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 Table of Contents  
CASE REPORT
Year : 2018  |  Volume : 2  |  Issue : 2  |  Page : 87-90

Waldenstrom macroglobulinemia with herpes zoster, a case report and review literature


1 Lab Oncology Unit, Dr. BRAI-RCH, New Delhi, India
2 Department of Medical Oncology, Dr. BRAI-RCH, New Delhi, India
3 Dr. R. P Centre for Ophthalamic Sciences, All Institute of Medical Sciences, New Delhi, India
4 Department of Engineering Management [student], RMIT University, Victoria, Melbourne, Australia
5 Department of Pathology, All Institute of Medical Sciences, New Delhi, India

Date of Web Publication10-Jul-2018

Correspondence Address:
Amar Ranjan
R. No. 422, Lab Oncology, Dr. BRAI-RCH, AIIMS, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CDR.CDR_43_17

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  Abstract 

Waldenstrom macroglobulinemia (WM) is a variant of lymphoplasmacytic lymphoma. In WHO classification of hematolymphoid malignancy 2016, WM has been placed in between lymphoma and plasma cell myeloma under the broad heading “Neoplasms of mature lymphocytes”. This is a rare and slowly progressive disorder, which needs therapy only when symptoms appear. The average age of diagnosis is 60–70 years. WM may progress to lymphoma in 2% cases per year. Here, we are discussing a case of WM having typical findings of this rare disease, who presented with 10%–12% plasma cell in bone marrow aspirate smear, high immunoglobulin M, high beta 2 microglobulin, bilateral axillary lymphadenopathy and gastrointestinal bleeding. At present, the patient is on chlorambucil plus prednisolone therapy and is doing well. Typically, this case presented with lesions of herpes zoster, which makes this case further uncommon.

Keywords: Herpes zoster, immunoglobulin M monoclonal gammopathy, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia


How to cite this article:
Ranjan A, Pramanik R, Wadhwani M, Ranjan L, Dutta R. Waldenstrom macroglobulinemia with herpes zoster, a case report and review literature. Clin Dermatol Rev 2018;2:87-90

How to cite this URL:
Ranjan A, Pramanik R, Wadhwani M, Ranjan L, Dutta R. Waldenstrom macroglobulinemia with herpes zoster, a case report and review literature. Clin Dermatol Rev [serial online] 2018 [cited 2018 Dec 10];2:87-90. Available from: http://www.cdriadvlkn.org/text.asp?2018/2/2/87/236340


  Introduction Top


Lymphoplasmacytic lymphoma (LPL) is a neoplasm of B lymphocytes and plasma cells. It usually involves bone marrow (BM), sometimes lymph nodes and spleen. This is a diagnosis of exclusion. Waldenstrom Macroglobulinemia (WM) is defined as LPL with BM involvement (>10% infiltration by plasma cells) and immunoglobulin M monoclonal gammopathy (IgM-MG) in blood (WM = LPL + BM involvement + IgM-MG).[1],[2]

As per WHO 2016 criteria, WM has been kept under the heading of mature B-cell neoplasm with subcategory of LPL. Plasma cell neoplasms also include WM partly.

Plasma cell neoplasms have been divided into five categories: MG of unknown significance (MGUS), plasma cell myeloma (PCM), plasmacytoma, monoclonal immunoglobulin (Ig) deposition disease (MIDD), and osteosclerotic myeloma. MIDD is characterized by visceral and soft-tissue deposition of Ig resulting in compromised organ function. WM/LPL is also an example of MIDD.[3]


  Case Report Top


A sixty four-year-old male presented with headache low back pain, and early fatigue for 2–3 years. History of hypertension and diabetes mellitus with a healed herpes zoster lesion in the right T10 dermatome was also present. On examination, there was bilateral axillary lymphadenopathy with no organomegaly. Laboratory investigations showed hemoglobin 96 g/L and beta 2 microglobulin 2.49 mg/L (0.8–2.1). Occult blood in stool was present. BM aspirate smear showed 12% abnormal lymphoid cells with plasmacytoid morphology. M band was seen on protein electrophoresis (serum and urine); immunofixation showed IgM lambda. 24-hour urinary protein excretion, serum IgM, and IgG level were found significantly high. Skeletal survey showed patchy osteopenia in ribs. The final diagnosis of Waldenstrom macroglobulinemia was considered. The patient is on chlorambucil and prednisolone therapy.

Due to severe fatigue and low hemoglobin level (96 g/L), the case was evaluated for cause of anemia. This revealed normal iron profile, normal gastrointestinal endoscopy (upper and lower) and negative Coombs test. After first positive report of occult blood in stool, repeat tests were found negative. Morphologically, anemia was normocytic and normochromic. Indication to start therapy in this case was anemia and fatigue.


  Discussion Top


Macroglobulinemia (WM) was first described by Jan Waldenström in 1944.[4] It has been classified in Revised European-American Classification/World Health Organization classification as a LPL.[5]

It is diagnosed by infiltration of lymphoplasmacytoid cells in BM in the presence of IgM protein in the blood.[6]

It presents with weakness, tiredness, weight loss, mucosal bleeding and sometimes skin rashes. Skin involvement although uncommon is due to lymphoplasmacytic cell infiltration in skin. Patients develop reddish-brown patches or plaques. Rarely, the patient may develop Schnitzler syndrome.[7] Schnitzler syndrome is an autoinflammatory dermatosis, usually misdiagnosed as urticaria. Therapy for lymphoplasmacytic infiltration only ameliorates the symptoms.[7],[8]

Skin lesions are caused by excess proteins in blood, which cause plugging of small blood vessels. Most common sites are toes, fingers, ears, etc. They present with skin erosions and ulcers. In immunocompromised conditions, patients with WM may develop shingles (reactivation of chickenpox virus) and herpes zoster. The case of herpes zoster presents with blisters in cluster, usually affecting single area of body. These may be itchy or painful. They may also develop cellulitis (bacterial infections). Chemotherapy may also cause skin lesions such as rashes, red bumps on the palms (neutrophilic eccrine hidradenitis), and hair loss.[7]

Macroglobulinemia

It is a condition in which the blood contains high levels of large proteins. The level of large protein may be too high to make blood thick and viscous leading to difficulty in flow through small blood vessels. This large protein is an antibody known as macroglobulin or IgM.[9]

According to Rajkumar and Connor, 2014, macroglobulinemia (IgM-MG) refers to excess of monoclonal IgM in blood. It includes MG of undetermined significance (MGUS), smoldering WM, WM, chronic lymphocytic leukemia, lymphoma variants, and primary amyloidosis.

LPL is a low-grade B-cell lymphoma consisting of small lymphocytes with plasmacytic differentiation. These cells are negative for CD5 and CD10. However, this immunophenotype is not specific for LPL. Other mature B-cell lymphomas may be associated with plasmacytic differentiation. Hence, LPL is a diagnosis of exclusion.[10]

The differential diagnosis of LPL/WM includes marginal zone lymphoma (MZL), CD5-negative mantle cell lymphoma, and CD10-negative follicular lymphoma.[11]

Smoldering multiple myeloma (MM) is an asymptomatic variant of clonal plasma cell disorder. It is diagnosed by the presence of a serum monoclonal component of Ig >3 g/dl and/or of >10% clonal BM plasma cells. There should be no evidence of end-organ damage (CRAB features, including hypercalcemia, renal failure, anemia or lytic bone lesions, or any additional myeloma-defining events including biomarkers of malignancy).[12]

WM is a rare entity. The median age of diagnosis is 63 years for black patients and 73 years for white patients with slight male preponderance. Incidence is higher in whites than in blacks.[13]

WM has to be differentiated with IgM MM. Lytic bony lesion and kidney lesion are diagnostic criteria of MM, which is rarely seen in WM. Localization of Ig in MM is intracytoplasmic, whereas in WM, it is on cell surface. On immunophenotyping, tumor cells in WM (lymphocytes, plasmacytoid lymphocytes, and plasma cells) show positivity for CD20, a B-cell marker. This is why WM falls under the category of lymphoma. Plasma cells in MM show positivity for CD138, which is a plasma cell marker. Moreover, this falls under the category of PCM.[14],[15]

Treon SPet al 2012 performed whole-genome sequencing of bone marrow LPL cells in 30 patients with WM. They showed MYD88 L265P mutation in 91% of patients with WM; in contrast to only 10% cases of IgM-MGUS, 7% cases of MZL and absent in almost all cases of myeloma including IgM-secreting variants. MYD88 L265P mutation can be demonstrated as leucine to proline substitution in codon 265 (L265P).[16]

Morie, 2013 highlighted some differentiating points which are being illustrated in [Table 1].
Table 1: Differential diagnosis of immunoglobulin M-multiple myeloma and Waldenstrom macroglobulinemia

Click here to view


Immunomarkers and genetics

Immunophenotyping of clonal lymphocytes of WM shows constant expression of pan-B-cell markers (CD20, CD22, CD19, CD24) and surface immunoglobulin (sIg) predominantly kappa. Plasma cells in WM are CD38+, but are also positive for CD19, CD20 & CD45 and negative for CD56. Expression of CD19 or CD 20 is not seen in either normal plasma cells or myeloma cells.[17]

Genetic study showed t [11,14] in MM [18] whereas MYD88 gene mutation is seen in WM.[19] Adam et al., 2015 studied that MYD 88 gene mutation is seen in 89% cases of WM, 7% cases of mucosa-associated lymphoid tissue lymphoma, and 4% cases of MZL. WM cases with negative MYD 88 mutation have shown better survival.[20]

Mutation of the C-X-C chemokine receptor type 4 was found in 29% of patients with WM.[21]

Numerous chromosomal abnormalities and somatic mutations have been seen in WM. Most common are 6q deletion (22%–46%), 13q14 deletion (13%–15%), trisomy 18 (11%–23%), trisomy 4 (4%–12%), and p53 deletion (4%–23%). The IgH gene rearrangement as part of a translocation is uncommon in WM unlike in MM.[22]

Cryoglobulinemia

Ten percent of macroglobulins in WM precipitate in the cold called cryoglobulins. It does not cause cold hypersensitivity, for example, Raynaud phenomenon and urticaria. It is of three types: Type I or simple cryoglobulinemia is the result of a monoclonal Ig, usually IgM. Types II and III cryoglobulinemia (mixed) contain rheumatoid factors (RF), usually IgM. RF forms complexes with Fc (crystallizable fragment of antibody). RF is of two types: monoclonal RF is composed of Type II cryoglobulinemia and polyclonal RF is composed of Type III cryoglobulinemia. Types II and III cryoglobulins constitute 80% of all cryoglobulins.[23]

Owen et al., 2001[24] proposed criteria for the diagnosis of Waldenström macroglobulinemia based on study of 111 cases of WM, which are as follows:

  • IgM MG of any concentration
  • BM infiltration with small lymphocytes, plasmacytoid cells, and plasma cells
  • Diffuse, interstitial, or nodular pattern of BM infiltration 1
  • Immunophenotype: surface Ig+, CD19+, CD20+, CD5–, CD10–, CD23–.


Treatment

IgM MGUS cases require lifelong monitoring as it has an average risk of progression to multiple myeloma by 1% case per year. These patients are followed clinically without treatment until progression. Complications are managed conservatively.[25]

This disease is incurable with current therapy. Asymptomatic WM with preserved hematologic function is kept for wait and watch. Symptomatic patients with modest hematologic compromise are managed with standard doses of rituximab alone without maintenance therapy. Patients with severe constitutional symptoms, profound hematologic compromise, symptomatic bulky disease, or hyperviscosity are treated with the DRC (dexamethasone, rituximab, and cyclophosphamide) regimen. Plasmapheresis is the first line of therapy for hyperviscosity. Relapsed cases after 2 years of completion of successful initial therapy should have a repeat therapy as original one. Patients having inadequate response to initial therapy or a response of <2 years' duration, an alternative agent, or combination should be used. All the relapsed cases are eligible for autologous stem cell transplant.[26]

Prognosis

Morel et al., 2009[27] studied 587 cases of WM and provided International Prognostic Scoring System, which illustrates three risk categories and average survival in months. This has been mentioned in [Table 2].
Table 2: Risk stratum and survival

Click here to view


Factor associated with prognosis value (each one having score 1):

  • Age, year >65
  • Hemoglobin, g/dL ≤11.5
  • Platelet count, No./Liter ≤100 x 109
  • β2-microglobulin, mg/L >3
  • Monoclonal IgM, g/dL >7



  Conclusion Top


WM is rare and slowly progressive disease and it needs wait and watch if there is no symptom. Therapy is only needed when symptoms appear. Despite being lymphoma, it involves primarily BM ± PB, sometimes LN and spleen. Protein electrophoresis should be done even if low plasma cell percentage is seen in BM aspirate smear. Cases presenting with skin lesions not responding to therapy would be investigated for the presence of WM. Careful clinical history and clinical examination is the key for its diagnosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Steven HS, Elias C, Nancy LH, Jaffe ES, Stefano AP, Harald S, et al. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue. 4th ed. Lyon: International Agency for Research on Cancer; 2008. p. 194-5.  Back to cited text no. 1
    
2.
Rajkumar SV, Connor RF. Treatment and prognosis of waldenström macroglobulinemia. In: Kyle RA, editor. UpToDate. Kyle RA (Ed): Wolters Kluwer; 2014.  Back to cited text no. 2
    
3.
McKenna RW, Kyle RA, Kuehl WM, Grogan TM, Harris NL, Coupland RW, Plasma cell neoplasms. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al, editors. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue. 4th ed. Lyon: Int. Agency for research on cancer; 2008, p. 209.  Back to cited text no. 3
    
4.
Waldenström J. Incipient myelomatosis or “essential” hyperglobulinemia with fibrinogenopenia: A new syndrome? Acta Med Scand 1944;117:216-22.  Back to cited text no. 4
    
5.
Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, et al. World health organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: Report of the clinical advisory committee meeting-airlie house, Virginia, november 1997. J Clin Oncol 1999;17:3835-49.  Back to cited text no. 5
    
6.
Ghobrial IM, Witzig TE. Waldenström macroglobulinemia. Curr Treat Options Oncol 2004;5:239-47.  Back to cited text no. 6
    
7.
Lehman JS. Waldenstrom's macroglobulinemia and the skin. Int Waldenstrom's Macroglobulinemia Found Torch 2010;1:14.  Back to cited text no. 7
    
8.
Tolkachjov SN, Wetter DA. Schnitzler syndrome with delirium and vertigo: The utility of neurologic manifestations in diagnosis. J Drugs Dermatol 2017;16:625-7.  Back to cited text no. 8
    
9.
Available from: http://www.medicinenet.com/script/main/art.asp?articlekey=40377. [Last accessed on 2018 Feb 15].  Back to cited text no. 9
    
10.
Burnworth B, Wang Z, Singleton TP, Bennington A, Fritschle W, Bennington R, et al. Clone-specific MYD88 L265P and CXCR4 mutation status can provide clinical utility in suspected waldenström macroglobulinemia/lymphoplasmacytic lymphoma. Leuk Res 2016;51:41-8.  Back to cited text no. 10
    
11.
Swerdlow SH, Berger F, Pileri SA, Harris NL, Jaffe ES, Stein H, et al. Lymphoplasmacytic lymphoma. In: Swerdlow SH, Campo E, Harris NL, editors. World Health Organization Classification of Tumors of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008. p. 194-5.  Back to cited text no. 11
    
12.
Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007;356:2582-90.  Back to cited text no. 12
    
13.
Gertz MA. Waldenström macroglobulinemia: 2015 update on diagnosis, risk stratification, and management. Am J Hematol 2015;90:346-54.  Back to cited text no. 13
    
14.
Gertz M. Waldenström macroglobulinemia: My way. Leuk Lymphoma 2013;54:464-71.  Back to cited text no. 14
    
15.
Gertz MA. Waldenström macroglobulinemia: 2013 update on diagnosis, risk stratification, and management. Am J Hematol 2013;88:703-11.  Back to cited text no. 15
    
16.
Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al. MYD88 L265P somatic mutation in waldenström's macroglobulinemia. N Engl J Med 2012;367:826-33.  Back to cited text no. 16
    
17.
San Miguel JF, Vidriales MB, Ocio E, Mateo G, Sánchez-Guijo F, Sánchez ML, et al. Immunophenotypic analysis of waldenstrom's macroglobulinemia. Semin Oncol 2003;30:187-95.  Back to cited text no. 17
    
18.
Fonseca R, Barlogie B, Bataille R, Bastard C, Bergsagel PL, Chesi M, et al. Genetics and cytogenetics of multiple myeloma: A workshop report. Cancer Res 2004;64:1546-58.  Back to cited text no. 18
    
19.
Monge J, Braggio E, Ansell SM. Genetic factors and pathogenesis of waldenström's macroglobulinemia. Curr Oncol Rep 2013;15:450-6.  Back to cited text no. 19
    
20.
Morie G. What is waldenström macroglobulinemia? Leuk Lymphoma 2013;54:2345-46.  Back to cited text no. 20
    
21.
Hunter ZR, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al. The genomic landscape of waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood 2014;123:1637-46.  Back to cited text no. 21
    
22.
Nguyen-Khac F, Lambert J, Chapiro E, Grelier A, Mould S, Barin C, et al. Chromosomal aberrations and their prognostic value in a series of 174 untreated patients with waldenström's macroglobulinemia. Haematologica 2013;98:649-54.  Back to cited text no. 22
    
23.
Adam MT. Available from: http://www. emedicine.medscape.com/article/329255-overview, Editor Herbert SD. [Last updated on 2015 Mar 03].  Back to cited text no. 23
    
24.
Owen RG, Barrans SL, Richards SJ, O'Connor SJ, Child JA, Parapia LA, et al. Waldenström macroglobulinemia. Development of diagnostic criteria and identification of prognostic factors. Am J Clin Pathol 2001;116:420-8.  Back to cited text no. 24
    
25.
Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004;351:1860-73.  Back to cited text no. 25
    
26.
Ansell SM, Kyle RA, Reeder CB, Fonseca R, Mikhael JR, Morice WG, et al. Diagnosis and management of waldenström macroglobulinemia: Mayo stratification of macroglobulinemia and risk-adapted therapy (mSMART) guidelines. Mayo Clin Proc 2010;85:824-33.  Back to cited text no. 26
    
27.
Morel P, Duhamel A, Gobbi P, Dimopoulos MA, Dhodapkar MV, McCoy J, et al. International prognostic scoring system for waldenstrom macroglobulinemia. Blood 2009;113:4163-70.  Back to cited text no. 27
    

1 A paratrabecular pattern of BM infiltration does not preclude a diagnosis of Waldenström macroglobulinemia but is more suggestive of follicular lymphoma. Lymph node biopsy and/or t(14;18) polymerase chain reaction analysis is advisable in these cases.



 
 
    Tables

  [Table 1], [Table 2]



 

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