Pediatr Blood Cancer 2015;62:905–908
BRIEF REPORT A Unique Description of Stage IV Extranodal Marginal Zone Lymphoma (EMZL) in an Adolescent Associated With Gamma Heavy Chain Disease Nupur Mittal,
1,2,3 MD, *
Bing Zhu,
MD, PhD,
4
Sujata Gaitonde, MD,4 Yang Lu,5 and Mary Lou Schmidt, MD1
Extranodal Marginal zone lymphoma (EMZL) is a rare, usually localized disease in children. Advanced stage EMZL in adults is considered incurable, with prolonged remissions after chemotherapy. Gamma heavy chain disease (gHCD) is a rare disease of adults associated with lympho-proliferative processes with no comparable reports in children. A case of stage-IV EMZL with gHCD in an
adolescent is discussed including treatment with Bendamustine plus Rituximab. The patient remains disease free 18 months from diagnosis. This case highlights necessity for careful diagnostic work-up to identify indolent lymphomas in children which may respond to less toxic chemotherapy than used for common pediatric lymphomas. Pediatr Blood Cancer 2015;62:905–908. # 2015 Wiley Periodicals, Inc.
Key words: bendamustine-rituximab; extranodal marginal zone lymphoma; gamma heavy chain disease; pediatric NHL
INTRODUCTION Extranodal marginal zone lymphoma (EMZL) is an extremely rare diagnosis in children generally limited to the eye, skin, or stomach [1]. Gamma heavy chain disease (gHCD) is a rare disease of adults mostly associated with lympho-proliferative processes [2]. Advanced stage EMZL in adults is considered incurable, although prolonged remissions may occur after multi-agent chemotherapy [3,4]. Consensus recommendations for therapy of EMZL in children do not exist.
CASE REPORT A 15-year-old African-American male presents with 3 month history of non-tender submandibular swellings unresponsive to antibiotics; nasal congestion, chronic cough, chest pain, snoring, and 20 lb weight loss with normal labs but CT imaging confirming 5 4 periauricular, 3 3 occipital, and 2 2 inguinal masses but no hepatosplenomegaly. FDG PET/CT imaging is shown (Fig. 1). EBV, CMV, TB, Hepatitis B, HIV, H. pylori, ANA, and rheumatoid factor, bone marrow aspirate and biopsy were all negative. Serum protein electrophoresis revealed no abnormal bands. Multiple sequential biopsies of involved tissue revealed CD20þ and CD43þ sheets of small B cells, largely negative for CD10, CD79a, CD138, and MUM1. There were abundant plasma cells at the periphery of the lymphoid infiltrate with scattered positivity for IgA/IgM and Kappa/Lambda. In addition, there was a large subset of plasma cells expressing IgG heavy chain, but lacking cytoplasmic light chain. Numerous T cells were present exhibiting an appropriate CD4:CD8 ratio. CD21 highlighted the irregularly expanded follicular dendritic cell mesh works underlying the infiltrate. Immunophenotyping revealed an aberrant B-cell population. FISH for MYC/ IGH and molecular studies for clonal B-cell and T-cell gene rearrangements were negative. These results were highly suggestive of an atypical lymphoplasmacytic proliferation consistent with MZL with gHCD (Fig. 1A–H). This is a previously unidentified and unreported case of stage IV EMZL in a previously healthy pediatric patient. Repeat PET/CT imaging revealed progressive lung disease prompting initiation of chemotherapy: Bendamustine (90 mg/m2 on days 1 and 2 of a 4-week cycle) and Rituximab (375 mg/m2 on day 1 C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25419 Published online 8 February 2015 in Wiley Online Library (wileyonlinelibrary.com).
of cycle) [5]. Within 9 days, cervical lymphadenopathy and respiratory distress improved markedly and after 4 of 6 cycles, the patient had a normal physical exam and post-therapy FDG PET/CT imaging is shown (Fig. 1J). Following the final cycle, he developed prolonged neutropenia with gingivitis which slowly resolved. Patient remains in complete remission 12 months from end of therapy.
DISCUSSION Marginal zone lymphomas (MZLs), consist of 5–15% of nonHodgkin lymphomas in adults, are subtyped depending on organ of origin-EMZL including mucosa associated lymphoid tissue (MALT) lymphomas, splenic and nodal MZLs [3]. The average age of presentation of EMZL is 60 years. Concurrent conditions include H. pylori gastritis; Chlamydia associated orbital infections and autoimmune processes. Most patients with EMZL present with stage I or II disease [3]. In the largest report on EMZL (n ¼ 180), 20% had stage IV disease, 8% had lung involvement, and 12% had involvement of multiple mucosal sites [4]. Very few cases/small series of pediatric EMZL have been reported; the largest included only 4 cases 18 years, with newly diagnosed stage III or IV indolent or mantle-cell lymphoma compared Bendamustine/Rituximab (B-R) to R-CHOP. For all indolent lymphomas and EMZL patients, the B-R regimen had significantly better PFS compared to R-CHOP (B-R: 57 monthsþ vs. R-CHOP 47 months) ,significantly increased rate of CR and significantly less serious adverse events especially grade 3–4 neutropenia [5]. B-R is now one of the frontline regimens per NCCN guidelines for adult EMZL. This regimen has not been previously reported to treat a pediatric patient for management of an indolent lymphoma. Management for pediatric MZL varies. Taddesse et al. reported 22 patients (four were EMZL) who received local radiation (56%), excision and close follow-up (22%), or chemotherapy alone (22%) with excellent outcome after short follow-up of 1–24 months [1]. Four patients with EMZL identified among 2,703 participants in NHL-BFM 90 and 95 studies, all of whom had
Pediatr Blood Cancer DOI 10.1002/pbc
2003/Taddesse-Heath et al. [1] 2003/Taddesse-Heath et al. [1] 2003/Taddesse-Heath et al. [1] 2003/Taddesse-Heath et al. [1] 2006/Claviez et al. NHL/BFM [7] 2010/Kram et al. [10] 2012/Naithani et al. [11] 2014/Kempf et al [12] 2014/Kempf et al. [12] 2014/Kempf et al. [12] 2013/Gabali et al. [13] 2012/Pongpruttipan et al. [14] 2011/Bombeccari et al. [15] 2008/Ryu et al. [16] 2010/Crandley et al. [17] 2007/Fuentes-Paez [18] 2006/Dargent et al. [19] 2004/Tiemann et al. [20] 2003/Dargent et al. [21]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
17/F 10/M 9/F 18/M 11/F 9/M 14/F 18/F 13/F 17/M 11/M 15/F 11/M 7/M 9/F 5/F 11/M 10/F 11/F
Age/Sex
IHC, immunohistochemistry; DFS, disease free survival.
Year case reported/Author
No. Submandibular/II Lacrimal/I Orbital/I Orbital/ NA Conjunctiva/I B/L conjunctiva/II Thymus/I Skin/II Skin/II Skin/II Lip/I Lung/IV Lip/I Lip/I Lip/I B/L Conjunctiva/II Skin/I Conjunctiva/I Sinonasal tract/II
Site/Stage NC NC NC L L NA NA K K L K L K K L K NA K K
Clonality (IHC) Monoclonal Monoclonal Monoclonal Equivocal Monoclonal Monoclonal Monoclonal Monoclonal Negative Monoclonal NA Monoclonal NA NA Monoclonal Monoclonal Monoclonal Monoclonal Monoclonal
Clonality (molecular) Lupus Neg Neg Neg Neg Neg Trisomy 18/Immunodeficiency Neg Neg Neg Neg Di George/Evans syndrome Neg Neg Neg Hyper IGM/CHARGE syndrome Neg Neg Neg
Associated immunodeficiency/Autoimmune condition
TABLE I. Summary of All Reported Pediatric (
BRIEF REPORT A Unique Description of Stage IV Extranodal Marginal Zone Lymphoma (EMZL) in an Adolescent Associated With Gamma Heavy Chain Disease Nupur Mittal,
1,2,3 MD, *
Bing Zhu,
MD, PhD,
4
Sujata Gaitonde, MD,4 Yang Lu,5 and Mary Lou Schmidt, MD1
Extranodal Marginal zone lymphoma (EMZL) is a rare, usually localized disease in children. Advanced stage EMZL in adults is considered incurable, with prolonged remissions after chemotherapy. Gamma heavy chain disease (gHCD) is a rare disease of adults associated with lympho-proliferative processes with no comparable reports in children. A case of stage-IV EMZL with gHCD in an
adolescent is discussed including treatment with Bendamustine plus Rituximab. The patient remains disease free 18 months from diagnosis. This case highlights necessity for careful diagnostic work-up to identify indolent lymphomas in children which may respond to less toxic chemotherapy than used for common pediatric lymphomas. Pediatr Blood Cancer 2015;62:905–908. # 2015 Wiley Periodicals, Inc.
Key words: bendamustine-rituximab; extranodal marginal zone lymphoma; gamma heavy chain disease; pediatric NHL
INTRODUCTION Extranodal marginal zone lymphoma (EMZL) is an extremely rare diagnosis in children generally limited to the eye, skin, or stomach [1]. Gamma heavy chain disease (gHCD) is a rare disease of adults mostly associated with lympho-proliferative processes [2]. Advanced stage EMZL in adults is considered incurable, although prolonged remissions may occur after multi-agent chemotherapy [3,4]. Consensus recommendations for therapy of EMZL in children do not exist.
CASE REPORT A 15-year-old African-American male presents with 3 month history of non-tender submandibular swellings unresponsive to antibiotics; nasal congestion, chronic cough, chest pain, snoring, and 20 lb weight loss with normal labs but CT imaging confirming 5 4 periauricular, 3 3 occipital, and 2 2 inguinal masses but no hepatosplenomegaly. FDG PET/CT imaging is shown (Fig. 1). EBV, CMV, TB, Hepatitis B, HIV, H. pylori, ANA, and rheumatoid factor, bone marrow aspirate and biopsy were all negative. Serum protein electrophoresis revealed no abnormal bands. Multiple sequential biopsies of involved tissue revealed CD20þ and CD43þ sheets of small B cells, largely negative for CD10, CD79a, CD138, and MUM1. There were abundant plasma cells at the periphery of the lymphoid infiltrate with scattered positivity for IgA/IgM and Kappa/Lambda. In addition, there was a large subset of plasma cells expressing IgG heavy chain, but lacking cytoplasmic light chain. Numerous T cells were present exhibiting an appropriate CD4:CD8 ratio. CD21 highlighted the irregularly expanded follicular dendritic cell mesh works underlying the infiltrate. Immunophenotyping revealed an aberrant B-cell population. FISH for MYC/ IGH and molecular studies for clonal B-cell and T-cell gene rearrangements were negative. These results were highly suggestive of an atypical lymphoplasmacytic proliferation consistent with MZL with gHCD (Fig. 1A–H). This is a previously unidentified and unreported case of stage IV EMZL in a previously healthy pediatric patient. Repeat PET/CT imaging revealed progressive lung disease prompting initiation of chemotherapy: Bendamustine (90 mg/m2 on days 1 and 2 of a 4-week cycle) and Rituximab (375 mg/m2 on day 1 C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25419 Published online 8 February 2015 in Wiley Online Library (wileyonlinelibrary.com).
of cycle) [5]. Within 9 days, cervical lymphadenopathy and respiratory distress improved markedly and after 4 of 6 cycles, the patient had a normal physical exam and post-therapy FDG PET/CT imaging is shown (Fig. 1J). Following the final cycle, he developed prolonged neutropenia with gingivitis which slowly resolved. Patient remains in complete remission 12 months from end of therapy.
DISCUSSION Marginal zone lymphomas (MZLs), consist of 5–15% of nonHodgkin lymphomas in adults, are subtyped depending on organ of origin-EMZL including mucosa associated lymphoid tissue (MALT) lymphomas, splenic and nodal MZLs [3]. The average age of presentation of EMZL is 60 years. Concurrent conditions include H. pylori gastritis; Chlamydia associated orbital infections and autoimmune processes. Most patients with EMZL present with stage I or II disease [3]. In the largest report on EMZL (n ¼ 180), 20% had stage IV disease, 8% had lung involvement, and 12% had involvement of multiple mucosal sites [4]. Very few cases/small series of pediatric EMZL have been reported; the largest included only 4 cases 18 years, with newly diagnosed stage III or IV indolent or mantle-cell lymphoma compared Bendamustine/Rituximab (B-R) to R-CHOP. For all indolent lymphomas and EMZL patients, the B-R regimen had significantly better PFS compared to R-CHOP (B-R: 57 monthsþ vs. R-CHOP 47 months) ,significantly increased rate of CR and significantly less serious adverse events especially grade 3–4 neutropenia [5]. B-R is now one of the frontline regimens per NCCN guidelines for adult EMZL. This regimen has not been previously reported to treat a pediatric patient for management of an indolent lymphoma. Management for pediatric MZL varies. Taddesse et al. reported 22 patients (four were EMZL) who received local radiation (56%), excision and close follow-up (22%), or chemotherapy alone (22%) with excellent outcome after short follow-up of 1–24 months [1]. Four patients with EMZL identified among 2,703 participants in NHL-BFM 90 and 95 studies, all of whom had
Pediatr Blood Cancer DOI 10.1002/pbc
2003/Taddesse-Heath et al. [1] 2003/Taddesse-Heath et al. [1] 2003/Taddesse-Heath et al. [1] 2003/Taddesse-Heath et al. [1] 2006/Claviez et al. NHL/BFM [7] 2010/Kram et al. [10] 2012/Naithani et al. [11] 2014/Kempf et al [12] 2014/Kempf et al. [12] 2014/Kempf et al. [12] 2013/Gabali et al. [13] 2012/Pongpruttipan et al. [14] 2011/Bombeccari et al. [15] 2008/Ryu et al. [16] 2010/Crandley et al. [17] 2007/Fuentes-Paez [18] 2006/Dargent et al. [19] 2004/Tiemann et al. [20] 2003/Dargent et al. [21]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
17/F 10/M 9/F 18/M 11/F 9/M 14/F 18/F 13/F 17/M 11/M 15/F 11/M 7/M 9/F 5/F 11/M 10/F 11/F
Age/Sex
IHC, immunohistochemistry; DFS, disease free survival.
Year case reported/Author
No. Submandibular/II Lacrimal/I Orbital/I Orbital/ NA Conjunctiva/I B/L conjunctiva/II Thymus/I Skin/II Skin/II Skin/II Lip/I Lung/IV Lip/I Lip/I Lip/I B/L Conjunctiva/II Skin/I Conjunctiva/I Sinonasal tract/II
Site/Stage NC NC NC L L NA NA K K L K L K K L K NA K K
Clonality (IHC) Monoclonal Monoclonal Monoclonal Equivocal Monoclonal Monoclonal Monoclonal Monoclonal Negative Monoclonal NA Monoclonal NA NA Monoclonal Monoclonal Monoclonal Monoclonal Monoclonal
Clonality (molecular) Lupus Neg Neg Neg Neg Neg Trisomy 18/Immunodeficiency Neg Neg Neg Neg Di George/Evans syndrome Neg Neg Neg Hyper IGM/CHARGE syndrome Neg Neg Neg
Associated immunodeficiency/Autoimmune condition
TABLE I. Summary of All Reported Pediatric (
