Copyright © 2012 John Wiley & Sons A/S
J Cutan Pathol 2012 doi: 10.1111/j.1600-0560.2012.01954.x John Wiley & Sons. Printed in Singapore
Journal of Cutaneous Pathology
Bi-clonal, multifocal primary cutaneous marginal zone B-cell lymphoma: report of a case and review of the literature Bi-clonality is a rare phenomenon seen in approximately 5% of chronic B-cell lymphoproliferative disorders. Both true bi-clonality and somatic hypermutation resulting in intraclonal evolution have been described. We present the case of a 37-year-old female who developed extranodal marginal zone B-cell lymphoma with immunohistochemical studies showing monotypic immunostaining of plasma cells for immunoglobulin lambda light chain on her right arm in 2008. Three years later, she developed a second focus of extranodal marginal zone B-cell lymphoma on her left arm, but immunohistochemical studies demonstrated monotypic immunostaining of plasma cells for immunoglobulin kappa light chain confirmed after repeat analysis. Evaluation for systemic lymphoma with laboratory and imaging studies was negative. Together, the findings were consistent with bi-clonal, multifocal extranodal primary cutaneous marginal zone B-cell lymphoma. We present this case to highlight a rare phenomenon within primary cutaneous marginal zone lymphomas. Keywords: bi-clonality, cutaneous marginal zone lymphoma, MALT lymphoma Nicholson KM, Patel KP, Duvic M, Prieto VG, Tetzlaff MT. Bi-clonal, multifocal primary cutaneous marginal zone B-cell lymphoma: report of a case and review of the literature. J Cutan Pathol 2012. © 2012 John Wiley & Sons A/S.
Bi-clonality is a rare phenomenon described in approximately 5% of chronic B-cell lymphoproliferative disorders whereby two or more distinct B-cell clones arise in the same patient. Bi-clonality has been most commonly described in the setting of atypical chronic lymphocytic leukemia (CLL) or hairy cell leukemia, but can also occur in mucosa-associated lymphoma tissue (MALT) lymphomas.1 B-cell lymphoproliferative disorders exhibiting bi-clonality can exhibit morphologic homogeneity, but irrespective of their histopathologic appearance, will contain distinct immunoglobulin heavy chain gene rearrangements. The frequency of bi-clonality in cutaneous
Kimberly M. Nicholson1 , Keyur P. Patel2 , Madeleine Duvic3 , Victor G. Prieto1,3 and Michael T. Tetzlaff1 1 Department
of Pathology, Division of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 2 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, and 3 Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Michael T. Tetzlaff, Department of Pathology, Division of Dermatopathology, The University of Texas MD Anderson Cancer Center, Unit 085, 1515 Holcombe Boulevard, Houston, TX 77030, USA Tel: (713) 792-2585 Fax: (713) 745-0778 e-mail:
[email protected] Accepted for publication April 8, 2012
marginal zone B-cell lymphoma is not known, but several cases have been recently described.2 – 5 We present another case of a 37-year-old female who developed bi-clonal, multifocal extranodal primary cutaneous marginal zone B-cell lymphoma over a 3-year time period, and we review the current literature on the subject. Report of a Case The propositus is a 37-year-old woman with a history of vitamin D deficiency who initially presented to her physician in Lebanon in 2009 after noticing
1
Nicholson et al.
A
C
B
D
Fig. 1. Histopathologic features of the right upper arm biopsy (left column) and left dorsal forearm biopsy (right column). A, C) Scanning magnification reveals a perivascular and periadnexal lymphoid infiltrate (hematoxylin/eosin, 2×). B, D) The infiltrate is composed of primarily small lymphocytes and plasma cells (hematoxylin/eosin, 10×).
an approximately 3-cm, pruritic, well-circumscribed violaceous plaque on the right upper arm. At that time, she was provided with a prescription for fluocinolone 0.025% cream. She applied the cream for 10 days as instructed on three separate occasions over a 2-year time period. She noted slight improvement in the plaque with use of the steroid, but never complete resolution. Given the failure to respond to therapy, a biopsy was performed in 2011 and demonstrated a moderately dense, pan-dermal mononuclear infiltrate with a periadnexal and perivascular distribution and extension into the superficial subcutis but without prominent epidermotropism (Fig. 1A,B). The infiltrate was comprised predominantly of small, mature lymphocytes with round, hyperchromatic nuclei, and there were admixed plasma cells. Immunohistochemical studies demonstrated a predominance of CD20-positive B-cells with an admixture of CD3-positive T-cells. These B-cells further showed frank immunoglobulin lambda light chain restriction, with near complete absence of labeling with antibodies for immunoglobulin kappa light chain (Fig. 2A–C). These findings supported the diagnosis of extranodal marginal zone lymphoma. The patient
2
then presented to our institution for further work-up and therapeutic options. At that time, physical exam demonstrated a separate 1.5 cm well-circumscribed faintly pink plaque on the left dorsal forearm, which had developed 3 months prior. Biopsy of this plaque revealed a similar, albeit less dense, nodular, perivascular and periadnexal infiltrate of small, mature lymphocytes admixed with plasma cells (Fig. 1C,D). Immunohistochemical studies again demonstrated a predominance of CD20-positive B-cells with an admixture of CD3-positive T-cells. However, in contrast to the initial lesion, the plasma cells now displayed a frank predominance of immunoglobulin kappa light chain expression with a kappa : lambda ratio of greater than 10 : 1 (Fig. 2D–F). Given this discrepancy, an in situ hybridization study for immunoglobulin light chain expression was repeated on both specimens, and the findings were confirmed. Molecular studies completed using polymerase chain reaction (PCR) demonstrated oligoclonal immunoglobulin heavy chain gene rearrangement for the original right upper arm specimen, while the left dorsal forearm specimen revealed a monoclonal immunoglobulin heavy chain gene rearrangement of
Biclonal marginal zone lymphoma
A
D
B
E
C
F
Fig. 2. Immunohistochemical features of the right upper arm biopsy (left column) and left dorsal forearm biopsy (right column). A, D) CD20 highlights the B-cell population (10×). B, E) Kappa light chain immunohistochemical staining was nearly absent in the right upper arm specimen but shows a clear predominance in the left dorsal forearm tissue (10×). C, F) Lambda light chain immunohistochemical staining shows monotypic immunostaining in the right upper arm lesion but is nearly absent in the tissue from the left dorsal forearm.
a non-overlapping size (data not shown). Therefore, despite the relative paucity of the B-cell infiltrate in the second biopsy specimen, the combined findings of striking light chain restriction – both by immunohistochemistry and in situ hybridization – together with the presence of monoclonal heavy chain gene rearrangement supported the diagnosis of primary cutaneous marginal zone lymphoma. Given these findings, the patient underwent further clinical evaluation for the possibility of a systemic lymphoma. Given the reported association of multiple cutaneous B-cell lymphomas with systemic lymphoma (in particular, Angioimmunoblastic T-cell lymphoma),2 we performed additional molecular and immunohistochemical studies on the second biopsy specimen (for which there was tissue available for study). PCR-based clonality assessment using T-cell receptor (TCR) beta and TCR-γ primers were consistent with a polyclonal T-cell population (data
not shown). Immunohistochemical studies revealed a mixed population of perivascular CD3-positive T-cells with a CD4 : CD8 ratio of approximately 2 : 1 with preservation of CD7 expression and scattered PD-1 positive T-cells (data not shown). Additional laboratory evaluation demonstrated a complete blood count, lactate dehydrogenase, quantitative immunoglobulins, beta-2-microglobulin, liver function tests, chemistry panel, RPR and Borrelia serologies that were all within normal limits. Serologic studies for Helicobacter pylori demonstrated an elevated IgM antibody. However, an upper endoscopic study revealed no abnormalities, and biopsies from the stomach and duodenum showed no evidence of either H. pylori infection or MALT lymphoma. A computed tomography scan of the chest, abdomen and pelvis was performed and was negative for systemic lymphoma. Given her negative systemic work-up and combined histopathologic
3
Nicholson et al. Table 1. Previous case reports of bi-clonal primary cutaneous marginal zone lymphoma and available descriptive data References
Age (years)
Sex
Site(s)
3
Unknown
Unknown
Unknown single site
3
Unknown
Unknown
Unknown single site
4
33
Male
5
33
Male
2
66
Male
Current report
37
Female
Left arm Right arm Right thigh Back Posterior left arm Left shoulder Upper back Posterior neck
IgG kappa IgG lambda IgG lambda IgM kappa Lambda Kappa Lambda Kappa Lambda Lambda Kappa Kappa
Right upper arm Left forearm
Lambda Kappa
findings, the patient was diagnosed with bi-clonal, multifocal primary cutaneous extranodal marginal zone B-cell lymphoma. She was treated with topical clobetasol 0.05% cream twice daily for 1 month and local radiation therapy with 2 Gy per fraction for a total of two fractions with a 9 MeV electron dose. She has since returned to Lebanon and has been lost to follow-up. Discussion Bi-clonality within chronic B-cell lymphoproliferative disorders has been described in CLL/small lymphocytic lymphoma, MALT lymphoma including cutaneous marginal zone lymphoma, hairy cell leukemia, large cell lymphoma and numerous composite lymphomas.1 Bi-clonality can present with aberrant immunoglobulin heavy or light chain rearrangements. Sanchez et al. evaluated the immunohistochemical and molecular characteristics of these heterogeneous B-cell lymphoproliferative disorders and found that such lesions showed unrelated IgH gene rearrangements and distinct genetic anomalies (as demonstrated by Fluorescence in situ hybridization). These findings argued that such lesions represent the independent development of truly distinct clones (i.e. biclonality) rather than intraclonal evolution.6 A rare variation of bi-clonality has also been described in composite lymphomas. Composite lymphoma is defined as two or more different types of lymphoma occurring within the same tissue or organ7 ; bi-clonality in composite lymphomas has been described in various combinations of diffuse large B-cell lymphoma, follicular lymphoma, lymphoblastic lymphoma, Waldenstrom’s macroglobulinemia, mantle cell
4
Light chain expression
Time elapsed
Associated disorders
0 days
None known
0 days
None known
2 years
None known
0 days
Hepatitis B
3 months 6 months
Angioimmunoblastic T cell lymphoma Diffuse large B cell lymphoma Vitamin D deficiency
2 years
lymphoma and non-Hodgkins lymphoma.1 However, in contrast to true bi-clonality, most composite lymphomas typically represent intraclonal evolution: distinct morphologic variants arising from a common progenitor clone.8 Bi-clonality in cutaneous marginal zone B-cell lymphoma has been described relatively recently (Table 1). In a larger series of cutaneous marginal zone lymphomas, Edinger et al. described two cases with bi-clonality. The first demonstrated clones for both IgG kappa and IgG lambda, while the second demonstrated clones for both IgG lambda and IgM kappa. However, in each of these patients, the two separate clones were identified in the same punch biopsy, obtained at the same time point.3 This is somewhat different from our patient, who developed a second dominant clone several years following her initial diagnosis. The same group reported an additional case of a 33-year-old male who developed bi-clonal marginal zone lymphoma with lambda immunoglobulin light chain restriction in a biopsy from the left arm, but kappa immunoglobulin light chain restriction in a biopsy from the right arm arising 2 years later. Interestingly, this patient also had biopsy-proven sub-clinical involvement of marginal zone lymphoma noted in mildly erythematous skin from the right thigh; the latter area was biopsied after persistent concern from the patient for recurrent disease despite the clinicians’ expectation of a normal result. Of note, many of this patient’s lesions were comprised of relatively sparse B-cell populations, similar to that seen in the second biopsy of our index case.4 Ferrara et al. also reported a patient with hepatitis B who developed multiple simultaneous papules and plaques with varying clinical
Biclonal marginal zone lymphoma morphology, and all that were biopsied were diagnosed as cutaneous marginal zone lymphoma. A plaque located on the back demonstrated distinct kappa immunoglobulin light chain restriction, while a papule on the left arm demonstrated lambda immunoglobulin light chain restriction. Notably, this patient also had spontaneous resolution of his papules with resultant anetoderma and mucin deposition.5 Finally, Bayerl et al. described a patient who developed multiple different papules and plaques over several years that were diagnosed as cutaneous marginal zone lymphoma with both kappa and lambda light chain restriction; ultimately this patient developed a systemic diffuse large B-cell lymphoma and simultaneous angioimmunoblastic T-cell lymphoma.2 Interestingly, retrospective PCR studies for a TCR gene rearrangement on each cutaneous marginal zone lymphoma demonstrated monoclonality for TCR-gamma with the same sized clone. In contrast, although there were perivascular T-cell infiltrates in our biopsy specimens, a thorough analysis of the second lesion revealed a mixed, apparently reactive T-cell population without evidence of clonality. Bi-clonality has been previously described in MALT lymphomas arising in tissues other than the skin, including salivary, lacrimal and gastric cases.8 – 11 Several studies exploring either multifocal gastric MALT lymphomas or composite MALT lymphomas with associated diffuse large B-cell lymphoma have verified the presence of two or more distinct, unrelated clonal populations. Yamauchi et al. evaluated the clonal relationship in multi-focal gastric MALT lymphoma via immunoglobulin heavy chain gene rearrangement analysis by PCR and demonstrated either two or more dominant clones in 51 of 86 evaluated specimens, with monoclonality seen in only 21. The remaining 14 specimens demonstrated either a polyclonal pattern or no PCR products.11 This suggests that true bi-clonality in non-cutaneous MALT lymphoma is probably an under-estimated phenomenon and may occur with equal frequency to intraclonal evolution. Similarly, Konoplev et al. examined the molecular profiles in four patients with multi-focal MALT lymphoma located at distinct sites (stomach and nasopharynx, stomach and lung, ocular and nasopharnyx, ocular and parotid). In each case, the second lesion evolved over time periods ranging from 1 to 32 months, and in three of the four cases, the second MALT lymphoma was found to have a completely unrelated IgH gene rearrangement. These results suggest that at least a subset of MALT lymphomas occurring at multiple sites more often arise independently as a second dominant B-cell clone.12
The cause of bi-clonality is unknown, but proposed to be related to chronic antigen stimulation leading to oligoclonal B-cell pools – out of which arise distinct, dominant clones. Chronic antigen stimulation has also been suggested to play an important role in MALT lymphomas, as evidenced by frequent association with a chronic inflammatory and/or infectious conditions (chronic sialadenitis or Sjogren’s syndrome, H. pylori infection, Borrelia burgdorferi infection, Hashimoto thyroiditis).13 Eradication of the chronic stimulus may result in complete remission of the MALT lymphoma as well, as seen in some cases associated with H. pylori.14 It is thus reasonable, if not expected, to see bi-clonality within MALT lymphomas given their potential association with chronic antigen stimulation. However, not all cases of MALT lymphoma are associated with a known/common inflammatory condition – particularly cutaneous marginal zone lymphoma. Currently, only one previously reported case of bi-clonal cutaneous marginal zone lymphoma was associated with a condition that might be considered a state of chronic antigen stimulation, hepatitis B.5 Our patient did not have any conditions that would support a chronic inflammatory state; her past medical history was notable only for vitamin D deficiency. However, multiple reports in the literature support the association of low vitamin D with chronic inflammatory and/or autoimmune conditions, including type I diabetes mellitus, multiple sclerosis, Crohn disease and rheumatoid arthritis among others. Importantly, 1,25(OH)2 D3 acts as a transcription factor on the promoter region of the IFN-gamma gene resulting in a switch toward primarily a Th1 cytokine profile; thus, deficiency of vitamin D could promote a pro-inflammatory state as proposed by many authors.15 Mechanisms other than chronic antigen stimulation may also underlie the development of multiple dominant cutaneous B-cell clones. Peng et al. evaluated the frequency of replication error phenotype in MALT lymphomas (mucosal, spleen, liver and muscle) and demonstrated microsatellite instability in 21 of 40 cases (52.5%). Interestingly, the replication error phenotype was also seen in 5 of 7 tumor-adjacent reactive lymphoid infiltrates, suggesting a possible source for the neoplastic B-cells. In this same study, the incidence of p53 mutations was significantly associated with the replication error phenotype and occurred in 11 of the 40 cases.16 These findings suggest that background genetic instability might account for stepwise compounding DNA mutations culminating in the development of MALT lymphoma. Again, this may not explain why in our case, and at least several other cases, bi-clonal cutaneous marginal zone lymphoma develops in otherwise healthy individuals.
5
Nicholson et al. There are little data describing outcome of B-cell lymphomas where bi-clonality is found. In the largest series of bi-clonal chronic B-cell lymphoproliferative disorders, 53 patients were evaluated for differences in clinical presentation and outcome; out of this group, only those with CLL were in sufficient numbers to compare to patients with a single dominant clone. Patients with CLL with two or more B-cell clones had a statistically significantly higher incidence of splenomegaly, lower total white blood cell and absolute lymphocyte counts. Bi-clonality conferred a slightly higher incidence of death, but this was not statistically significant. In addition, those CLL patients with two or more B-cell clones were more likely to require treatment for their disease during the followup period of the study, arguing that they possibly endured a more aggressive clinical course.1 To date, the clinical significance of bi-clonality in MALT lymphomas is not known. Long-term survival in patients with multifocal MALT lymphoma in the absence of bone marrow involvement does not significantly differ when compared to those with unifocal disease; this implies that multifocality, even when involving distinct sites or different tissues, does not necessarily suggest dissemination.17 Future studies are necessary to determine whether bi-clonality in cutaneous marginal zone lymphoma confers any prognostic
significance. However, a single case report demonstrating development of nodal angioimmunoblastic T-cell lymphoma and diffuse large B-cell lymphoma could suggest that these patients are at risk for the development of additional lymphoproliferative disorders, and may require closer clinical follow-up.2 Our patient unfortunately traveled from outside the United States to seek care at our institution, and long-term clinical follow-up has not been available. In summary, bi-clonal primary cutaneous marginal zone lymphoma is a relatively recently recognized entity and may be more common than previously appreciated. Patients may develop lesions demonstrating unrelated clones at either the same time point or months to years following the initial diagnosis (as seen in our index case). Chronic antigen stimulation probably plays a role in the development of bi-clonality, but as demonstrated in our case and in several others, there is often no known chronic inflammatory state in a given patient to create suspicion for the diagnosis. Regarding clinical behavior, outcomes in patients with bi-clonal primary cutaneous marginal zone lymphoma are mostly unknown. However, given the possible association in one case with aggressive systemic lymphomas, close clinical follow-up is recommended.
References 1. Sanchez ML, Almeida J, Gonzalez D, et al. Incidence and clinicobiologic characteristics of leukemic B-cell chronic lymphoproliferative disorders with more than one B-cell clone. Blood 2003; 102: 2994. 2. Bayerl MG, Hennessy J, Ehmann WC, Bagg A, Rosamilia L, Clarke LE. Multiple cutaneous monoclonal B-cell proliferations as harbingers of systemic angioimmunoblastic Tcell lymphoma. J Cutan Pathol 2010; 37: 777. 3. Edinger JT, Kant JA, Swerdlow SH. Cutaneous marginal zone lymphomas have distinctive features and include 2 subsets. Am J Surg Pathol 2010; 34: 1830. 4. Edinger JT, Lorenzo CR, Breneman DL, Swerdlow SH. Primary cutaneous marginal zone lymphoma with subclinical cutaneous involvement and biclonality. J Cutan Pathol 2011; 38: 724. 5. Ferrara G, Cusano F, Robson A, Stefanato CM. Primary cutaneous marginal zone Bcell lymphoma with anetoderma: spontaneous involution plus de novo clonal expansion. J Cutan Pathol 2011; 38: 342.
6
6. Sanchez ML, Almeida J, Lopez A, et al. Heterogeneity of neoplastic cells in Bcell chronic lymphoproliferative disorders: biclonality versus intraclonal evolution of a single tumor cell clone. Haematologica 2006; 91: 331. 7. Kim H. Composite lymphoma and related disorders. Am J Clin Pathol 1993; 99: 445. 8. Delville JP, Heimann P, El Housni H, et al. Biclonal low grade B-cell lymphoma confirmed by both flow cytometry and karyotypic analysis, in spite of a normal kappa/ lambda Ig light chain ratio. Am J Hematol 2007; 82: 473. 9. Bahler DW, Miklos JA, Swerdlow SH. Ongoing Ig gene hypermutation in salivary gland mucosa-associated lymphoid tissue-type lymphomas. Blood 1997; 89: 3335. 10. Cabras AD, Candidus S, Fend F, et al. Biclonality of gastric lymphomas. Lab Invest 2001; 81: 961. 11. Yamauchi A, Tomita Y, Miwa H, Sakamoto H, Sugiyama H, Aozasa K. Clonal evolution of gastric lymphoma of mucosa-associated lymphoid tissue type. Mod Pathol 2001; 14: 957.
12. Konoplev S, Lin P, Qiu X, Medeiros LJ, Yin CC. Clonal relationship of extranodal marginal zone lymphomas of mucosaassociated lymphoid tissue involving different sites. Am J Clin Pathol 2010; 134: 112. 13. Piris MA, Arribas A, Mollejo M. Marginal zone lymphoma. Semin Diagn Pathol 2011; 28: 135. 14. Vanagunas A. Eradication of Helicobacter pylori and regression of B-cell lymphoma. Biomed Pharmacother 1997; 51: 156. 15. Borges MC, Martini LA, Rogero MM. Current perspectives on vitamin D, immune system, and chronic diseases. Nutrition 2010; 27: 399. 16. Peng H, Chen G, Du M, Singh N, Isaacson PG, Pan L. Replication error phenotype and p53 gene mutation in lymphomas of mucosaassociated lymphoid tissue. Am J Pathol 1996; 148: 643. 17. Raderer M, Vorbeck F, Formanek M, et al. Importance of extensive staging in patients with mucosa-associated lymphoid tissue (MALT)-type lymphoma. Br J Cancer 2000; 83: 454.