Cryoglobulinemic Nephropathy, Difficulties in Diagnosis of Non-Hodgkin’s Lymphoma – Case Report
Published Date: November 18, 2016
Cryoglobulinemic Nephropathy, Difficulties in Diagnosis of Non-Hodgkin’s Lymphoma – Case Report
Paulina Trzebiatowska1, Barbara Bullo-Piontecka1, Alicja Debska-Slizien1, and Agnieszka Perkowska-Ptasinska2
1University Clinical Centre in Gdansk, Clinic of Nephrology, Transplantation and Internal Medicine, 80-952 Gdansk, Debinki 7, Poland
2University of Warsaw, Clinic of Transplantation, Nephrology and Internal Medicine Transplantation Institute, 02-006 Warszawa, Nowogrodzka 59, Poland
*Corresponding author: Paulina Trzebiatowska, University Clinical Centre in Gdansk, Clinic of Nephrology, Transplantation and Internal Medicine, 80-952 Gdansk, Debinki 7, Poland, Tel: +48-583-492-557; Fax: +48-583-491-186; E-mail: firstname.lastname@example.org.
Trzebiatowska P, Bullo-Piontecka B, Debska-Slizien A, Perkowska-Ptasinska A (2016) Cryoglobulinemic Nephropathy, Difficulties in Diagnosis of Non-Hodgkin’s Lymphoma – Case Report. Arc Cas Rep CMed 2(4): 131. https://doi.org/10.19104/crcm.2016.131
Cryoglobulinemia is defined as the presence of specific immunoglobulins in serum (cryoglobulins), which demonstrate reversible precipitation at the temperature below 37°Celsius. In many cases production of cryoglobulins is the consequence of a hidden disease process (infection, e.g. HCV; lymphoproliferative or autoimmune diseases). In this study we present the case of a 54-year-old male patient with cryoglobulinemic vasculitis and nephropathy. Initially, the patient was diagnosed with essential mixed cryoglobulinemia (EMC). However, additionally, there were some abnormalities, difficult to explain: low platelets and hemoglobin level, together with hepatosplenomegaly. This prompted further investigations towards lymphoproliferative disease. At the time, bone marrow biopsy and immunophenotyping of peripheral blood lymphocytes detected MLDUS ( monothypic lymphoproliferative disorder of undetermined significance), so-called “early lymphoma”. After the next five years (2009-2014) of close follow-up and regular investigations, the diagnosis of non-Hodgkin’s lymphoma (NHL) was established. In this report we present diagnostic and therapeutic problems and challenges, which appeared prior to the correct diagnosis of the disease which caused cryoglobulinemia. The paper shows 15-years observation of the course of vasculitis, and discusses important issues connected with cryoglobulinemia, lymphoma and nephropathy.
Keywords: Cryoglobulinemia; Lymphoma; Nephropathy
P: Prednisone; CYC: Cyclophosphamide; TPE: Therapeutic Plasma Exchange (Plasmapheresis); MP: Methylprednisolone; MTX: Methotrexate; AZA: Azathioprine; RTX: Rituximab; R-COP: Rituximab, Cyclophosphamide, Vincristine, Prednisone; MMF: Mycophenolate Mofetil; DUB: Diurnal Urinary Protein Loss; HGB: Hemoglobin; PLT: Platelet Count; C4, C3 – C4, C3 Complement Protein; RBC: Red Blood Cells; MC: Mixed Cryoglobulinemia; ESRD: End Stage Renal Disease; DAA: Direct Acting Antivirals; EMC: Essential Mixed Cryoglobulinemia; CT: Computer Tomography; B-Cell NHL: B-Cell Non-Hodgkin’s Lymphoma; HPF: High-Power Field; RF: Rheumatoid Factor; ANA: Anti Nuclear Antibodies; ANCA: Anti-Neutrophil Cytoplasmic Antibodies; MLDUS: Monothypic Lymphoproliferative Disorder Of Undetermined Significance; HIV: Human Immunodeficiency Virus, HBV: Hepatitis B Virus; HCV: Hepatitis C Virus; ESR: Erythrocyte Sedimentation Rate; LE Cells: Lupus Erythematosus Cells; USR: Unheated Serum Reagin (Test in the serology of syphilis), NHL: Non-Hodgkin Lymphoma.
Cryoglobulinemia is defined as the occurrence of specific immunoglobulins in serum (cryoglobulins), which demonstrate reversible precipitation at lower temperatures [1,2]. This may be asymptomatic, or it may lead to the clinical syndrome of systemic vasculitis, caused by formation of deposits of cryoglobulin in the walls of blood vessels - cryoglobulinemic vasculitis . In most of clinical cases production of cryoglobulins is the consequence of another condition . There are three types of cryoglobulins. In type I, monoclonal cryoglobulins occur mainly in the course of multiple myeloma, Waldenström macroglobulinemia, monoclonal gammopathy, lymphoproliferative diseases or immunoglobulin light chain disease; the cryoglobulins most commonly belong to the IgM class, and less frequently to IgG, IgA or light chains. Cryoglobulins of type II (characterized by presence of monoclonal IgM, with rare occurrence of IgA or IgG in complex with polyclonal IgG) and type III (occurrence of polyclonal IgM in complex with IgG) are considered mixed types (mixed cryoglobulinemia), and most commonly they develop secondary to chronic infections (HCV, HBV, syphilis, Lyme Disease and others). They may also develop in the course of autoimmune (SLE, RA, Sjögren syndrome) and lymphoproliferative diseases [1,5]. The most common cause of MC is chronic HCV infection (more than 80% of the patients) , while infection with other hepatitis viruses rarely contributes to MC (HBV < 5% of the cases) [5,7,8]. In some cases the triggering factor cannot be identified (essential mixed cryoglobulinemia, EMC).
The clinical picture in MC typically includes: vascular purpura, arthralgia, and general weakness, all three together compose so-called Meltzer triad, identified in the majority of patients at the time of diagnosis. Other findings include: changes in the kidneys and gastrointestinal tract, hepatosplenomegaly, peripheral neuropathy. Cutaneous changes in the form of raised purpura appear in almost all patients (98%). However, the disease may also manifest with some other skin changes as urticaria, livedo reticularis or ulcerations [2,5,6]. Also, there might be vascular lesions in the form of skin necrosis, especially in the distal phalanges of both upper and lower limbs .
Involvement of the kidneys in mixed cryoglobulinemia manifests mostly with proteinuria with microscopic erythrocyturia. Nephrotic syndrome may develop in about 20% of patients. Dominant in renal biopsy is the picture of membranoproliferative glomerulonephritis with the presence of immune complexes (usually IgM, IgG, C3 and C1q) located in the glomerular mesangium, within the capillary walls (subendothelial or intrabasilar, and (very rarely subepithelial deposits), and also within the capillary lumen (typical picture of “pseudothrombi”). At the level of ultrastructure (analysis with electron microscope), deposits of immune complexes are either amorphous, or take some more organized form (microtubules, “fingerprint” deposits). Arterial hypertension is detected frequently (in about 80% of patients with MC) and is present from the very onset of disease, even in patients without signs of nephropathy. In the majority of cases renal involvement develops slowly, and does not lead to end stage renal disease (ESRD), in spite of persistent abnormalities in urine analysis and a certain degree of renal failure [10,11].
Treatment of cryoglobulinemia depends on its type, severity of signs and symptoms, as well as the background disease. The therapy is aimed at reduction of in vivo cryoglobulin precipitation and the ensuing inflammatory lesions. Treatment is not required in asymptomatic patients, even if they have high readings of cryocrit (percentage content of cryoglobulins in serum) . In patients with mild to medium-degree manifestations of disease (purpura, arthralgia, peripheral sensory neuropathy) low-dose steroids are used as the first-line therapy. Patients with severe MC (nephropathy, skin ulcerations, motor-sensory neuropathy, and generalized vasculitis) are treated with high-dose steroids, optionally in combination with cyclophosphamide (CYC). An effective form of therapy can also be removal of the circulating immune complexes with plasmapheresis (TPE), especially in patients with active nephropathy . Considering the fact that MC in HCV-positive patients is associated with a process of antigen stimulation, the most effective therapy consists of the eradication of HCV. Antiviral therapy must be adjusted on an individual basis; due to restrictions concerning the use of INF and ribavirin [1,13]. Recently, also, some new antiviral agents of much greater efficacy against HCV infection have become available, so-called direct acting antivirals (DAA) . Efficacy of DAA in treatment of cryoglobulinemia in the course of HCV infection has not been definitely established .
An advance in treatment of cryoglobulinemia in the course of B-lymphocyte clonal proliferation is the use of rituximab, chimeric monoclonal antibody against CD20 antigen expressed on the surface of B lymphocytes [1,13].
This study describes the clinical case of a patient with a long history of cryoglobulinemic vasculitis and cryoglobulinemic glomerulonephritis, with the cause of cryoglobulinemia remaining undetermined for several years (EMC), until the diagnosis of Non-Hodgkin’s Lymphoma (NHL) was established 10+ years later.
The patient, a 54-year-old male, was referred to the nephrology outpatient clinic with suspicion of nephropathy in the course of vasculitis in 2008. The course of disease is presented in Table 1. The first manifestations of disease appeared at the break of 1999/2000 and included: weakness, fever, recurrent pharyngeal infections, conjunctivitis and diarrhea with a minor admixture of fresh blood. Due to prolonged diarrhea, the patient was hospitalized for evaluation at the Infectious Diseases Hospital (Jan., 2000), where the infectious cause of diarrhea was ruled out, but suspicion of a systemic connective tissue disease was raised. During another hospitalization (Rheumatology Hospital, Jan., March, 2000) the patient was also presenting arthro-muscular complaints (mainly in the lower limbs), sensation disorders in the left lower limb, and periodically severe abdominal pain. Haemorrhagic rash appeared on the skin, and vesicular lesions emerged on the skin of the feet. Also signs of paresis of the dorsiflexor muscles of the left foot and signs of hypoesthesia were observed. Given such a clinical picture, diagnosis of peroneal neuritis (mononeuritis multiplex) was established. Arterial blood pressure ranged from normal levels 120/85 mmHg to 170/105 mmHg. Laboratory tests performed during hospitalization revealed anemia with hemoglobin 12 g/dL, increased levels of markers of inflammation (ESR 44-65), positive Waaler-Rose test (1:160), positive latex fixation test, positive LE cell test, and falsely positive USR reaction. Platelet count (288 K/mm3), WBC (6.1 K/mm3), and creatinine level (0.8–0.9 mg/dL) were within the normal ranges. Tests for anti-nuclear antibodies, anti-DNA and HBsAg antigen were negative. In the light of these results, suspicion of polyarteritis nodosa was raised. Oral therapy with prednisone (P) 40 mg/day and CYC 100 mg/day was applied with a resulting major clinical improvement. The patient remained under the care and supervision of the rheumatology outpatient clinic. At that time the presence of c-ANCA antibodies was detected once (titer 1:320; Jan., 2001), with a re-test proving negative, and no recurrence of positive results throughout the follow-up period. Treatment with CYC was continued for 1 year, dose 50 mg/day, and then methotrexate (MTX) (July, 2001 – May, 2002), and later azathioprine (up to Oct., 2008) were used as maintenance therapy. Increased creatinine level was first detected in 2001 (1.33 mg/dL), and erythrocyturia in 2002. Until 2008 proteinuria was not noted, and creatinine concentration was mostly within the normal range, or was only slightly elevated. During the follow-up period in the outpatient setting, purpura of varied intensity was continuously observed on the lower limbs, and testing for serum cryoglobulin was positive. Diagnosis of MC (type II) was established. The patient was tested for HCV RNA to check for the most common cause of MC, with a negative result. Due to occurrence of signs of active nephropathy: proteinuria about 2.0 g/day, erythrocyturia and exacerbation of manifestations of cryoglobulinemia (severe skin lesions, progression of arterial hypertension, abdominal complaints), in 2008 the patient was referred to the nephrology outpatient clinic, and then to the Department of Nephrology for further evaluation and treatment. In Oct., 2008 a kidney biopsy was taken, which revealed proliferative inflammatory changes in the mesangium, and within the capillaries of some glomerular segments, as well as segmental crescent cells in 5 out of 30 non-sclerotic glomeruli - membranoproliferative glomerulonephritis (Figures 1–3). Immunomorphology examination revealed only trace deposits of IgM and C3 in some glomerular segments (Figure 4). Ultrastructural examination confirmed signs of inflammation and proliferation in the mesangium and within the glomerular capillaries, and demonstrated doubling of the contour of some glomerular capillaries, but did not reveal the presence of electron-dense deposits in glomerular structures. Laboratory tests done in that period did not reveal abnormalities in the peripheral blood count, whereas creatinine level increased to 1.4 mg/dL and persistent proteinuria and erythrocyturia were noted. Immunological assays revealed a positive rheumatoid factor (534 IU/mL), increased IgM (4.4 g/L), decreased IgG (3.17 g/L) and IgA (0.5 g/L), as well as decreased C4 (0.04 g/L) and a normal level of C3 (1.17 g/L). Viral hepatitis C was excluded again; however, status post HBV infection was confirmed by positive results for both anti-HBc and anti-HBs. HBV virus presence was not detected (negative testing for HBV DNA). Liver function tests were normal. In Nov., 2008, due to severe manifestations of the disease, plasmapheresis was performed three times and pulse doses of methylprednisolone (MP) were given (3 × 1.0 g). Oral treatment with AZA was continued. In March, 2009, due to progressing severity of nephropathy – increasing proteinuria (daily protein loss 3.61 g) and erythrocyturia – the patient was hospitalized again at the Department of Nephrology. At that time the cryocrit value was 87.5 %. Also decreased IgG (2.28 g/L) and IgA (0.36 g/L), as well as increased IgM (7.05 g/L) were detected. Treatment with pulse doses of CYC was initiated. In total, the patient was administered six pulse doses of CYC, 1.0 g each (Apr.-Oct., 2009). In Oct., 2009 anemia with HGB decreased to 10.8 g/L, thrombocytopenia with PLT 104 K/mm3, and an increase of creatinine level up to 1.6 g/dL were observed. At that time diagnostics towards lymphoproliferative diseases were carried out. Bone marrow biopsy, CT-scan of the abdomen and chest, and immunophenotyping of lymphocytes of peripheral blood were performed. Bone marrow biopsy revealed an increased percentage of lymphoid cells and immunophenotyping of peripheral lymphocytes demonstrated an increased percentage of B cells, and expression of one type of kappa light chains. It was adjudicated, however, that there was no ground for the diagnosis of a lymphoproliferative disease. In the CT-scan a slight enlargement of the spleen (dimensions 14 × 10 cm) was noted. At this stage, the earlier HBV infection was assumed to be the cause of cryoglobulinemia. Following CYC therapy, a gradual improvement of renal parameters (reduction of proteinuria and erythrocyturia), as well as regression of cutaneous lesions were observed. After four pulse doses of CYC, cryocrit decreased to 21% (Figure 5). In Nov., 2009 mycophenolate mofetil (MMF) 0.5 g b.i.d. was added to treatment as maintenance therapy. Further clinical improvement and reduction of markers of cryoglobulinemia were observed. Cryocrit was decreasing steadily (May, 2010: 11.43 %). In 2010 proteinuria ranged from 0.47 to 0.99, periodically minor erythrocyturia was noted, serum creatinine level was about 1,1 -1,3 mg/dL. Minor thrombocytopenia persisted (PLT about 120 K/mm3) and anemia (HGB ca. 12 g/L), without leukopenia. No new cutaneous lesions were observed.
Table 1: The Clinical Course and Outcome of the Presented Patient with Cryoglobulinemia. (P – prednisone; CYC – cyclophosphamide; TPE- therapeutic plasma exchange(plasmaferesis); MP – Methylprednisolone; MTX – methotrexate; AZA – azathioprine; RTX – rituximab; R-COP – rituximab, cyclophosphamide, vincristine, prednisone; MMF – mycophenolate mofetil; HGB – hemoglobin; PLT – platelet count; C4, C3 – C4, C3 complement protein; RBC – red blood cells; EMC- essential mixed cryoglobulinemia; B-cell NHL - B-cell non-Hodgkin’s lymphoma; RF – rheumatoid factor; ANA – anti nuclear antibodies; HBV – hepatitis B virus; ESR - erythrocyte sedimentation rate; LE cells- Lupus Erythematosus cells; USR - unheated serum reagin (test in the serology of syphilis), NHL - Non-Hodgkin lymphoma)
In Apr., 2010 the patient had an episode of hemorrhage from the lower portion of the gastrointestinal tract and in May, 2010 he had an episode of pulmonary embolism.
In Nov., 2011 the patient complained of periodic occurrence of subfebrile states, weight loss (about 6 kg), appearance of edema of the lower limbs, and new sites of purpura on the skin. Diurnal proteinuria increased again up to 3.06 g, erythrocyturia was present, creatinine level was 1.1 mg/dL, and blood count revealed anemia with HGB 11 g/dL and thrombocytopenia with PLT 101 K/mm3. Patient did not consent to a new renal biopsy. Treatment was continued: steroids and MMF 1.0 g/day.
Figure 1: Most of the segments demonstrate increased cell content, also within the lumen of the glomerular capillaries. In some capillaries neutrophiles are seen. A small area of necrosis of the bundle (arrow) and a minor crescent cell (double arrow). H-E staining.
In the period from 2012 till May, 2014, and particularly from 2013, remission of nephropathy was observed (daily protein loss 0.3-0.4 g, without erythrocyturia, creatinine normal). The only deviation from normal in laboratory tests was persistent thrombocytopenia with PLT down to 89 K/mm3 and anemia with HGB about 12 g/dL. Cryocrit value was 4.55%. A follow-up CT-scan was performed and revealed hepatosplenomegaly (spleen dimensions 210 × 77 mm), no evidence of enlarged lymph nodes. Treatment was continued: MMF 1.0 g/day, Prednisone 5.0 mg/day.
Figure 2: A major distension of the mesangium associated with gain in cell count and matrix in the area (segmental mesangial proliferation) was seen in the left upper segment of the vascular bundle. In the right lower segment – gain in extracellular matrix of the mesagium (mesangial sclerosis). AFOG staining
At the break of May/June, 2014, following a viral upper respiratory tract infection complicated with bronchitis, aggravation of manifestations of disease occurred, including exacerbation of markers of nephropathy: increase of serum creatinine to 1.68 mg/dl, re-occurrence of erythrocyturia (entire HPF covered), increase of diurnal proteinuria to 1.35 g and exacerbation of cutaneous lesions, increase of peripheral edema and deterioration of control of arterial blood pressure. Anemia with HGB 11.9 g/dL, and thrombocytopenia with PLT 71 K/mm3 were again observed. Patient was referred to the department for extended diagnostics. During hospitalization MMF was discontinued and pulse doses of MP (3 × 0.5 g) were administered. Comprehensive diagnostics towards the secondary causes of cryoglobulinemia were carried out. CT-scans of the chest and abdomen did not reveal lymphadenopathy, but the previously reported hepatosplenomegaly was noted again: spleen non-homogenous, dimensions 174 × 95 mm. Bone marrow biopsy was taken and immunophenotyping of peripheral blood lymphocytes was performed again. Bone marrow biopsy revealed signs of infiltration with lymphoid cells. Based on immunophenotyping of peripheral blood lymphocytes, a picture of B-cell NHL was identified. Diagnosis of splenic marginal zone lymphoma with involvement of bone marrow was established. Chemotherapy with R-COP regime (rituximab, cyclophosphamide, vincristine, and prednisone) was initiated, and was applied for 8 cycles (until Jan., 2015). The applied treatment resulted in regression of renal manifestations (diurnal protein loss 0 g, without erythrocyturia), normalization of creatinine level (0.85 mg/dL), improvement of blood count parameters (HGB 14.6 g/dL, PLT 146 K/mm3), reduction of cryocrit to 1.67%, normalization of immunoglobulin levels (IgA 0.14 U/mL, IgG 9.86 U/mL, IgM 1.34 U/mL), as well as regression of cutaneous lesions and a marked improvement of the patient’s overall condition and well-being. The patient’s follow-up included one more year (until Oct., 2016), and throughout this period complete clinical and laboratory remission of the disease was observed.
Figure 3: The gain in argentophilic extracellular matrix was seen in some segments. Doubling of moderately numerous glomerular capillaries (arrow) was observed. Silver-staining with Jones method.
Figure 4: Trace deposits of IgM along the countour of some peripheral glomerular capillaries (arrow). The same picture was obtained in slides stained for the presence of C3. Immunomorphology examination.
Figure 5: Cryocrit values (percentage content of cryoglobulins in serum) across the years of follow up.
The patient who was subjected to extensive investigations and treatment for cryoglobulinemic vasculitis with renal involvement for a period of fifteen years was studied in this case. In clinical practice, diagnosis of cryoglobulinemia, and especially of its background may be difficult, as in the case presented here. The suggested diagnostic criteria for MC (developed by a team of Italian researchers in 1989) are presented in Table 2 . According to these criteria the patient presented the so-called “full syndrome”.
Suggested Diagnostic Criteria for Mixed Cryoglobulinemia .
*criteria detected in the presented patient: Cryoglobulinemia – full syndrome: a) Cryoglobulins mixed type (+/- decreased C4) + purpura + leukocytoclastic vasculitis; b) Cryoglobulins mixed type (+/- decreased C4) + 2 minor clinical criteria + 2 minor serology/pathology criteria
Cryoglobulinemia – partial syndrome or probable cryoglobulinemia
a) Cryoglobulins mixed type or low C4 + 1 minor clinical criterion + 1 minor serology +/- pathology criterion; b) Purpura and/or leukocytoclastic vasculitis + 1 minor clinical criterion + 1 minor serology +/- pathology criterion; c) Two minor clinical criteria + 2 minor serology +/- pathology criteria
Essential or secondary cryoglobulinemia: Absence or presence of established contributing criteria (infectious, immunological or malignancy-related).
Based on retrospective analysis of the course of the disease, we may suppose the lymphoma could have been developing for many years in a latent manner, or initially the patient suffered from “early B-cell lymphoma”. The term “early lymphomas” is used to describe expansion of peripheral B lymphocytes and their infiltration in the liver and bone marrow. As opposed to “true lymphoma” infiltrations, those of “early lymphomas” demonstrate the tendency to remain unchanged for years, or even decades, and convert to an overt type of lymphoma in only about 10 % of the cases. “Early lymphomas” are referred to as MLDUS . However, we cannot be sure that the NHL diagnosed some years later (2014) actually developed from an “early lymphoma”. This is because the available data indicates that the clone of B lymphocytes, giving rise to a lymphoma, is usually different from that responsible for the development of MLDUS . We would consider it more likely that the patient had the lymphoma right from the start, with its latent and less easily diagnosable course due to vigorous treatment with steroids (MP, P) and CYC. It is worth noting that P and CYC are two out of four drugs included in the R-COP regime of chemotherapy. This hypothesis is supported by the course of the disease, marked with transient remissions followed by relapses of progressively greater severity, as well as by a decrease in dimensions of the spleen and liver observed following application of CYC (Table 1).
It could also be speculated that, according to the authors of this study, these are purely theoretical considerations, with treatment of MC-related vasculitis, especially CYC, favoring development of the malignant disorder [16–19]. Dependence of cancer risk on cumulative dose was described i.e. in a study on the treatment of NHL with CYC. In the group of patients who received a cumulative dose of CYC < 20 g only a non-significant increase in risk of cancer of the urinary bladder (2.4-fold) was observed, while the risk was increased to 6-fold in patients who received a total of 20-49 g, and to 14.5-fold in those who received > 50 g . Other available data demonstrates that in patients treated with CYC a high relative risk of serious malignant neoplasms appears after exceeding the cumulative dose of 36 g . The patient described in our study received a total of 30 g CYC, which could increase the risk of malignancy, but – as described above and summarized in Table 1 – exacerbations of the manifestations of disease, later discovered to be related to the development of lymphoma, occurred during the pauses in CYC therapy. We should also mention the other medications used, including AZA, MMF and MTX. Treatment with AZA and MTX increases the risk of cancerogenesis . In the period 2009-2014 the patient was receiving antiproliferative agent MMF. The available publications [23–25], concerning mainly patients after renal transplant, do not prove an increased oncogenic potential of MMF, and some authors even tend to discuss its “antineoplastic” profile . Only a few relapses of nephropathy were observed during treatment with MMF, whereas it is very likely that lymphoma was developing slowly during that period, which can be deduced from the progressive increase in dimensions of the spleen (splenic lymphoma), and occurrence of very vivid manifestations of vasculitis, which prompted another round of extensive diagnostics, and led to the diagnosis of NHL (Table 1). On the grounds of the collected data on the applied therapies, it can be concluded that with great probability the lymphoma in that patient did not result from the applied treatment of vasculitis (CYC, AZA, MMF, MTX). Particularly severe relapse of lymphoma were observed after discontinuation of CYC therapy, which is part of the R-COP chemotherapy for NHL that the patient received after the diagnosis of NHL in 2014; and which resulted in complete regression of all the manifestations of disease. Remission of the disease has continued till now (Oct, 2016).
Taking into account the whole clinical picture, it can be assumed with great probability that the patient suffered from vasculitis and glomerulonephritis in the course of MC, which was induced by NHL. However this cannot be decided whether this was the so-called “early lymphoma” which later converted into NHL, or a primary NHL diagnosed so late.
It is important, however, not to cease trying to determine the cause of cryoglobulinemia, including possible lymphoproliferative diseases. The obtained results should be interpreted in a broad context, including both the course of the disease and the effects of the applied treatments. Such an approach should particularly be taken in patients whose remissions are short, and relapses progressively more severe.
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