proven to be the case in this patient. REFERENCES 1. Koch CA, Li CY, Mesa RA, Tefferi A: Nonhepatosplenic extramedullary hematopoiesis: Associated diseases, pathology, clinical course, and treatment. Mayo Clin Proc 78:1223-1233, 2003 2. Wand JC, Tobin MS: Mechanism of extramedullary haematopoiesis in rabbits with saponin-induced myelofibrosis and myeloid metaplasia. Br J Haematol 51:277-280, 1982 3. Weinschenker P, Kutner JM, Salvajoli JV, et al: Wholepulmonary low-dose radiation therapy in agnogenic myeloid metaplasia with diffuse lung involvement. Am J Hematol 69:277-280, 2002

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4. Woodward N, Ancliffe P, Griffiths MH, Cohen S: Renal myelofibrosis: An unusual cause of renal impairment. Nephrol Dial Transplant 15:257-258, 2000 5. Tamiolakis D, Ptassopoulos P, Simopoulos C, et al: Renal extramedullary hematopoietic tumor diagnosed by fine needle aspiration: A case report. Acta Clin Belg 58:299301, 2003 6. Perazella MA, Buller GK: Nephrotic syndrome associated with agnogenic myeloid metaplasia. Am J Nephrol 14:223-225, 1994 7. Oesterling JE, Keating JP, Leroy AJ, et al: Idiopathic myelofibrosis with myeloid metaplasia involving the renal pelves, ureters, and bladder. J Urol 147:1360-1362, 1992 8. Fernbach SK, Feinstein KA: Extramedullary hematopoiesis in the kidneys in infant siblings with myelofibrosis. Pediatr Radiol 22:211-212, 1992 9. Moskovitz B, Malberger E, Brenner B, Gaitini D, Vardi Y, Bolkier M: Renal extramedullary hematopoiesis simulating hypernephroma. Eur Urol 19:343-345, 1991 10. Kopecky KK, Moriarty AT, Antony AC, Baker MK: Extramedullary hematopoiesis in acute lymphocytic leukemia masquerading as hepatic, renal, and splenic microabscesses. AJR Am J Roentgenol 147:846-847, 1986 11. Schnuelle P, Waldherr R, Lehmann KJ, et al: Idiopathic myelofibrosis with extramedullary hematopoiesis in the kidneys. Clin Nephrol 52:256-262, 1999

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12. Pamuk ON, Pamuk GE, Altiparmak MR, Sonsuz A, Solakoglu S, Kilicaslan I: Nephrotic syndrome associated with agnogenic myeloid metaplasia. Leuk Lymphoma 43: 661-663, 2002 13. Holt SG, Field P, Carmichael P, et al: Extramedullary haematopoeisis in the renal parenchyma as a cause of acute renal failure in myelofibrosis. Nephrol Dial Transplant 10: 1438-1440, 1995 14. Kwak HS, Lee JM: CT findings of extramedullary hematopoiesis in the thorax, liver and kidneys, in a patient with idiopathic myelofibrosis. J Korean Med Sci 15:460462, 2000 15. Sharma AK: Tumefactive extramedullary hematopoiesis of the kidney in a patient with idiopathic thrombocytopenic purpura. AJR Am J Roentgenol 167:795-796, 1996 16. Saisorn I, Leewansangtong S, Sukpanichnant S, Ruchutrakool T, Leemanont P: Intrarenal extramedullary hematopoiesis as a renal mass in a patient with thalassemia. J Urol 165:507-508, 2001 17. Bane AL, Enright H, Sweeney EC: Chronic myelomonocytic leukemia revealed by uncontrollable hematuria. Arch Pathol Lab Med 125:657-659, 2001 18. Redlin L, Francis RS, Orlando MM: Renal abnormalities in agnogenic myeloid metaplasia. Radiology 121:605608, 1976