Unusual Manifestations of Paraprotein-Associated Hematological Diseases: Report of 2 Cases and Literature Review

    

    

    Figure 1: Peripheral blood smear (A-E) showing leukoerythroblastic reaction
and bone marrow aspirate smear (F) showing plasma cell infiltration. A: An
erythroblast; B: A plasma cell; C: A promyelocyte; D: A nucleated red blood
cell; E: A myelocyte; F: Bone marrow plasma cell infiltration.
    

At that time, based on the aforementioned clinical, laboratory and imaging findings, in our differential diagnosis we included qualitative and quantitative platelet abnormalities, other bleeding disorders and bone marrow suppression and/or infiltration due to infectious agents, malignant disorders, collagen and hematological diseases. Laboratory results were negative for the presence of antiphospholipid antibodies, her Tuberculin Skin Test (TST) and Interferon-γ Release Assay (IGRA) were also negative, while the rest of the autoimmune panel did not reveal a specific abnormality apart from low C3 and even lower C4 levels. On the other hand, serum ferritin levels were within normal limits. Bone Marrow Biopsy (BMB) was then undertaken while at the same time a bone marrow smear was examined, immunophenotyping of the bone marrow aspirate was requested and a bone marrow sample was sent in search for PML/RARa translocation due to the bleeding diathesis and the occasional presence of blasts in the PB smear. The results were negative for the presence of acute leukemia, however an increased Β2 microglobulin value at 11.4mg/lt was noted while a quantitative serum immunoglobulin test indicated an IgG of 9,000mg/dL with associated immunoparesis. Serum and urine immunofixation detected the presence of a IgGλ paraprotein, while her Positron Emitting Tomography combined with Low-Dose Computed Tomography (PET/CT) was unremarkable, just like her portal venous Doppler imaging. Finally, the patient’s result of BMB was only consistent with the presence of an IgGλ MM, since a bone marrow infiltration by monoclonal cIgGλ plasma cells by 80% was evident. The patient’s karyotype came back normal but her Lactate Dehydrogenase (LDH) value was elevated, so her Revised International Staging System (R-ISS) stage was calculated as III. The patient asked then to be referred to a tertiary Hematology Clinic with expertise in treating MM patients, in order to receive the appropriate treatment.

Case report 2

A 76-year-old male retired high-school teacher, former smoker (he had quit 30 years ago and had a smoking history of 10 pack-years), was referred to our Hematology Department because of a serum paraprotein found during evaluation of episodes of hemoptysis since 5 months ago and worsening the last 24 hours. A comprehensive systems’ review was otherwise unremarkable. The patient’s personal history included coronary artery disease with associated heart failure and his physical examination was remarkable for stage I obesity, mild hypoxia (oxygen saturation 92%) and bibasilar (but mostly on the right) coarse crackles. Our patient had been first admitted in a Pulmonary clinic due to his main symptom and abnormal findings on chest CT, i.e., crazy paving appearance and alveolar infiltrates in his Right Lower Pulmonary Lobe (RLL) with concomitant GGOs (commented on CT report as probable alveolar hemorrhage), an adjacent nodular lesion ~1cm in contact with the oblique fissure, intrathoracic lymphadenopathy (with a reported maximum diameter of 12mm), and 2 subpleural nodules with a diameter of ~2-3 mm, possibly representing granulomas. Abnormal laboratory results included absolute lymphocytosis, mild normocytic anemia, high ESR, moderate chronic kidney disease [Creatinince Clearance (CrCl) ~65ml/min and estimated glomerular filtration rate using the MDRD formula ~52ml/min/1.73 m2] with a normal urine sediment examination, a positive d-dimer test (but without any evidence of pulmonary embolism on CT pulmonary angiogram), a positive Direct Antiglobulin Test (DAT), raised levels of rheumatoid factor and low levels of complement, and a low A/G ratio. Therefore, in our differential diagnosis we included vasculitis, connective tissue disease, pulmonary alveolar proteinosis, lower respiratory tract infection, malignancy and PCD.

Bronchoscopy and Bronchoalveolar Lavage (BAL) were undertaken and revealed Diffuse Alveolar Hemorrhage (DAH). PB smear examination provided evidence of absolute lymphocytosis with small, mature lymphocytes and rouleaux formation. His PB immunophenotyping was not compatible with Chronic Lymphocytic Leukemia (CLL) diagnosis and a quantitative serum immunoglobulin test indicated raised IgG and IgM, hence at that time our differential also included a Lymphoproliferative Disease (LPD) with plasmacytic differentiation. The Bence-Jones protein urine test was negative but serum immunofixation revealed the presence of a IgGκ paraprotein. Whole-body low-dose CT was without findings and a BMB was then undertaken, which was consistent either with the presence of Marginal Zone Lymphoma (MZL) plus a biclonal plasmacytic differentiation (monoclonal cIgGκ as well as a small percentage of monoclonal cIgMκ plasma cells were observed), or MZL plus its plasmacytic component plus MGUS. PET/CT showed unhomogeneous hypermetabolism implying a bibasilar, reticular interstitial pattern which was attributed to the underlying LPD. A new CT scan showed a marginal improvement regarding the lung parenchyma but some lymph nodes had increased in size. Pending further therapeutic decisions, the patient was referred to a specialized Hematology laboratory so that his bleeding diathesis would be further investigated, since his platelet count and routine coagulation tests were all normal.

Discussion

Initially, we report herein a patient with IgGλ MM and atypical clinical presentation as well as laboratory results, including massive splenomegaly, hepatomegaly, intraabdominal lymphadenopathy, leukoerythroblastic reaction, spherocytes and absent haptoglobins. Nevertheless, her most unsettling symptom was hemoptysis, a manifestation of her bleeding diathesis (in spite of her mild thrombocytopenia and normal coagulation tests) that had also expressed itself with spontaneous bruising, epistaxis, and increased blood loss during menstruation. The aforementioned RUL GGO might have been another evidence of the patient’s bleeding diathesis, representing a possible, isolated site of alveolar hemorrhage. Unfortunately, we did not have a chance to further evaluate this radiological finding with bronchoscopy and BAL.

Our second patient was diagnosed with a low-grade LPD ± MGUS, complicated by hemoptysis due to DAH as it was proven by BAL. His bleeding diathesis did not have as well a straightforward explanation, since his platelet count and coagulation tests were normal. Interestingly, in both patients an IgG paraprotein was evident, first hinted by a high ESR and low A/G ratio and then confirmed with serum electrophoresis and immunofixation.

Certain MM patients or individuals with other PCDs have an increased risk of developing a coagulation disorder and subsequent bleeding, in addition of course to those patients that develop severe thrombocytopenia. In general, MM patients may be exposed to a high risk of both spontaneous and peri-interventional bleeding, since about 15% of MM patients present with a bleeding diathesis [6,7]. The same holds true for MGUS, since monoclonal gammopathy may have various manifestations, including bleeding diathesis, related to adsorption of biologically active molecules on clonal cells or aggregated paraprotein [8]. However, clinically important bleeding complications such as hemoptysis among PCD patients are not usually seen [7].

The relevant mechanisms of coagulation abnormalities in MM are complex and reflect an abnormal interaction between clonal plasma cells, inflammatory pathways and M proteins on one side and platelets, von Willebrand Factor (vWF), coagulation factors and the vasculature on the other [7,9,10]. The literature is rich mostly with case reports commenting on MM patients with Acquired von Willebrand syndrome (AVWS) [11-20], acquired haemophilia A [19,21-25], dysfibrinogenemia due to antibodies directed against fibrinogen [26-29] or due to defects in fibrin polymerization [30- 33], excessive fibrinolysis [34,35], increased plasma viscosity caused by high protein concentration in the blood [36-38], the presence of cryoglobulins [39], as well as specific coagulation factors’ deficiencies, such as Factor V (FV) and FX deficiency [40-42]. Moreover, there are reports of an acquired heparin-like coagulation inhibitor [10,43,44] and Thrombotic Thrombocytopenic Purpura (TTP) [45,46], while impaired platelet function has also been under the spotlight [9,20,47]. Similar mechanisms have been described in individuals with MGUS, i.e., AVWS [48-63], presence of cryoglobulins [64,65] or acquired coagulation inhibitor [66], and Immune Thrombocytopenia (ITP) [67], while only one case series has been published up until now (in French) regarding patients with MZL, paraprotein and bleeding diathesis due to AVWS [68], as well as 2 case reports [69,70] regarding patients with splenic MZL (SMZL), with one of the patients also having a biclonal gammopathy [69]. There is also a case report of a MZL patient with spontaneous hematomas due to acquired FX deficiency [71] and a case report of a patient with acquired hemophilia A and a circulating Monoclonal B Lymphocytic population (MBL) with a marginal zone phenotype [72]. Lastly, bleeding diathesis among systematic immunoglobulin light chain (AL) amyloidosis patients is also attributed to AVWS, activation of the fibrinolytic system, decreased synthesis of coagulation factors in advanced liver disease, as well as amyloid infiltration of blood vessels [10,16,41,73,74]. The International Myeloma Working Group (IMWG) has issued recommendations for prophylactic and therapeutic anticoagulation in MM patients [75] but interestingly enough, not for a possible bleeding diathesis among them or other patients with PCD. Moreover, it is currently unknown if only laboratory-evident coagulopathy has any prognostic role [41].

Mass disease or organomegaly in MM patients is usually due to extramedullary plasmacytomas or amyloidosis and found in approximately 10% of patients [1]. Splenomegaly and hepatomegaly are thought to be rare clinical findings in patients with MM but without amyloidosis, with respective incidence of <1% and 4-5 % in newly-diagnosed patients [76-80]. Patients that develop MM after having been diagnosed with Gaucher disease could also have organomegaly (as well as lymphadenopathy) since before their MM diagnosis [81,82] while there is also a recent case report describing a MM patient with acquired hemophagocytic lymphohistiocytosis as initial manifestation of MM, and thus splenomegaly [83]. It should be kept in mind that organomegaly is much commoner among patients with AL and rare plasma cell dyscrasias such as POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Multiple myeloma and Skin changes) syndrome [84,85], while patients with primary plasma cell leukaemia also have a higher incidence of hepatosplenomegaly and lymphadenopathy compared to MM patients [86]. Regarding lymphadenopathy among MM patients, case reports have been infrequently published in the literature [87-91], while not so current patient series have reported an incidence of ≤1% [76,78,80]. Finally, to the best of our knowledge, leukoerythroblastic reaction in a MM patient has been reported only once before [79], while there is no report regarding the presence of spherocytes in MM. Finally, with regard to MM and low or absent haptoglobins, haptoglobin levels have been found actually increased among MM patients [92,93].

The common symptom of our 2 patients was their bleeding diathesis (manifested mainly as hemoptysis), while they also shared low complement levels, the presence of an IgG paraprotein and a seemingly intact coagulation system (since their standard coagulation assays were normal). So, it would not be inappropriate to attribute their common clinical picture to their common and bibliographically well-established laboratory finding, e.g., their IgG paraprotein, despite the fact that the last one has been reported to have the lowest bleeding rate [94-97].

Additional considerations regarding our first patient were, to start with, that her bleeding diathesis could be ascribed in part also to her mild thrombocytopenia, which in turn could be also attributed to a chronic, immune-active Hepatitis B Virus (HBV) infection (positive HBsAg and high viral load) and hypersplenism (either due to splenomegaly or not), yet our patient had no evidence of impaired hepatic synthetic function and decompensated cirrhosis, second, that at the time of her diagnosis she might also have an overt hemolysis due to the observed massive splenomegaly, hence justifying the absent haptoglobins and the presence of leukoerythroblastic reaction, basophilic stippling and spherocytes, third, that the constellation of organomegaly, lymphadenopathy and thrombocytopenia might have been suggestive of an undiagnosed Gaucher disease, yet the lack of bone marrow infiltration by Gaucher cells is against such possibility, and four, that the patient might have congenital ahaptoglobinemia (or anhaptoblobinemia) [98], thus the undetectable haptoglobin level. Finally, her low complement levels could be indicative of vasculitis, or the patient’s hemoptysis could be independent of her paraproteinemia and only due to a local cause that we did not have the chance to investigate further. Yet, her generalized bleeding diathesis and bleeding pattern (mostly her late onset bruising, epistaxis and heavy menstrual bleeding) combined with her normal coagulation studies point to an AVWS [99].

Regarding our second patient, an apparent consideration due to his raised levels of rheumatoid factor and low levels of complement was the possibility of vasculitis-driven hemoptysis, however his urine increment came back normal. Another concern we have is that his bleeding symptoms were limited only in his respiratory tract. His specialized coagulation investigation results are still pending but again, based on his normal coagulation studies, we believe that his diagnosis possibly is AVWS due to IgG paraprotein. We acknowledge however that hemoptysis is rare among patients with AVWS or paraproteinemia (excluding cases of pulmonary plasmacytomas or other PCD localized involvement), at least according to current literature [100-105] (Table 1).

  

    
Author (year of publication)
    
Article category
    
No of patients
    
Sex
    
Age (years)
    
Other manifestations
    
Primary disease diagnosis 
    
Diagnosed hemostatic abnormality
    
Reference
  
  

    
Bolaman (2008)
    
Letter to the editor
    
1
    
Female
    
49
    
Anemia
    
MM
    
NR
    
[100]
  
  

    
Morita (2010) 
    
Case report
    
1
    
Female
    
84
    
Dyspnea, hematuria, progressive anemia, malaise,    cough
    
MM
    
NR
    
[101]
  
  

    
Szeto (2013)
    
Case report
    
1
    
Male
    
67
    
Cough, progressive dyspnea, malaise
    
MM
    
NR
    
[102]
  
  

    
Coucke (2014)
    
Case report
    
1
    
Male
    
36
    
Anemia
    
WM
    
AVWS 
    
[103]
  
  

    
Clay (2018)
    
Case report
    
1
    
Female
    
48
    
No
    
Systemic AL amyloidosis with cardiac involvement
    
NR
    
[104]
  
  

    
Uwingabiye (2018)
    
Case report
    
1
    
Male
    
59
    
Renal failure, anemia, thrombocytopenia,    hemothorax
    
PCL
    
anti-factor XI antibodies
    
[105]
  
  

    
Present study
    
Case series
    
2
    
1 female
    
52
    
Epistaxis, spontaneous bruising
    
MM
    
NR
    

  
  

    
1 male
    
76
    
Mild dyspnea
    
MZL plus a biclonal plasmacytic differentiation    or MZL plus its plasmacytic component plus MGUS
    
NR
  
  

    
AL: Immunoglobulin Light-Chain Amyloidosis;    AVWS: Acquired Von Willebrand Syndrome; BMA: Bone Marrow Aspiration; BMB:    Bone Marrow Biopsy; LPL: Lymphoplasmacytic Lymphoma; MGUS: Monoclonal    Gammopathy Of Undetermined Significance; MM: Multiple Myeloma; MZL: Marginal    Zone Lymphoma; PCL: Plasma Cell Leukemia; WM: Waldenström Macroglobulinemia. 
  

Table 1: Case reports of patients with plasma cell dyscrasias who presented with hemoptysis as prominent symptom.