Mantle Cell Lymphoma associated with Membranoproliferative and Membranous Glomerulonephritis : Report of Two Cases

Mantle Cell Lymphoma associated with Membranoproliferative and Membranous Glomerulonephritis: Report of Two Cases Elena Zakharova1*, Ekaterina Stolyarevich2, Eugeny Nikitin3 1Nephrology Department, Head, Moscow City Botkin Memorial Hospital 2Nephropathology Department, Head, Moscow City Nephrology Centre 3Hematology Day Patient Department, Head, Moscow City Botkin Memorial Hospital Cancer Science & Research: Open Access Open Access Case Report


Introduction
Renal involvement in patients with Non-Hodgkin Lymphomas (NHL) with a broad spectrum of clinical and pathology variants has been widely described in the literature.Clinical presentations include Acute Kidney Injury (AKI), Nephrotic Syndrome (NS), proteinuria and/or hematuria, arterial hypertension or Chronic February 2011 after respiratory illness with high-grade fever her proteinuria increased to 6.0 g/L, she was admitted to the local hospital.Work-up found Hb 9.9 g/dL, ESR 120 mm/hour, serum creatinine 179 µmol/L, urea 8.8 mmol/L, total protein 5.6 g/dL, LDH 551 U/L, other total blood count and blood chemistry tests, as well as coagulation tests were within normal range.Proteinuria spontaneously decreased to 2.0 g/L, urine sediment contained RBC 90-100 hpf.Electrocardiogram was normal, echocardiography showed mild left ventricular hypertrophy.Kidney, abdomen and pelvis ultrasound were unremarkable but solitary liver cyst.Thyroid gland ultrasound revealed nodular goiter with slightly enlarged regional lymph nodes (thyroid hormones within normal range).Plain chest and skeletal X-ray didn't find anything significant; however total body CT revealed mediastinal and abdominal lymph nodes enlargement.Serum and urine immunochemistry detected high β2-microglobuline level, increase of circulating immune complexes, containing IgG, IgA, IgM and C3, and traces of Bence-Jones kappa light chains in the urine.She was referred to our clinic for kidney biopsy.
At admission: conscious, alert, slightly depressed.Body temperature 36.9°C,RR 18 per minute, pulse regular 80 per minute, BP 150/80 mm Hg.Pale, slightly undernourished, with moderate pedal edema.HEENT otherwise normal.Single small, soft, painless right anterior cervical lymph node, other peripheral lymph nodes not felt.Lungs: clear.Heart: regular rhythm, no murmur.Abdomen soft, non-tender, bowel sounds normal.Liver, spleen and kidneys not felt.Urine normally coloured, urine output 800 ml/24 hours.Routine work-up data were consistent with the previous evaluation.

Kidney Biopsy
Light microscopy: sections of formalin fixed paraffinembedded tissue were stained with H&E, Masson's trichrome, periodic acid-Shiff and Congo red.11 glomeruli were found, all of them enlarged, with lobular appearance due to the mesangial and endocapillary proliferation.Capillary walls thickened, some of them double-contoured [Figure 1].Interstitial edema, diffusefocal intensive interstitial infiltration with lymphocytes and neutrophils [Figure 2].Arteries and arterioles otherwise normal.Congo red staining was negative.
Infections screening: RPR-test for Тreponema Pallidum, HBsAg, anti-HCV and anti-HIV-antibodies and tuberculin skin test -all negative, CRP within normal range.

Repeated Serum and Urine Immunochemistry:
Immunoglobulines within normal range, non-selective glomerular proteinuria 3.0 g/24 hours, monoclonal secretion not detected.Follow-up: during the next 4 years the patient was regularly evaluated in the outpatient setting.She was receiving L-thyroxin, ARB's and diuretics, and doing well.Her edema resolved; blood pressure was well controlled; she gained 4 kilograms of weight.Repeated serum and urine immunochemistry, kidney and abdomen ultrasound, chest CT and gastroscopy did not show any significant changes.At the follow-up visit in April 2015 her proteinuria decreased to 1.3 g/24 hours, her total protein became normal and creatinine decreased to 106 µmol/L.July 2015 she developed high-grade fever, face puffiness and neck lymph nodes enlargement, which resolved spontaneously.August 2015 she again developed fever with her legs flush skin, resolved spontaneously.September 2015 she developed chill, nausea, skin rush, loin erythema, and was re-admitted to our nephrology unit October 1 2016.Liver, spleen and kidneys not felt.Urine normally coloured, urine output 1400 ml/24 hours.

Cervical lymph node biopsy
Light Microscopy: subtotal effacement of the lymph node architecture with follicle-like structures with rather narrow germinal centers and distinctly expanded mantle zone, presented with small lymphoid cells with the uniform disperse chromatin pattern and angular nuclei; with confluence areas in the interfollicular zone.Some follicles demonstrate germinal centers colonization by small lymphoid cells with irregular nuclei form.Throughout some spread intermediate sinuses are contoured and filled with hystocytes with admixture of small lymphoid cells.
Immunohistochemistry: using anti CD5, CD10, CD20, CD23, BCL-2, BCL-6, Ki-67 and CyclinD1 antibodies: folliclelike structures cells express CD20, cells of distinctly expanded mantle zone with confluent areas and proliferates formation in the cortical zone express CD%, CyclinD1, BCL-2.Reaction with anti CD10 and BCL-6 antibodies in malignant cells are negative (positive are only cells of colonized preexisting follicles light germinal centers).Proliferative activity index Ki-67 is average 10%, high in the germinal centers of preexisting follicles.CD23 staining reveals reduced net of follicular dendritic cells in the follicle-like structures with signs of colonization.

Pathologist
Conclusion: pathology findings and immunophenotype are characteristic for mantle cell lymphoma, classic variant, with mainly mantle-cell growth and subtotal involvement of the lymph node.

Repeated bone marrow biopsy (light microscopy):
findings are same as in 2011, lymphoid hyperplasia is not seen.

Mantle Cell Lymphoma associated with Membranoproliferative and Membranous Glomerulonephritis: Report of Two Cases
Copyright: © 2016 Zakharova et al.

Case 2
Caucasian male, year of birth 1948, first admitted to our nephrology unit September 21 2015.
Main Complains: edema, decreased urine output, dyspnea at exercise and skin rush.
Previous medical history: inguinal hernia, right leg superficial veins non-occlusive thrombosis with phlebectomy in 2013, taking warfarin, and then aspirin.

History of Present Illness:
April 2015 he felt dizziness and experienced seeing spots, his blood pressure was found as high as 200/130 mm Hg.He received ACE-inhibitors and diuretics.His blood pressure decreased to 140/80mm Hg.Outpatient work-up found proteinuria 3.5 g/L, ESR 54 mm/hour, serum creatinine 166 µmol/L, total protein 5.0 g/dL, cholesterol 8.5 mmol/L, other blood chemistry and total blood count parameters within normal range.Prostate-specific antigen, thyroid hormones, CRP and rheumatoid factor -otherwise normal.Electrocardiogram and echocardiography showed nothing but mild left ventricular hypertrophy.Plain chest X-ray unremarkable.Abdomen and kidney ultrasound and abdomen MRI found only moderate hepatomegaly and gall stones.Gastroscopy and colonoscopy revealed gastric polyp, multiple colon polyps and giant cecum polyp (hyperplastic by histology).He was continued on ACEinhibitors, diuretics and aspirin and was doing well till September 2015, when he developed massive edema and was referred to our clinic.

Kidney Biopsy
Light Microscopy: sections of formalin fixed paraffinembedded tissue were stained with H&E, Masson's trichrome, periodic acid-Shiff and Congo red.14 glomeruli were found, all of them enlarged, without proliferative changes.Capillary walls thickened, single-contoured (Figure 4).Diffuse-focal interstitial fibrosis and tubular atrophy about 10% of parenchyma with concomitant lymphohystocyte infiltration in the areas of sclerosis.Arteries with muscle layer hypertrophy and arteriosclerosis, arterioles otherwise normal (Figure 5).Congo red staining was negative.
Infections Screening: RPR-test for Тreponema Pallidum, HBsAg, anti-HCV and anti-HIV-antibodies and tuberculin skin test -all negative, CRP within normal range.

Low Extremities Doppler Ultrasound: occlusive thrombosis of distal common femoral vein and long saphenous vein.
Membranous Glomerulonephritis: Report of Two Cases.Cancer Sci Res Open Access 3(1): 1-7.

Mantle Cell Lymphoma associated with Membranoproliferative and Membranous Glomerulonephritis: Report of Two Cases
Copyright: © 2016 Zakharova et al.
Pathologist conclusion: pathology findings and immunophenotype are characteristic for mantle cell lymphoma.

Bone Marrow Biopsy
Light Microscopy: Elements of all three hematopoietic lineages are present, 4 lymphoid intra-and paratrabecular cell clusters.

Pathologist Conclusion:
Pathology findings and immunophenotype are characteristic for mantle cell lymphoma.
Treatment and Follow-Up: During hospital stay the patient received antihypertensive medications, diuretics and anticoagulants and antiplatelet agents.His edema subsided, urine output increased, and his right leg veins thrombosis was recanalized.For lymphoma treatment the patient was given 6 cycles of RB (ribomustine and rituximab) since December, 2015 to June, 2016 with subsequent rituximab maintenance.At the latest follow-up visit (October 3 2016) he was doing well, edema almost completely resolved, blood pressure 140/85 mm Hg, peripheral lymph nodes not palpable.His total blood count parameters were normal, proteinuria decreased from 8.6g/24 hours to 4.0g/24 hours, serum total protein increased from 3.7 g/dL to 5.5 g/dL, serum creatinine decreased from 266 µmol/L to 121 µmol/L.
Final Diagnosis: Mantle cell lymphoma; stage IV, with peripheral lymph nodes, bone marrow and gastric involvement (MIPI=7, high risk: age 67, LDH 1.5 times higher upper normal

Mantle Cell Lymphoma associated with Membranoproliferative and Membranous Glomerulonephritis: Report of Two Cases
Copyright: © 2016 Zakharova et al.
Our first case presented with proteinuria, microhematuria and impaired renal function, her kidney biopsy revealed immune-complex MPGN.Given the peripheral and visceral lymph nodes enlargement, weight loss, elevated LDH, high number of serum immune complexes, mild Bence-Jones proteinuria and well-established association of immune-complex MPGN with blood malignancies [8] we suspected lymphoma or lymphoplasmacytic lymphoma, but bone marrow biopsy didn't have any diagnostic yield, peripheral lymph nodes were not available for the biopsy due to the small size, and repeated test didn't detected monoclonal proteins neither in the serum or in urine.At that point we considered thyroid cancer to be causative for lymphadenopathy and immune-complex MPGN; however thyroidectomy with thyroid and regional lymph nodes pathology study ruled out this diagnosis.Patient was doing well under nephroprotective treatment, and demonstrated skin vasculitis and lymph node involvement progression after 4 years of followup.Her neck lymph node biopsy, performed almost 6 years after the first presentation of the disease, was confirmative for MCL.We suppose that MCL was complicated by paraneoplastic MPGN at the onset; however renal manifestations dominated over lymphoma signs and symptoms, which hampered the diagnosis despite of the high index of clinical suspicion and repeated targeted search.Chemotherapy, started after MCL diagnosis lead to the regression of lymph nodes and spleen involvement, and also resulted in the decrease of proteinuria and disappearance of hematuria with the stabilization of renal function.Of interest her serum creatinine already decreased before the chemotherapy start, reflecting the fact she had AKI on the top of CKD.As lymphoid infiltration of kidney was not found by biopsy, we presume that elements of nonspecific interstitial edema were responsible for her AKI at the time of biopsy.
Our second case presented with severe nephrotic syndrome, arterial hypertension and impaired renal function, his kidney biopsy revealed MN.Given the peripheral lymph nodes enlargement, gastric neoplasm, normal anti-phospholipase A2 receptor antibodies level, and well defined paraneoplastic origin of almost 25% of MN cases [4][5][6] we suspected gastric malignancy.Gastrobiopsy findings ruled out gastric cancer and were characteristic for MCL; bone marrow biopsy confirmed the diagnosis.Important finding was positive lupus anticoagulant, taken together with two episodes of vein thrombosis this is suggestive for antiphospholipid syndrome.We could not repeat the test for lupus anticoagulant, but this diagnosis (even though not proven) is very likely, as secondary antiphospholipid syndrome was described in patients with lymphomas [28,29].We presume that in this case MCL was complicated by paraneoplastic GN at the onset or soon after the onset, but the severity of renal manifestations masked lymphoma signs and symptoms and defined the diagnostic algorithm.MN pattern, found by kidney biopsy, guided the search for malignant disease, which promptly lead the diagnosis of lymphoma.However, the type of lymphoma was unexpected as MN was not previously described in MCL.Chemotherapy started after the MCL diagnosis resulted in the substantial decrease of proteinuria with the increase of serum total protein and restoration of renal function.The latter reflects CKD with superimposed AKI due to severe nephrotic syndrome.AKI resolved along with its partial remission of NS.It is worthy of special notice, that his serum creatinine decreased more than by half -from 266 µmol/L to 121 µmol/L.

Conclusion
Paraneoplastic glomerulonephritis in MCL is a rare condition, occasionally described in the literature.Renal biopsy is crucial for the diagnosis.In our two patients renal disease manifestations dominated in the clinical presentation and demanded kidney biopsy.Pathology patterns of immune-complex MPGN and MN defined high index of suspicion for malignant disease and guided targeted search, resulted in MCL diagnosis.To our knowledge this is the fifth description of MPGN and first description of MN in patients with MCL.Chemoptherapy for MCL in both cases resulted in partial remission of glomerulonephritis with restoration of renal function.

Bone Marrow Biopsy (light microscopy): Medullary
: conscious, alert.Body temperature 36.4°C,RR 17 per minute, pulse regular 64 per minute, BP 140/90 mm Hg.Obese (BMI 32).Skin normally coloured, with few macular rush elements on the low extremities.Massive low extremities, scrotal and penile edema.HEENT otherwise normal.Soft, painless right axillary and left supraclavicular lymph nodes up to 25 mm in diameter.Lungs: clear.Heart: regular rhythm, no murmur.Abdomen soft, non-tender, bowel sounds normal.Liver, spleen and kidneys not felt.Urination difficulty due to the penile edema, urine output 600 ml/24 hours.