Table of Contents  
CASE REPORT
Year : 2017  |  Volume : 10  |  Issue : 3  |  Page : 293-296  

Waldenstrom's macroglobulinemia: An unusual cause of nonhealing leg ulcers


1 Department of Medicine, AFMC, Pune, Maharashtra, India
2 Department of Medicine, Command Hospital, Pune, Maharashtra, India

Date of Web Publication19-May-2017

Correspondence Address:
Navjyot Kaur
Department of Medicine, AFMC, Sholapur Road, Pune - 410 040, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-2870.206572

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  Abstract 

Waldenstrom's macroglobulinemia (WM) is one of the rare hematological malignancies and accounts for 1%–2% of all blood cancers. While fatigue is the most common presentation; hyperviscosity syndrome, symptomatic cryoglobulinemia, and cold agglutinin disease (CAD) are the characteristic symptoms. However, they occur only in 5%–15% of all patients of WM. We discuss a 63-year-old patient who presented with nonhealing ulcers on both lower limbs and severe anemia. His blood clotted in ethylenediaminetetraacetic acid sample tubes, and there was difficulty in getting blood cross matched for transfusing him. During evaluation, he was found to have high erythrocyte sedimentation rate, albumin globulin reversal with serum protein electrophoresis, and immunofixation suggestive of immunoglobulin M monoclonal gammopathy. There was evidence of autoimmune hemolytic anemia and skin biopsy from ulcers revealed hyaline thrombosis and deposition of cryoglobulins. He was diagnosed to have WM with cryoglobulinemia and CAD.

Keywords: Cold agglutinin disease, cryoglobulinemia, Waldenstrom's macroglobulinemia


How to cite this article:
Kaur N, Sharma S, Mohan A, Puri P. Waldenstrom's macroglobulinemia: An unusual cause of nonhealing leg ulcers. Med J DY Patil Univ 2017;10:293-6

How to cite this URL:
Kaur N, Sharma S, Mohan A, Puri P. Waldenstrom's macroglobulinemia: An unusual cause of nonhealing leg ulcers. Med J DY Patil Univ [serial online] 2017 [cited 2019 Sep 20];10:293-6. Available from: http://www.mjdrdypu.org/text.asp?2017/10/3/293/206572


  Introduction Top


Waldenstrom's macroglobulinemia (WM) is a rare blood cancer and accounts for 2% of all hematological cancers.[1] It is characterized by the production of large amounts of monoclonal immunoglobulin M (IgM). The most common presentation of WM is fatigue due to anemia.[2] Anemia in WM may occur due to the infiltration of marrow by tumor cells, due to autoantibodies, gastrointestinal bleed, or it may be dilutional due to increased plasma volume. Hyperviscosity syndrome due to the large amount of circulating IgM is quite characteristic of disease but only 15% of patients have the symptoms of hyperviscosity.[3] The cryoglobulins are noted in about 20% of WM patients but are symptomatic in only 5% cases.[4] The symptoms of cryoglobulinemia range from Raynaud's phenomenon to skin ulcers. The CAD is noted in <10% of WM cases and is associated with cold agglutinin titers of more than 1:1000 in most of the cases.[5] We present a case of 63-year-old male who presented with nonhealing ulcers on both lower limbs and severe anemia and was diagnosed to have WM with cryoglobulinemia and CAD.


  Case Report Top


Sixty-three-year-old male was admitted in surgical ward with nonhealing ulcers of 2 months duration. On examination, he was pale and had large ulcers on both lower limbs [Figure 1]. The evaluation revealed hemoglobin of 4.4 g/dl and erythrocyte sedimentation rate of 56 mm/h. Corrected reticulocyte count was 3%. Peripheral blood smear (PBS) revealed normocytic normochromic anemia, with red blood cell (RBC) aggregates. The whole blood sample in ethylenediaminetetraacetic acid tube got clotted repeatedly; hence, blood was drawn into prewarmed sterile collection tube (at 37°C). The blood was centrifuged to separate serum which was subsequently refrigerated at 4°C. The precipitate was seen after 2 h of refrigeration confi rming the presence of cryoglobulins. His complement levels were low (C3: 29 mg/dL (normal: 50–120) and C4: 11 mgdL (normal: 20–50). There was difficulty in getting blood cross matched for transfusion. The antiglobulin (Coomb's) test was positive using anti-C3 and was negative with anti-IgG, and the titers of cold agglutinin recorded were 1:2048. Liver function tests (LFTs) revealed a total bilirubin of 3.4 mg/dL with an indirect fraction of 2.7 mg/dL. Total protein was 7.9 gm/dL; albumin was 2.1 g/dL, and there was reversal of albumin globulin ratio. Lactate dehydrogenase was 679 IU/L and rest LFTs, and renal function tests were normal. He was normoglycemic, and the Doppler study of arterial and venous system of bilateral lower limbs was normal. There were no lytic lesions on the skeletal survey. Hepatitis B virus DNA and hepatitis C virus RNA were negative. The skin biopsy from the ulcers revealed hyaline thrombosis with minimal inflammation and deposition of cryoglobulins. Bone marrow (BM) aspiration and biopsy were suggestive of lymphoplasmacytic lymphoma with lymphoid lineage cells positive for CD19 and CD20 and plasma cells positive for CD38 and CD138. Serum protein electrophoresis (SPEP) and immune fixation showed an M band with IgM lambda restriction [Figure 2] and [Figure 3]. The Contrast-enhanced computed tomography of chest, abdomen, and pelvis revealed splenomegaly. Based on SPEP, immunofixation, BM studies and absence of lytic lesions on skeletal survey, a diagnosis of WM was made, which has presented with its rare but specific clinical manifestations.
Figure 1: Nonhealing leg ulcer

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Figure 2: Serum protein electrophoresis showing M band

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Figure 3: Immunofixation showing immunoglobulin M lambda restriction

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  Discussion Top


WM also known as lymphoplasmacytic lymphoma is classified as a subtype of non-Hodgkin Lymphoma by the World Health Organization. More common in elderly Caucasian males, WM appears to show a familial preponderance.[6] Clinical features of WM occur either due to tumor cell infiltration in organs such as BM, lymph nodes, liver and spleen and/or due to large amounts of circulating pentameric IgM and/or due to autoantibodies, and/or due to deposition of amyloid. [Table 1] summarizes the various clinical features of WM and the possible mechanisms.
Table 1: Clinical features of Waldenstrom's macroglobulinemia

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The presence of cryoglobulins may lead to clotting of blood in collection tubes. For diagnosis, a prewarmed sample tube and needle should be used to avoid the precipitation of cryoglobulins. In WM, we expect to have type 1 cryoglobulinemia resulting from high-level monoclonal Ig M. These Ig can precipitate on exposure to cold and in vivo such aggregates can obstruct the small vessels or initiate vasculitis causing Raynaud's phenomenon, arthralgia, skin lesions such as purpura and ulcers.[7] Erythematous macules and purpuric papules seen in all three types of cryoglobulinemia are more common presentation (90%–95%) whereas ulcers and infarction generally seen in type 1 cryoglobulinemia are less common (10%–15%).[8] Pathologically, the cryoglobulin deposits are seen as eosinophilic material inside the lumen of vessels. There may be evidence of leukocytoclastic vasculitis as well.[9] In our patient, we could demonstrate the eosinophilic deposits in skin vessels, so we assume that the ulcers were due to cryoglobulinemic activity of IgM.

The common clinical manifestations of CAD are anemia (35%), acrocyanosis (24%), fatigue (21%), dyspnea on exertion (7%), and hemoglobinuria (3%).[10] CAD may also be associated with skin ulcers but very rarely.[9] CAD develops due to IgM antibody against I/i antigen on RBC surface.[11] Since I/i antigen is present on the surface of all RBCs; it is difficult to get blood cross matched for transfusion in such patients.

Diagnosis

WM is diagnosed when BM shows >10% infiltration by small B-lymphocytes with plasmacytoid/plasmacytic differentiation, and there is IgM monoclonal gammopathy.[12] Immunophenotyping of B-cells show CD19+, CD20+, sIgM +, CD5, and CD10.[13] Over 50% of cases show deletion of 6q on cytogenetic analysis. Closest differential of WM is IgM multiple myeloma which is very rare disease itself with a prevalence of 0.5%.[14] IgM multiple myeloma is more likely to have lytic bone lesions on skeletal survey and also the renal dysfunction is more common with IgM multiple myeloma. BM in myeloma shows a purely plasmacytic infiltrate, and the immunophenotyping shows CD38 and CD138 positivity whereas it is negative for CD19, CD20, and sIg. The characteristic cytogenetic abnormality is t (11;14)(q13;q32), 13q deletion, and t (4;14).[5]

Cryoglobulinemia was diagnosed in our patient based on the demonstration of precipitation of cryoglobulins at 4°C, by the presence of clinical symptoms which can be attributed to cryoglobulins and the demonstration of eosinophilic material in pathological thromboticskin vessels. Besides his complement levels were low. However, definite diagnosis requires the measurement of concentration of cryocrit and direct evidence of cryoglobulins from pathological specimens either by elution and cryoprecipitation and/or immunofixation [15] which was not done in our patient because of lack of required expertise and technical facilities in our hospital as well as nearby government tertiary care center. Our patient was diagnosed to have WM with which cryoglobulinemia is commonly associated; this made our diagnosis even more secure. CAD was diagnosed in our patent based on PBS showing RBC aggregates, presence of high titres of cold agglutinin, and positive Coomb's test.[10]

Management

Symptomatic patients should be given rituximab-based regimens. These include dexamethasone + rituximab + cyclophosphamide, bendamustine + rituximab, fludarabine + rituximab, fludarabine + cyclophosphamide + rituximab, and cladribine + rituximab. Ibrutinib, an orally administered drug has been recently approved by the Food and Drug Administration and EMA as the primary treatment of WM. If the patient is asymptomatic; usually no treatment is given, and the patient is followed up. Plasma exchange is recommended for hyperviscosity syndrome. For CAD and cryoglobulinemia, treatment of choice remains rituximab and steroids.

Our patient had WM with CAD and cryoglobulinemia. He was managed with blood transfusion and rituximab + dexamethasone to which he showed good initial clinical response. His Hb at the time of discharge was 9.2 g/dL and his leg ulcers showed improvement [Figure 4].
Figure 4: Follow-up image of leg ulcers

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Purpose of reporting

The case highlights an unusual cause of nonhealing ulcers in an elderly patient. Our patient had WM with two of its uncommon but very characteristic complications.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Vos JM, Minnema MC, Wijermans PW, Croockewit S, Chamuleau ME, Pals ST, et al. Guideline for diagnosis and treatment of Waldenström's macroglobulinaemia. Neth J Med 2013;71:54-62.  Back to cited text no. 1
    
2.
Rajkumar SV. Epidemiology, pathogenesis, clinical manifestations and diagnosis of Waldenstrom macroglobulinemia. In: Schrier S, Kyle R, Connor R, editors. UpToDate. Waltham: UpToDate; 2012.  Back to cited text no. 2
    
3.
Dimopoulos MA, Kyle RA, Anagnostopoulos A, Treon SP. Diagnosis and management of Waldenstrom'smacroglobulinemia. J Clin Oncol 2005;23:1564-77.  Back to cited text no. 3
    
4.
Merlini G, Baldini L, Broglia C, Comelli M, Goldaniga M, Palladini G, et al. Prognostic factors in symptomatic Waldenstrom's macroglobulinemia. Semin Oncol 2003;30:211-5.  Back to cited text no. 4
    
5.
Ghobrial IM. Are you sure this is Waldenstrom macroglobulinemia? Hematology Am Soc Hematol Educ Program 2012;2012:586-94.  Back to cited text no. 5
    
6.
Treon SP, Hunter ZR, Aggarwal A, Ewen EP, Masota S, Lee C, et al. Characterization of familial Waldenstrom's macroglobulinemia. Ann Oncol 2006;17:488-94.  Back to cited text no. 6
    
7.
Owen RG, Pratt G, Auer RL, Flatley R, Kyriakou C, Lunn MP, et al. Guidelines on the diagnosis and management of Waldenström macroglobulinaemia. Br J Haematol 2014;165:316-33.  Back to cited text no. 7
    
8.
Terrier B, Karras A, Kahn JE, Le Guenno G, Marie I, Benarous L, et al. The spectrum of type I cryoglobulinemia vasculitis: New insights based on 64 cases. Medicine (Baltimore) 2013;92:61-8.  Back to cited text no. 8
    
9.
Nash JW, Ross P Jr., Neil Crowson A, Taylor J, Morales JE, Yunger TM, et al. The histopathologic spectrum of cryofibrinogenemia in four anatomic sites. Skin, lung, muscle, and kidney. Am J Clin Pathol 2003;119:114-22.  Back to cited text no. 9
    
10.
Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood 2013;122:1114-21.  Back to cited text no. 10
    
11.
Vijay A, Gertz MA. Waldenstrom macroglobinemia. Blood 2007;109:1-12.  Back to cited text no. 11
    
12.
Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, et al. Clinicopathological definition of Waldenstrom's macroglobulinemia: Consensus panel recommendations from the Second International Workshop on Waldenstrom's macroglobulinemia. Semin Oncol 2003;30:110-5.  Back to cited text no. 12
    
13.
Coimbra S, Neves R, Lima M, Belo L, Santos-Silva A. Waldenström's macroglobulinemia – A review. Rev Assoc Med Bras 2014;60:490-9.  Back to cited text no. 13
    
14.
Atrash S, Zhang Q, Papanikolaou X, Heuck C, Bakhous A, Muzaffar J, et al. Characterstics and Prognosis of IgM Multiple Myeloma. ASH 2013 Meeting Abstract, 2013.  Back to cited text no. 14
    
15.
Quartuccio L, Isola M, Corazza L, Ramos-CasalsM, Retamozo S, Ragab GM, et al. Validation of the classification criteria for cryoglobulinaemic vasculitis. Rheumatology (Oxford). 2014;53:2209-13.  Back to cited text no. 15
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

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