Mantle cell lymphoma as a component of composite lymphoma: clinicopathologic parameters and biologic implications

Human Pathology (2012) 43, 467–480

www.elsevier.com/locate/humpath

Progress in pathology

Mantle cell lymphoma as a component of composite lymphoma: clinicopathologic parameters and biologic implications☆ Thomas G. Papathomas MD a,b , Ioannis Venizelos MD a , Cherie H. Dunphy MD c , Jonathan W. Said MD d , Michael L. Wang MD e , Elias Campo MD f , Steven H. Swerdlow MD g , John C. Chan MD h , Carlos E. Bueso-Ramos MD, PhD i , Dennis D. Weisenburger MD h , L. Jeffrey Medeiros MD i , Ken H. Young MD, PhD i,⁎ a

Department of Pathology, Hippokration General Hospital of Thessaloniki, 54642 Thessaloniki, Greece Department of Pathology, Erasmus MC University Medical Center Rotterdam, 3015 GE Rotterdam, The Netherlands c Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA d Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA e Department of Myeloma/Lymphoma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA f Department of Anatomic Pathology, Hospital Clinic, University of Barcelona, 08014 Barcelona, Spain g Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA h Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA i Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA b

Received 10 July 2011; revised 30 August 2011; accepted 31 August 2011

Keywords: Mantle cell lymphoma; Composite lymphoma; Clonal relationship; Small lymphocytic lymphoma; Chronic lymphocytic leukemia; Follicular lymphoma; Plasma cell neoplasm; Marginal zone lymphoma; Classical Hodgkin lymphoma; Plasmablastic lymphoma; Burkitt lymphoma

Summary Composite lymphoma is a rare circumstance in which 2 or more distinct types of lymphoma occur in a single anatomical location. Although composite lymphoma has been increasingly identified with the advent of molecular genetic techniques, this topic has only rarely been a specific focus of the medical scientific literature. In this review, we focus on mantle cell lymphoma occurring as a major pathologic component of composite lymphoma and emphasize the clinicopathologic features of these tumors and associated biologic implications. To date, 26 cases of composite lymphoma including a component of mantle cell lymphoma have been previously published. Issues of clonal relatedness between the individual lymphoma components and emerging biologic implications as well as potential diagnostic pitfalls are evaluated. © 2012 Elsevier Inc. All rights reserved.

☆

The study is supported by The University of Texas MD Anderson Cancer Center Institutional R&D Fund, The University of Texas MD Anderson Cancer Center Institutional Research Grant Award, The myeloma SPORE Research Development Program Award, Gundersen Medical Foundation Award, and Forward Lymphoma Fund. This study is also partially supported by NCI/NIH (R01CA138688 and 1RC1CA146299). ⁎ Corresponding author. The University of Texas MD Anderson Cancer Center, Department of Hematopathology, Houston, Texas 77230-1439. E-mail address: [email protected] (K. H. Young). 0046-8177/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2011.08.024

468

1. Introduction The term composite lymphoma (CL), first proposed by Custer in 1954, has been inconsistently used over the years but is most commonly used to describe the occurrence of 2 unrelated types of lymphoma involving the same anatomical site [1]. Traditionally, the definition of CL has been based on morphological and immunophenotypic examination [2]. The application of molecular genetic techniques to the analysis of CLs, however, has shown clonal relatedness in a subset of CL cases in which the components were thought to be independent based on traditional criteria. Müller-Hermelink et al [3] recognizing these issues have attempted to provide a more up-to-date and practical definition, stating “the term composite lymphoma should be reconsidered as a merely descriptive term for one morphological manifestation encompassing at least 2 different biologic processes, namely, clonal transformation and coexistence of 2 clonally unrelated types of lymphoma, which may have the same pathogenetic background (eg, immunodeficiency-related) or may occur independently by chance.” Of note, it is suggested that a hematopathologist should designate and quantify each individual component [1], particularly in the context of different natural histories, prognosis, and therapeutics. In-depth molecular understanding of CLs also may shed new light on our understanding of lymphomagenesis. In this review, we focus on and provide a comprehensive review of mantle cell lymphoma (MCL) occurring as a component of CL, with a special emphasis on the clinicopathologic features and biologic implications of this circumstance and the aim of identifying some of the research questions that need to be addressed for this rare manifestation of lymphoma. Relevant articles were obtained using the following database: National Library of Medicine's Pubmed covering the period up to the present day (May 2011) using the keywords composite mantle cell lymphoma, synchronous mantle cell lymphoma, mantle cell lymphoma transformation, extranodal mantle cell lymphoma, and composite lymphoma. References within these articles were also reviewed. Because the term MCL was first widely accepted in 1992 [4], a few cases of MCL designated by older names (eg, centrocytic lymphoma and intermediate differentiated lymphocytic lymphoma) potentially may not have been captured in the search.

2. CL with an MCL as major pathologic component MCL occurring in the context of a CL is exceedingly rare. In this comprehensive, retrospective literature review, we identified 26 cases of CL in which MCL was 1 component. Almost all documented cases (Table 1) were case reports [13-28] or included as a part of small case series with a different focus from that of this study. The other component

T. G. Papathomas et al. in these CL cases included follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), classical Hodgkin lymphoma (cHL), plasma cell neoplasms (PCN), marginal zone lymphoma (MZL), plasmablastic lymphoma (PBL), and Burkitt lymphoma (BL). The age range extended from the 5th to 10th decades, with a median age of 69.5 years. These were 13 women and 13 men. Sixteen CLs involved lymph nodes, and 9 involved extranodal sites including spleen (n = 3), soft tissues of the head region (n = 3), gastrointestinal tract (n = 2), and bone marrow (n = 1). One patient with CL had simultaneous involvement of lymph node and eyelid. FL was found to be the most frequent partner of MCL in these CLs, in 8 (30.8%). In decreasing order of frequency, other partners of MCL included CLL/SLL, 5 (19%); cHL, 5 (19%); PCN, 4 (15.4%); MZL, 2 (7.6%); PBL, 1 (3.8%); and BL, 1 (3.8%). Seven patients (27%) had a history of lymphoma before diagnosis of CL: 4 MCLs, 2 FLs, and 1 designated as a chronic lymphoproliferative disease.

2.1. FL-MCL Among the 8 known CL cases of FL-MCL in the literature, 5 were mainly nodal, whereas 3 involved extranodal sites: small intestine, orbit, and spleen (Fig. 1). All but 1 (case 4) were clonally unrelated or indefinite [5-12]. However, there is no definite proof of clonal independence in FL-MCL CLs for a few reasons. First, there is no continuity among the techniques used to determine clonal relatedness, and microdissection was performed in only 3 cases (all of which were in the unrelated/indefinite subset) [5-7]. Second, Roullet et al [6] found some evidence of clonal relatedness, as analysis of IGK by PCR (VK-Kde region) revealed the same monoclonal rearrangement, in contrast with other data emerging from their investigation, such as (1) separate translocations in immunophenotypically different cell subpopulations and (2) IGH analysis by PCR detected monoclonality only in the MCL component, supporting clonal unrelatedness. Therefore, in an effort to reconcile these findings, a common (ancestral) clonal origin with subsequent divergence could be speculated as suggested by Roullet et al [6]. The MCL component demonstrated an in situ growth pattern in 3 cases, a mixed mantle zone and nodular growth pattern in 2 cases, a diffuse growth pattern in 2 cases, and a mantle zone growth pattern in 1 case (Table 2). The finding of an in situ MCL component in these CL cases adds further to the notion that in situ MCL (along with in situ FL/intrafollicular neoplasia) is increasingly recognized in the routine clinical practice, either as an incidental finding in the setting of lymphoid hyperplasia or rarely with an unrelated lymphoproliferative disorder or metastatic nonlymphoid malignancy [29]. Whether these lesions will ever progress to clinically significant disease or simply correspond to relatively stable clonal proliferations of lymphoid cells is as

Clinicopathologic features of CLs with a MCL component with a special emphasis on the clonal relationship between the individual lymphoma components

Case Subtypes of no./Ref lymphoma

Age/ Medical history/clinical sex presentation and signs

Anatomical site

Clonal Methods used to detect any relationship evidence of clonal relationship

1 [5]

MCL + FL

58/F NA/small bowel obstruction

Unrelated

Microdissection, IgVH sequencing

2 [6]

MCL + FL

Unrelated

3 [7]

MCL + FL

84/F Recurrent rectal carcinoma/multiple radiologically detected splenic masses, suggestive of metastatic carcinoma 65/M NA/persistent left inguinal lymphadenopathy

Small intestine, mesenteric lymph nodes: MCL involvement Spleen

4 [8]

MCL + FL

Microdissection, FISH and immuno-FISH, IgH and IgK PCR analysis Microdissection, FISH, IGH PCR analysis Microdissection, IgVH sequencing

5 [9]

MCL + FL

6 [10] MCL + FL 7 [11] MCL + FL

8 [12] MCL + FL 9 [13] MCL + CLL/SLL

10 [14] MCL + CLL/SLL

11 [15] MCL + CLL/SLL 12 [16] MCL + CLL/SLL

13 [5] MCL + CLL/SLL 14 [17] MCL + cHL

15 [19] MCL + cHL 16 [19] MCL + cHL 17 [20] MCL + cHL

70/F Long-standing history (17 y) of nodal FL/chronic peripheral lymphadenopathy 67/F 1-y history of MCL involving the Waldeyer ring/right cervical lymphadenopathy 40/M 6-y history of FL/generalized lymphadenopathy 56/M Unremarkable/generalized lymphadenopathy (laterocervical, supraclavicular, axillary, retroperitoneal, inguinal) 73/M NA/retrobulbar ache, proptosis (3 mm), chemosis, lymphangiectasis, slight limitation of downgaze 73/M Long-standing history (22 y) of malignant melanoma/4-mo history of a lump in his left thigh with multiple hard left inguinal lymph nodes 86/F Alzheimer disease, elevated blood pressure, arthritis/ bilateral cervical and axillary lymphadenopathy and on CT scan: mediastinal and retroperitoneal lymphadenopathy 86/M NA/cervical, axillary and inguinal lymphadenopathy and hepatomegaly 84/F Diabetes, coronary artery disease, and stage 2 chronic kidney disease/anemia, thrombocytopenia and splenomegaly 69/F NA/laryngectomy and bilateral neck dissection for a T3 squamous cell carcinoma of the vocal cords 45/M 3-y history of MCL/residual disease, resection of an abdominal lymph node and the spleen 61/M 10-y history of chronic lymphoproliferative disorder/isolated splenomegaly 66/M Unremarkable/left cervical lymphadenopathy, a left tonsillar mass, and a nodular eyelid mass 69/F Rheumatoid arthritis, asthma, posttherapeutic hypothyroidism/right cervical and bilateral axillary, lymphadenopathy

Lymph node spleen, liver, PB: MCL involvement Lymph node of the left cervical region Lymph node of the right cervical region Lymph node of the cervical region Lymph node of the inguinal region

Intraconal and superonasal orbit, mid- and posterior orbit Lymph node of the left inguinal region PB/BM: CLL

Unrelated Related

Indefinite a IgH PCR analysis NA NA Indefinite b FISH, IgH PCR analysis

Unrelated

FISH

Unrelated

FISH

Lymph node PB: CLL/SLL + MCL Unrelated

FISH, conventional cytogenetics, IgH and IgK PCR analysis

Lymph node: MCL + CLL/SLL PB: Unrelated CLL/SLL +MCL Bone Marrow PB: CLL/SLL + MCL Unrelated

IgH PCR analysis c FISH

Lymph nodes PB: CLL/SLL + MCL Unrelated

Microdissection, IgVH sequencing

Lymph node

Related

Spleen

Unrelated

Microdissection, IgVH sequencing [17] LDI PCR analysis of IgH-associated chromosomal translocations [18] Microdissection, IgVH sequencing

Eyelid and lymph node of the left cervical region Lymph node of the axillary region

Unrelated

Microdissection, IgVH sequencing

NA

NA

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Mantle cell lymphoma as a component of composite lymphoma

Table 1

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Table 1 (continued) Case Subtypes of no./Ref lymphoma

Age/ Medical history/clinical sex presentation and signs

Anatomical site

Clonal Methods used to detect any relationship evidence of clonal relationship

18 [21] MCL + cHL

80/F 4-year history of MCL, rheumatoid arthritis, chronic thyroiditis, esophageal cancer, and subsequent gastric cancer/CT scan findings: bilateral enlargement of the lacrimal glands and enlarged lymph nodes 75/F NA/slightly nodular, upper eyelid mass, proptosis (3 mm)

Lymph node of the right inguinal region

NA

19 [12] MCL + plasma cell neoplasm

20 [22] MCL + PCN 21 [23] MCL(i

+ ii) d

+ PCN

22 [24] MCL + PCN

64/M NA/generalized lymphadenopathy and splenomegaly 62/M NA/vocal fatigue and an erythematous nasopharyngeal mass

91/F NA/high-grade tumor, splenomegaly, B symptoms

FISH, IGH PCR analysis

Microdissection, IGH PCR analysis

Nasopharynx

Unrelated

Microdissection, IGH PCR analysis [23], microdissection, FICTION analysis, capillary gel electrophoresis, immunoglobulin variable region RFLP/IgH [24] Microdissection, FICTION analysis, capillary gel electrophoresis, immunoglobulin variable region RFLP/IgH FISH, IgVH sequencing FISH, IgVH gene PCR analysis (without sequencing)

Lymph node of the left cervical region

Unrelated

Spleen Lymph node of the posterior cervical region

Unrelated Unrelated

Large intestine 18/26 lymph nodes: PBL, omental lymph node: MCL

Related

IGH PCR analysis, FISH e

Perisplenic lymph node, spleen: MCL

Related

FISH

Abbreviations: Ref, reference; F, female; M, male; NA, not available; BM, bone marrow; PB, peripheral blood; CT, computed tomography; FICTION, fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms; RFLP, restriction fragment length polymorphism; WBC, white blood cell. a No sufficient evidence to prove common clonality; microdissection, gene sequencing techniques, and FISH were not possible owing to tissue consumption. b Both FL and MCL shared the same Ig class restriction (IgM/D/κ), and in addition, a single band of rearrangement was evidenced by PCR analysis; albeit, no laser capture microdissection was performed and, hence, there is no direct evidence of the coexistence of 2 different clones. c PCR-based IgH rearrangement molecular studies showed that the B-cell clone found in the lymph node was different from the one which predominated in blood. d Two immunophenotypically distinct MCLs. e These studies were performed on 2 separate tissue blocks consisting exclusively of lymph nodes replaced by PBL and MCL.

T. G. Papathomas et al.

23 [25] MCL + SMZL 78/M NA/isolated splenomegaly 24 [26] MCL + nodal MZL 72/F Long-standing history (37 y) of breast cancer/superficial swelling in the posterior cervical region 25 [27] MCL + PBL 82/M Prostatic cancer, systemic lupus erythematosus, ischemic heart disease, atrial fibrillation/weight loss, fatigue and imaging studies: masses in the cecum and ascending colon, splenomegaly, abdominal and thoracic lymphadenopathy 26 [28] MCL + BL 57/F 2-y history of MCL (initial leukemic presentation)/precipitous increase in WBC count with a concomitant drop in hemoglobin and platelet count and splenomegaly

Eyelid orbit (superonasal and nasal, Unrelated anterior), retroperitonal, inguinal, epigastric and coeliac lymph nodes, lung and bone marrow: MCL involvement Lymph node of the inguinal region Unrelated

NA

Mantle cell lymphoma as a component of composite lymphoma

471

A

B

C

D

E

F MCL MCL MCL

CD3

CD5

CD5

G

H

I

CD10

Cyclin D1

Cyclin D1

Fig. 1 Histologic and immunophenotypic features of MCL with FL. A, B and C, Nodular pattern of atypical lymphoid cells with variably expanded mantle zones (hematoxylin and eosin stain, original magnification ×20, ×40, and ×100). D, CD3 staining normal small T cells in the interfollicular areas (immunoperoxidase stain, original magnification ×20). E and F, CD5 staining normal small T cells in the interfollicular areas and B cells in the focally expanded mantle zone. Arrows in F show the MCL in situ component (immunoperoxidase stain, original magnification ×20 and ×100). G, Strong CD10 staining of atypical centrocytes and centroblasts within a follicle (immunoperoxidase stain, original magnification ×20). H and I, Cyclin D1 staining of atypical lymphoid cells in the mantle zones (immunoperoxidase stain, original magnification ×20 and ×100).

yet unclear [30-33]. Given the uncertain clinical behavior, it has been recently proposed for these tissue-based lesions to be designated as FL- or MCL-like B cells of uncertain significance, respectively [33]. As in situ MCL can occur in a lymphoid organ that appears normal by routine histologic examination, to prevent in situ MCL being missed, it may be valuable that cyclin D1, CD5, and BCL-2 (for in situ FL) be included in the diagnostic panel for revealing potential coexistence. From a histopathologic perspective, it is not uncommon to see partial involvement by an overt lymphoma before this particular diagnosis is rendered [33].

2.2. CLL/ SLL-MCL The occurrence of either diffuse large B-cell lymphoma or cHL arising in the setting of CLL/SLL is well known [34]. In

contrast, CLL/SLL has only rarely been reported to occur simultaneously with MCL (Fig. 2). To date, 10 CLL/SLLMCL cases have been described in the literature. In 5 of these patients, CLL/SLL and MCL were synchronous and involved the same anatomical site and are thus included here as true CLL/SLL-MCL CL [5,13-16,35,36]. All of the latter cases displayed clonal unrelatedness, indicating different clonal origins for the 2 components. Given that (1) a subset of CLL/SLL cases shows CD23 negativity or aberrant expression of cyclin D1 within proliferation centers [37] and (2) 1 case of CLL/SLL-MCL (case 11) displayed only a few CD23+ B cells in the absence of pseudofollicles, although flow cytometry showed that 10% of lymph node cells were CD5−/CD23+high/Ig− B cells [15], pathologists attempting to pinpoint the type of lymphoma should be aware of such immunophenotypic variations and use an integrated approach to establish the correct diagnosis

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Table 2

Clinicopathologic features of CLs with an MCL component with a special emphasis on histology growth pattern and immunophenotypic profile of MCL component

Case no./Ref

Subtypes of lymphoma

Morphology (MCLc)

Immunophenotypic studies (MCLc)

Clinical follow-up

1 [5]

MCL + FL

Diffuse growth pattern

22 cycles of polychemotherapy over a period of 2 y; ANED at 8 y

2 [6]

MCL + FL

In situ MCL

3 [7]

MCL + FL

4 [8] 5 [9]

MCL + FL MCL + FL

6 [10]

MCL + FL

Mantle zone and nodular growth pattern Diffuse growth pattern Mantle zone and nodular growth pattern In situ MCL

7 [11]

MCL + FL

In situ MCL

8 [12] 9 [13] 10 [14]

MCL + FL MCL + CLL/SLL MCL + CLL/SLL

Mantle zone growth pattern Diffuse growth pattern Nodular growth pattern

CD20+, CD5+, cyclin D1−, CD23−, CD43+, bcl-2+, κ−, λ−, p53−, p27−, Ki-67 expression: 1%-2% CD20+, CD5−, cyclin D1+, CD23−, CD43−, bcl-2+, Ki-67 expression: b5% a CD20+, CD79a+, CD5+, cyclin D1+, CD23−, CD10−, p27 CD20+, cyclin D1− b CD20+, CD5+, cyclin D1+, IgD+, bcl-2+, bcl-6−, CD10−, CD3−, Ki-67 expression: b20% CD20+, CD5−, cyclin D1+, IgD+, bcl-2+, bcl-6−, CD3−, CD23−, CD43−, CD10−, MUM-1−, Ki-67 expression: b5% CD20+, CD5+, cyclin D1+, IgDWI, bcl-2WI, bcl-6−, CD10−, CD3−, p27PWI, Ki-67 expression: 8% CD20+, CD5+, cyclin D1+ CD20+, CD5+, cyclin D1+, CD23− CD20+, CD5+, cyclin D1+, CD23−

11 [15] 12 [16]

MCL + CLL/SLL MCL + CLL/SLL

NA Multifocal nodular and interstitial growth pattern c

CD20+, CD5+, CD23− CD5+brightly, CD19+high, CD20+high, CD22+ , FMC-7+, IgM κ+, CD10−, CD23− d

13 [5]

MCL + CLL/SLL

Nodular growth pattern

14 [17]

MCL + cHL

15 [19]

MCL + cHL

Sinusoidal growth pattern with an extracapsular extension Nodular growth pattern

CD20+, CD5+/−, cyclin D1+, CD23−, CD43+, bcl-2+, IgD+, κ−, λ+, p53−, p27 −, Ki-67 expression: 3%-10% CD20+, cyclin D1+, Oct-2+, BOB1+

16 [19]

MCL + cHL

Diffuse growth pattern

17 [20]

MCL + cHL

Diffuse and vaguely nodular growth pattern

CD20+, CD5 −, cyclin D1+, CD23−, bcl-2+, CD43+, IgD+, CD10−, bcl-6 −, CD15−, CD30−, EBV−, LMP− CD20+, CD5−/+, cyclin D1+, CD23−, bcl-2+, CD43+, IgD+, CD10 −, bcl-6−, CD15−, CD30−, EBV−−, LMP− CD20+, CD79a+, CD3−, CD5−, cyclin D1+, CD23−, κ−, λ+

18 [21]

MCL + cHL

Diffuse growth pattern

CD20+, cyclin D1+

19 [12]

MCL + PCN

Diffuse growth pattern

CD20+, CD5WI, cyclin D1+, p53−

The patient refused staging and therapy; dead of unknown causes at 13 mo Splenectomy at 2 y; AWD at 4.5 y No chemotherapy; ANED at 4 mo NA NA

R-CHOP chemotherapy; alive in complete remission at 27 mo Radiotherapy and CHOP chemotherapy; DOD at 20 mo A watch-and-wait policy adopted; NA 12 cycles of palliative oral chemotherapy (chlorambucil) and prednisone; AWD at 16 mo NA 6 cycles of bendamustine and rituximab in the first-line setting + maintenance therapy in the form of rituximab; alive in complete remission at 18 mo NA NA Diagnostic splenectomy; NA

CHOP chemotherapy and fludarabine/cyclophosphamide/ AWD after chemotherapy and finally dead of pneumonia at 11 mo Reduced-dose 2-CdA and mitoxantrone (R-CdM) regimen for MCL; conventional therapy for CL/dead of traumatic subdural hematoma at 7 mo Chemotherapy—chlorambucil; DOD at 56 mo

T. G. Papathomas et al.

Surgical resection of the eyelid tumor and cervical lymph node; NA

MCL + BL 26 [28]

Nodular growth pattern

MCL + SMZL MCL + nodal MZL MCL + PBL 23 [25] 24 [26] 25 [27]

Nodular growth pattern Mantle growth pattern Nodular growth pattern

MCL + PCN 22 [24]

Abbreviations: MCLc, MCL component; AWD, alive with disease; ANED, alive with no evidence of disease; DOD, died of disease; NA, not available; ND, not done due to advanced age; NE, not evaluable; WI, weak immunostaining; PWI, partially weak immunostaining; R, rituximab; CHOP, cyclophosphamide, hydroxyldaunorubicin (doxorubicin), oncovin (vincristine) and prednisone. a In situ hybridization for κ and λ failed to display detectable immunoglobulin transcripts in the mantle zones (or in follicular lymphoma nodules). b CD5+, CD23−, IgM/Dκ isotype (immunophenotyping profile of the lymph node determined by flow cytometric analysis of isolated cells). c Extensive bone marrow involvement by small cell non-Hodgkin lymphoma; lymphomatous involvement accounting for a minimum of 65% of the provided sample. Neoplastic lymphocytes ranging from small to medium in size and showing round to indented nuclear contours, moderately clumped chromatin, and scant clear cytoplasm. d Peripheral blood and bone marrow flow cytometry analysis demonstrated 2 immunophenotypically distinct CD5+ monoclonal B-cell populations: κ monotypic MCL and λ monotypic B-cell chronic lymphocytic leukemia (CD19+, CD20+dim, CD22+, CD23+, monotypic λ light chains + dim, CD10− and FMC-7 −). e+f Monotypic λ and κ light chain restriction respectively based on flow cytometric analysis. g Immunohistochemistry for Ig λ was performed on frozen section.

Fludarabine for 6 mo, splenectomy; DOD at 4 mo

Diagnostic splenectomy; ANED at 1 y Radiotherapy; ANED at 2 y Chemotherapy/NA

Rituxan (withdrawal from a trial); DOD at 28 mo

MCL + PCN 21 [23]

Nodular growth pattern

CD20 +, CD5 +, cyclin D1+, IgM+ e CD20+, CD5+, cyclin D1+, IgA+ f CD20+, CD5+, cyclin D1+, CD3−, CD23−, CD138−, IgG −, IgM−, κ−, λ− CD20+, CD5+, cyclin D1+, CD23−, CD10−, Ig λ+g CD20+, CD5+, cyclin D1+, CD23−, IgD+, IgM+, bcl-2+ CD20+, CD79a+, CD5+, cyclin D1+, bcl-2+, CD10 −, CD138−, MUM1− CD20+, CD5+, cyclin D1+, bcl-2+, CD43+, CD10−, Ki-67 expression: 30%

MCL + PCN 20 [22]

Diffuse and focally vaguely nodular growth pattern Diffuse growth pattern

CD20+, CD5−, cyclin D1+, IgD+, IgM+, κ+, λ−

CHOP chemotherapy; dead of unknown causes within days of the end of the first cycle Surgical resection and radiotherapy; ANED at 55 mo[23,24]

Mantle cell lymphoma as a component of composite lymphoma

473

in the context of a CL, including detailed histopathologic analysis, immunophenotypic studies, cytogenetics, and molecular investigation. One case of CLL/SLL-MCL described by Addada et al [13] consisted of a metastatic melanoma and CLL/SLL-MCL together in a single lymph node, an extremely rare example of 3 synchronous tumor within the same anatomical compartment [38-40].

2.3. cHL-MCL Five cases of CL consisting of MCL and cHL have been reported to date including 3 nodal, 1 extranodal (spleen), and 1 displaying nodal as well as extranodal (eyelid) involvement [17-21]. There have been no reported CL cases of MCL and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). NLPHL also rarely coexists with other B-cell lymphoproliferative disorders [41-43]. To our knowledge, only 1 case of a FL-NLPHL CL has been reported [43]. Another interesting issue is the description of a case of cHL-MCL CL with synchronized dissemination of 2 components in 2 separate anatomical locations (eyelid and lymph node) [19]. This rare case, along with an additional CL case with cHL and peripheral T-cell lymphoma in 2 distinct anatomical sites (liver and lymph node) [44], suggests a key role of microenvironmental factors [45,46]. Another intriguing observation concerns 2 cases of cHLMCL CL developing sequentially in the setting of MCL, which occurred 3 and 4 years earlier, respectively [17,21]. Such a patient reinforces and further expands the concept that patients with non-Hodgkin lymphoma (NHL) have an increased frequency of developing cHL [41]. As either the cHL or MCL component can be prevalent [17,21], a high index of suspicion is required when dealing with a lymphoproliferative disorder after the occurrence of MCL in order to not miss the diagnosis of an unusual CL (Fig. 3). Epstein-Barr virus (EBV) infection is a known contributor to the pathogenesis of a proportion of cHL cases. The presence EBV in the cHL component of some case reported (Table 3) provides additional evidence that EBV can play a role in the development of cHL in CLs, irrespective of clonal relatedness [19,41,47-50]. Two other studies have reported that a subset of cHL-NHL CLs displayed EBV positivity in each component, implying an origin from a common EBV-infected progenitor cell [41,50]. However, it remains possible that EBV infection (or reactivation) functions as a nonpathogenic epiphenomenon given that (1) EBV infection might occur secondarily at the same time or after cHL transformation [49], in a way analogous to that previously described in a malignant T-cell clone [51] and (2) a subset of clonally related cHL-NHL CLs were actually EBV negative [52-56], suggesting a different pathogenesis independent of EBV. Of note, Tinguely et al [17,18] reported a unique case of a clonally related cHL-MCL CL with EBV+ and EBV− Hodgkin and Reed-Sternberg (HRS) cells (Table 3), the

474

T. G. Papathomas et al.

A

B

C

CD20

D

CD3

F

E

Clonality Analysis

SLL region

MCL

CD5

Cyclin D1

Fig. 2 Histologic and phenotypic features of MCL with small lymphocytic lymphoma. A, Nodular pattern of atypical lymphoid cells with expanded mantle zone and internodular areas (hematoxylin and eosin stain, original magnification ×20). B, Differential CD20 staining of atypical lymphoid cells in the nodular and internodular areas (immunoperoxidase stain, original magnification ×20). C, CD3 staining small T cells in the internodular areas (immunoperoxidase stain, original magnification ×20). D, Weak CD5 staining of atypical lymphoid cells in the nodular and internodular areas (immunoperoxidase stain, original magnification ×20). E, Cyclin D1 staining of atypical lymphoid cells in the expanded mantle zone and internodular areas with focal negative area of small lymphocytic lymphoma (immunoperoxidase stain, original magnification ×20). F, IgH PCR analysis on a MCL–small lymphocytic lymphoma composite case showing that the 2 lymphoid populations are clonally unrelated.

A

B

C

Cyclin D1

D

E

CD30

F

CD30

EBV

Fig. 3 Histologic and phenotypic features of nodular MCL with cHL. A, Nodular pattern of atypical lymphoid cells with few scattered large mononucleated large cells (hematoxylin and eosin stain, original magnification ×100). B, Typical Reed-Sternberg cells in a MCL nodule (immunoperoxidase stain, original magnification ×200). C, The surrounding atypical lymphoid infiltrate is intensely stained by cyclin D1 (immunoperoxidase stain, each original magnification ×200). D and E, CD30 staining revealed strong membrane and Golgi positivity in the Reed-Sternberg cells (immunoperoxidase stain, original magnification ×100 and ×200). F, EBV-encoded RNA (EBER) staining showed scattered positive Reed-Sternberg cells in the background of MCL component (in situ hybridization, original magnification ×200).

Mantle cell lymphoma as a component of composite lymphoma only example of molecularly verified immunoglobulin heavy chain gene (IgH)–associated translocation in MCL and cHL. This case provides evidence that (1) IGH/CCND1 translocation is an early step in the pathogenesis of cHLMCL CL and most likely happens as a misguided VDJ recombination in a shared precursor during early B-cell development; (2) a pregerminal center (GC) tumor cell precursor gives rise to a HRS cell precursor. Whether the latter shares a common precursor or is a direct descendant of the MCL clone has not been elucidated; (3) the GC microenvironment plays an important role in Hodgkin Lymphoma (HL) pathogenesis because mutated Ig variable region (V) gene rearrangements were present only in HRS cells; and (4) EBV infection of HRS cell precursors occurs in the GC, contrasting experimental evidence supporting a different developmental (pre-GC) stage for this particular event [57,58]. Given the distinctive mutation patterns observed in EBV+ and EBV− HRS cells, coupled with the fact that only a subclone of HRS progenitor cell was EBV infected [17], one could speculate that EBV infection plays an important role in the direct development of cHL, whereas other transforming events may reflect pathogenetic mechanisms unrelated to EBV that account for the development of the EBV− cHL component of CLs.

2.4. PCN-MCL We identified 4 clonally unrelated cases of MCL associated with PCN, which are indeed bonafide CL, 2 arising from the extranodal soft tissue of the head (eyelid and orbit and nasopharynx) [12,22-24]. One additional case of a concomitant extranodal MCL and plasma cell myeloma was reported [59]. As far as the latter case is concerned, Yamaguchi et al [59] performed clonality analysis using polymerase chain reaction (PCR) of the IgH gene complementarity–determining region 3, including a single-cell assay, and confirmed clonal independence. However, the designation “PCN-MCL CL” should be used cautiously. First, clonal plasma cell differentiation in MCL has recently been documented [24,60,61]. Others have proposed that these cases represent a novel morphological type of MCL [24,60], after no convincing evidence was found concerning the differentiation of MCL cells into clonal PCs [62,63]. Second, 4 (50%) of 8 patients with MCL associated with a clonal plasma cell population displayed a monoclonal paraprotein [24,61], and monoclonal IgM and IgG have been detected in 18% and 5% of MCL cases, respectively, in 1 study [64]. Thus, given the potential difference between the prognosis and therapy of PCN-MCL CL compared with MCL with plasmacytic differentiation (Fig. 4), hematopathologists should always attempt to use a molecular approach to determine the clonal relationship between the 2 components with clonal independence establishing a diagnosis of a PCN-MCL CL. However, it should be stressed that neither immunohistochemistry nor the presence of the

475

t(11;14)(q13;q32) in both the MCL and the plasmacytic component are sufficient to make this discrimination because not all clonally related cases display identical monotypic Ig light-chain expression between the 2 populations, in part, because of potential intraclonal variation [24,65], and the t(11;14)(q13;q32) can be observed in nonhyperdiploid plasma cell myeloma [66]. Instead, immunohistochemistry and fluorescence in situ hybridization (FISH) cytogenetics can be used for the differential diagnosis of this unique variant of MCL from other low-grade B-cell lymphomas with plasmacytic differentiation.

2.5. MZL-MCL We identified 2 cases of MZL-MCL CL in the literature, 1 case composed of nodal (N) MZL and the other splenic (S) MZL [25,26]. In an exploration of leukemic B-cell chronic lymphoproliferative disorders with more than 1 B-cell clone, Sanchez et al [36] described an additional case of synchronous extranodal MZL (mucosa-associated lymphoid tissue lymphoma) and MCL, and the presence of biclonality was confirmed by an IgH rearrangement molecular study. These 2 cases of MZL-MCL CL showed remarkable compartmentalization of the 2 lymphomatous populations [25,26], providing strong evidence that these lymphomas arise from and remain confined to the discrete microanatomical sites of their postulated nonneoplastic counterparts during the early stages of their development [26,34]. Apart from this topographic distribution, it is worth noting that IgH VH gene mutations, indicative of the influence of the mutational machinery of the follicular GC, characterize a subset of MCL (15%-40%) and SMZL (50%), whereas a subset of nodal marginal zone lymphoma (NMZL) (14%25%) demonstrates an unmutated IgH VH gene sequence, implying a naïve B-cell origin for neoplastic cells [67,68]. From a diagnostic standpoint, it is important to exclude the possibility of a MZL-like MCL, and given the immunohistochemical aberrancies that have been described in both MCL and MZL [69-71], a panel of immunostains (CD5 and cyclin D1) in combination with cytogenetics or FISH techniques for t(11;14)(q13;q32) is highly recommended Table 3 Histopathologic characteristics of Hodgkin lymphoma in the context of CLs with an MCL component, with a special emphasis on EBV status and the clonal relatedness of the individual components Case no./Ref

Type of cHL

EBV presence in HRS cells

Clonal relatedness

14 15 16 17 18

Lymphocyte-rich Nodular sclerosis Nodular sclerosis Nodular sclerosis Unclassifiable

+/− + + − +

Yes No No NA NA

[17] [19] [19] [20] [21]

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T. G. Papathomas et al.

A

B

C

D

E

F

Cyclin D1

CD138

G

H

I

Kappa

Lambda

Cyclin D1

t(11;14)

Fig. 4 Histologic and phenotypic features of MCL with clonal plasma cells. A and B, Nodular pattern of atypical lymphoid cells in the expanded mantle zones. Clonal plasma cells are present within a nodule (hematoxylin and eosin stain, original magnification ×20 and ×100). C, Cluster of clonal plasma cells in a nodule (hematoxylin and eosin stain, original magnification ×400). D and E, Cyclin D1 stain showing nuclear positivity in the MCL component, whereas the staining in the plasma cells is undetermined or very weakly positive (immunoperoxidase stain, original magnification ×20 and ×400). F, CD138-positive clonal plasma cells within tumor nodules (immunoperoxidase stain, original magnification ×20). G and H, κ Light chain stain showing numerous positive plasma cells compared with only a rare positive cell with the corresponding λ light chain stain (messenger RNA in situ hybridization stains, original magnification ×100). I, fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms analysis showing PCs with clonal κ light chain staining and the t(11;14). Clusters of κ light chain–positive plasma cells harbor the t(11;14) in their nuclei. The red spots within the nuclei represent hybridization signals of the CCND1 gene on chromosome 11, whereas the green spots are hybridization signals of the IgH gene on chromosome 14. The t(11;14) fusion signals are identified as yellow or fused red-green signals, as illustrated by the arrows (fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms, original magnification ×1000).

to distinguish this MCL variant from a true MZL-MCL CL (Fig. 5).

2.6. PBL-MCL and BL-MCL According to the 2008 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, histologic transformation of MCL to large cell lymphoma does not occur [34]. It is acknowledged, however, that, at time of relapse, some MCL cases can display morphological features of histologic progression that potentially fulfill the criteria for being classified as pleomorphic MCL

variant [34]. We suggest, however, that this is a matter of definition and is, in part, semantic. Certainly patients with MCL can progress to a histologic appearance that can overlap with diffuse large B-cell lymphoma or even BL and might be classified as such, if IGH/CCND1 and cyclin D1 overexpression were not also identified. This being said, it seems to us that many cases reported as the pleomorphic variant of MCL represent histologic transformation to a higher grade B-cell lymphoma the same cases are clonally related. In further support of this concept, Aukema et al [72] also have included neoplasms with t(11;14)(q13; q32)(CCND1/IGH) plus 8q24/MYC rearrangements as a form of double-hit B-cell lymphoma.

Mantle cell lymphoma as a component of composite lymphoma

A

D

477

B

NMZL

MCL

CD23

CD79a

F

E

BCL-2

C

Cyclin D1

Ki-67

Fig. 5 Histologic and phenotypic features of nodular MCL with MZL. Nodular pattern of atypical lymphoid cells with variably confined central regions and expanded marginal zones (hematoxylin and eosin stain, original magnification 40×) (A); weak CD23 staining highlighted a small follicular dendritic cell network in an MCL nodule (immunoperoxidase stain, original magnification ×200) (B); both the nodules and the surrounding infiltrate between the nodules displayed CD20 (not shown), CD79, and BCL-2 (C and D); note that the MCL component (both in nodules and peripheral rim) is more intensely stained than the MZL component (immunoperoxidase stain, each original magnification ×20); cyclin D1 staining revealed a strong nuclear positivity for the nodular (MCL) component (immunoperoxidase stain, original magnification ×100) (E); Ki-67 staining showed scattered atypical lymphoid cells in perinodular MZL areas but rare in the MCL component (immunoperoxidase stain, original magnification ×100) (F).

In the literature, we identified 2 cases reported as MCL transforming into extranodal PBL or BL [27,28]. Although an increasing amount of evidence indicates a close relationship between PBL and plasmablastic transformation of PCN [73-77], the event of clonal plasmablastic transformation has, to our knowledge, been reported only twice in other B-cell NHL (FL and MCL) [27,78]. PBLs arising secondarily in the setting of CLL/SLL have been found to have distinct clonal origins [79,80]. These highly unusual forms of FL and MCL transformation are characterized by extranodal localization; EBV negativity; retention of the t(14;18)(q32; q21) or the t(11;14)(q13;q32), respectively; and a common clonal link, suggesting either divergent evolution from a common progenitor cell or direct evolution from the FL or MCL clone [27,78,81]. In addition, Ouansafi et al [78] identified an MYC gene rearrangement in association with the IGH/BCL-2 translocation in the transformed PBL component, in accord with previously published studies [75,82,83], implying a pivotal role for MYC oncogenic dysregulation in the pathogenesis of PBL. Felten et al [28] documented an MCL transforming to BL containing an IGH/CCND1 translocation and MYC gene rearrangement. MYC gene abnormalities are uncommon secondary events that occur in a subset of MCLs associated with leukemic

involvement; these cases have a characteristic morphology (blastoid, pleomorphic, or even BL-like) and an aggressive clinical course with a poor prognosis [72,84-86].

3. Immunophenotypic profile of the MCL component in the setting of CL With regard to variations from the typical immunophenotype of MCL, cyclin D1–negative (2 FL-MCL CLs) and/or CD5-immunonegative patterns (5/8) were the only aberrancies displayed in the MCL component of CLs (Table 2). Two of these CD5− cases concerned in situ MCLs, suggesting that MCL is initially CD5 negative and that CD5 expression occurs later after the acquisition of additional genetic lesions and evolution to overt MCL [10,29]. Nevertheless, CD5 expression may be unstable and not necessarily related to the acquisition of genetic abnormalities. In fact, CD5 immunonegativity has been reported in a subgroup of conventional MCL along with a small subgroup of indolent MCL with peripheral blood involvement, t(11;14) translocation, and somatic hypermutations [30,87]. Whether the latter subset represents the favorable end of the spectrum in the evolution

478 of MCL or an indolent form of MCL is uncertain [30]. In this context, Fernàndez et al [88] recently provided evidence based on genomic and expression profiling data that this indolent MCL seems to correspond to a specific biologic MCL subtype characterized by a constellation of clinicobiologic features encompassing (1) a predominant nonnodal and asymptomatic presentation; (2) stable disease; (3) high rate of IGVH gene mutations; (4) lack of genomic complexity; and (5) absence of SOX11 expression. In addition, they showed that indolent MCL cases had a small cell variant morphology and exhibited CD5 negativity more frequently than conventional MCL cases [88].

4. Conclusion In conclusion, we have provided a review of all known CLs with an MCL component reported in the literature thus far, providing further insight into the process of lymphomagenesis and highlighting the heterogeneity of this poorly understood circumstance. With the small number of cases and heterogeneous therapy, we cannot make definitive recommendations. However, we have attempted to make surgical pathologists and hematopathologists aware of the clinicopathologic spectrum of MCL as a major pathologic part of CL. We further show that a complete diagnostic workup is needed in cases of MCL, not only to establish the correct diagnosis and exclude various morphological mimics but also in directing ancillary testing to detect clonal relatedness and, hence, provide prognostic and therapeutic implications in CLs with an MCL component. To gain a better understanding of this subtype of CL, further clonality studies are warranted.

Acknowledgments The authors thank Dr Valerie A. White (Department of Pathology and Laboratory Medicine, Vancouver General Hospital and University of British Columbia, Vancouver, Canada), Machiko Tsukaguchi (Department of Hematology, Sakai Municipal Hospital, Osaka, Japan), and Alessandra Stacchini (Flow Cytometry Unit, Department of Pathology, Molinette Hospital, Turin, Italy) for providing clinicopathologic data and follow-up information (cases 8/19 and cases 18 and 7, respectively); Taxiarchis V. Kourelis (Department of Medicine, Saint Francis Hospital and Medical Center, Hartford, CT) as well as Michele R. Roullet and Adam Bagg (Pathology Sciences Medical Group/Eastern Virginia Medical School, Norfolk, VA, & Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA) for providing additional histopathologic and immunophenotypic data (cases 2 and 12, respectively).

T. G. Papathomas et al.

References [1] Ioachim HL, Medeiros LJ. Composite lymphoma. In: Ioachim HL, Medeiros LJ, editors. Ioachim's lymph node pathology. Philadelphia, USA: Lippincott Williams & Wilkins; 2008. p. 452-9. [2] Gonzalez CL, Medeiros LJ, Jaffe ES. Composite lymphoma—a clinicopathological analysis of 9 patients with Hodgkins disease and B-cell non-Hodgkin lymphoma. Am J Clin Pathol 1991;96:81-9. [3] Müller-Hermelink HK, Zettl A, Pfeifer W, Ott G. Pathology of lymphoma progression. Histopathology 2001;38:285-306. [4] Banks PM, Chan J, Cleary ML, et al. Mantle cell lymphoma. A proposal for unification of morphologic, immunologic, and molecular data. Am J Surg Pathol 1992;16:637-40. [5] Fend F, Quintanilla-Martinez L, Kumar S, et al. Composite low grade B-cell lymphomas with two immunophenotypically distinct cell populations are true biclonal lymphomas. A molecular analysis using laser capture microdissection. Am J Pathol 1999;154:1857-66. [6] Roullet MR, Martinez D, Ma L, et al. Coexisting follicular and mantle cell lymphoma with each having an in situ component: a novel, curious, and complex consultation case of coincidental, composite, colonizing lymphoma. Am J Clin Pathol 2010;133:584-91. [7] Zamò A, Zanotti R, Lestani M, et al. Molecular characterization of composite mantle cell and follicular lymphoma. Virchows Arch 2006; 448:639-43. [8] Tsang P, Pan L, Cesarman E, Tepler J, Knowles DM. A distinctive composite lymphoma consisting of clonally related mantle cell lymphoma and follicle center cell lymphoma. HUM PATHOL 1999;30: 988-92. [9] Ilgenfritz RB, Le Tourneau A, Arborio M, et al. Composite mantle cell and follicular lymphoma. A case report. HUM PATHOL 2009;40: 259-63. [10] Aqel N, Barker F, Patel K, Naresh KN. In-situ mantle cell lymphoma— a report of two cases. Histopathology 2008;52:256-60. [11] Demurtas A, Aliberti S, Bonello L, et al. Usefulness of multiparametric flow cytometry in detecting composite lymphoma: study of 17 cases in a 12-year period. Am J Clin Pathol 2011;135:541-55. [12] Looi A, Gascoyne RD, Chhanabhai M, et al. Mantle cell lymphoma in the ocular adnexal region. Ophthalmology 2005;112:114-9. [13] Addada J, Anoop P, Swansbury JG, et al. Synchronous mantle cell lymphoma, chronic lymphocytic leukaemia and melanoma in a single lymph node. Acta Haematol 2010;123:194-6. [14] Perdigão J, Alaiz H, Lúcio P, et al. Mantle cell lymphoma and chronic lymphocytic leukemia: report of a rare disease association and review of the literature. J Hematopathol 2010;3:91-9. [15] Lima M, Pinto L, Dos Anjos Teixeira M, et al. Guess what: chronic 13q14.3+/CD5-/CD23+ lymphocytic leukemia in blood and t(11;14)(q13;q32)+/CD5+/CD23− mantle cell lymphoma in lymph nodes! Cytometry B Clin Cytom 2003;51:41-4. [16] Kourelis TV, Kahl BS, Benn P, et al. Treatment of synchronous mantle cell lymphoma and small lymphocytic lymphoma with bendamustine and rituximab. Acta Haematol 2011;126:40-3. [17] Tinguely M, Rosenquist R, Sundström C, et al. Analysis of a clonally related mantle cell and Hodgkin lymphoma indicates Epstein-Barr virus infection of a Hodgkin/Reed-Sternberg cell precursor in a germinal center. Am J Surg Pathol 2003;27:1483-8. [18] Schmitz R, Renné C, Rosenquist R, et al. Insights into the multistep transformation process of lymphomas: IgH-associated translocations and tumor suppressor gene mutations in clonally related composite Hodgkin's and non-Hodgkin's lymphomas. Leukemia 2005;19: 1452-8. [19] Caleo A, Sánchez-Aguilera A, Rodríguez S, et al. Composite Hodgkin lymphoma and mantle cell lymphoma: two clonally unrelated tumors. Am J Surg Pathol 2003;27:1577-80. [20] Hayes SJ, Banerjee SS, Cook Y, et al. Composite mantle-cell lymphoma and classical Hodgkin lymphoma. Histopathology 2006;48: 621-3.

Mantle cell lymphoma as a component of composite lymphoma [21] Senhara T, Aosasa K, Shibano S, Tsukaguchi M. [Picture in clinical hematology no. 39: composite hodgkin lymphoma and mantle cell lymphoma]. Rinsho Ketsueki 2009;50:517. [22] Cachia AR, Diss TC, Isaacson PG. Composite mantle-cell lymphoma and plasmacytoma. HUM PATHOL 1997;28:1291-5. [23] Wang HY, Karandikar N, Payne D, et al. A 3-way collision tumor of the upper respiratory tract: a composite of 2 immunophenotypically distinct mantle cell lymphomas and a plasmacytoma. HUM PATHOL 2008;39:781-7. [24] Visco C, Hoeller S, Malik JT, et al. Molecular characteristics of mantle cell lymphoma presenting with clonal plasma cell component. Am J Surg Pathol 2011;35:177-89. [25] Lefebvre C, Fabre B, Vettier C, et al. Composite splenic marginal zone lymphoma and mantle cell lymphoma arising from 2 independent B-cell clones. HUM PATHOL 2007;38:660-7. [26] Rodig SJ, Healey BM, Pinkus GS, et al. Mantle cell lymphoma arising within primary nodal marginal zone lymphoma: a unique presentation of two uncommon B-cell lymphoproliferative disorders. Cancer Genet Cytogenet 2006;171:44-51. [27] Cooper CL, Joshua DE, Lee CS, et al. Extranodal plasmablastic lymphoma arising in mantle cell lymphoma. Histopathology 2007;51: 856-9. [28] Felten CL, Stephenson CF, Ortiz RO, Hertzberg L. Burkitt transformation of mantle cell lymphoma. Leuk Lymphoma 2004;45:2143-7. [29] Carbone A, Santoro A. How I treat: diagnosing and managing “in situ” lymphoma. Blood 2011;117:3954-60. [30] Espinet B, Solé F, Pedro C, et al. Clonal proliferation of cyclin D1– positive mantle lymphocytes in an asymptomatic patient: an earlystage event in the development or an indolent form of a mantle cell lymphoma? HUM PATHOL 2005;36:1232-7. [31] Nodit L, Bahler DW, Jacobs SA, et al. Indolent mantle cell lymphoma with nodal involvement and mutated immunoglobulin heavy chain genes. HUM PATHOL 2003;34:1030-4. [32] Bassarova A, Tierens A, Lauritzsen GF, et al. Mantle cell lymphoma with partial involvement of the mantle zone: an early infiltration pattern of mantle cell lymphoma? Virchows Arch 2008;453:407-11. [33] Campo E, Swerdlow SH, Harris NL, et al. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 2011;117:5019-32. [34] World Health Organization Classification of Tumours. In: Swerdlow SH, Campo E, Harris NL, et al, editors. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Geneva: IARC Press; 2008. p. 233-68. [35] Medlicott SA, Brown HA, Roland B, et al. Multiple lymphomatous diverticulosis and comorbid chronic lymphocytic leukemia: novel manifestations of ileocolic mantle cell lymphoma. Int J Surg Pathol 2007;15:408-13. [36] 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;102:2994-3002. [37] Lu J, Chang KL. Practical immunohistochemistry in hematopathology: a review of useful antibodies for diagnosis. Adv Anat Pathol 2011;18: 133-51. [38] El Demellawy D, Ross C, Sur M, Alowami S. Synchronously diagnosed lymph nodal collision tumor of malignant melanoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: case report. Diagn Pathol 2007;2:34. [39] Cantor AS, Moschos S, Jukic DM. A principal case of multiple lymphoid collision tumors involving both B-cell chronic lymphocytic leukemia and metastatic malignant melanoma. Dermatol Online J 2010;16:6. [40] St Peter SD, Roarke MC, Conley CR, Pockaj BA. Sentinel lymph node biopsy demonstrating concomitant melanoma and mantle cell lymphoma. Surgery 2002;131:216-8. [41] Jaffe ES, Zarate-Osorno A, Kingma DW, et al. The interrelationship between Hodgkin's disease and non-Hodgkin's lymphomas. Ann Oncol 1994;5(Suppl 1):7-11.

479

[42] Delabie J, Greiner TC, Chan WC, Weisenburger DD. Concurrent lymphocyte predominance Hodgkin's disease and T-cell lymphoma. A report of three cases. Am J Surg Pathol 1996;20:355-62. [43] Dargent JL, Lespagnard L, Meiers I, et al. Composite follicular lymphoma and nodular lymphocyte predominance Hodgkin's disease. Virchows Arch 2005;447:778-80. [44] Sanchez S, Holmes H, Katabi N, et al. Composite lymphocyte-rich Hodgkin lymphoma and peripheral T-cell lymphoma associated with Epstein-Barr virus: a case report and review of the literature. Arch Pathol Lab Med 2006;130:107-12. [45] Coupland SE. The challenge of the microenvironment in B-cell lymphomas. Histopathology 2011;58:69-80. [46] Aldinucci D, Gloghini A, Pinto A, et al. The classical Hodgkin's lymphoma microenvironment and its role in promoting tumour growth and immune escape. J Pathol 2010;221:248-63. [47] de Leval L, Vivario M, De Prijck B, et al. Distinct clonal origin in two cases of Hodgkin's lymphoma variant of Richter's syndrome associated with EBV infection. Am J Surg Pathol 2004;28:679-86. [48] Mao Z, Quintanilla-Martinez L, Raffeld M, et al. IgVH mutational status and clonality analysis of Richter's transformation: diffuse large B-cell lymphoma and Hodgkin lymphoma in association with B-cell chronic lymphocytic leukemia (B-CLL) represent 2 different pathways of disease evolution. Am J Surg Pathol 2007;31:1605-14. [49] Huang Q, Wilczynski SP, Chang KL, Weiss LM. Composite recurrent hodgkin lymphoma and diffuse large B-cell lymphoma: one clone, two faces. Am J Clin Pathol 2006;126:222-9. [50] Kingma DW, Medeiros LJ, Barletta J, et al. Epstein-Barr virus is infrequently identified in non-Hodgkin's lymphomas associated with Hodgkin's disease. Am J Surg Pathol 1994;18:48-61. [51] Langer R, Geissinger E, Rüdiger T, et al. Peripheral T-cell lymphoma with progression to a clonally related, Epstein Barr virus+, cytotoxic aggressive T-cell lymphoma: evidence for secondary EBV infection of an established malignant T-cell clone. Am J Surg Pathol 2010;34:1382-7. [52] Bräuninger A, Hansmann ML, Strickler JG, et al. Identification of common germinal-center B-cell precursors in two patients with both Hodgkin's disease and non-Hodgkin's lymphoma. N Engl J Med 1999;340:1239-47. [53] Bellan C, Lazzi S, Zazzi M, et al. Immunoglobulin gene rearrangement analysis in composite hodgkin disease and large B-cell lymphoma: evidence for receptor revision of immunoglobulin heavy chain variable region genes in Hodgkin-Reed-Sternberg cells? Diagn Mol Pathol 2002;11:2-8. [54] van den Berg A, Maggio E, Rust R, et al. Clonal relation in a case of CLL, ALCL, and Hodgkin composite lymphoma. Blood 2002;100: 1425-9. [55] Kanzler H, Küppers R, Helmes S, et al. Hodgkin and Reed-Sternberglike cells in B-cell chronic lymphocytic leukemia represent the outgrowth of single germinal-center B-cell–derived clones: potential precursors of Hodgkin and Reed-Sternberg cells in Hodgkin's disease. Blood 2000;95:1023-31. [56] Küppers R, Sousa AB, Baur AS, et al. Common germinal-center B-cell origin of the malignant cells in two composite lymphomas, involving classical Hodgkin's disease and either follicular lymphoma or B-CLL. Mol Med 2001;7:285-92. [57] Babcock GJ, Hochberg D, Thorley-Lawson AD. The expression pattern of Epstein-Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity 2000;13:497-506. [58] Bechtel D, Kurth J, Unkel C, Küppers R. Transformation of BCRdeficient germinal-center B cells by EBV supports a major role of the virus in the pathogenesis of Hodgkin and posttransplantation lymphomas. Blood 2005;106:4345-50. [59] Yamaguchi M, Ohno T, Miyata E, et al. Analysis of clonal relationship using single-cell polymerase chain reaction in a patient with concomitant mantle cell lymphoma and multiple myeloma. Int J Hematol 2001;73:383-5. [60] Young KH, Chan WC, Fu K, et al. Mantle cell lymphoma with plasma cell differentiation. Am J Surg Pathol 2006;30:954-61.

480 [61] Naushad H, Choi WW, Page CJ, et al. Mantle cell lymphoma with flow cytometric evidence of clonal plasmacytic differentiation: a case report. Cytometry B Clin Cytom 2009;76:218-24. [62] Weisenburger DD. Mantle-zone lymphoma. An immunohistologic study. Cancer 1984;53:1073-80. [63] Swerdlow SH, Zukerberg LR, Yang WI, et al. The morphologic spectrum of non-Hodgkin's lymphomas with BCL1/cyclin D1 gene rearrangements. Am J Surg Pathol 1996;20:627-40. [64] Preud'homme JL, Gombert J, Brizard A, et al. Serum Ig abnormalities in mantle cell lymphoma. Blood 1997;90:894-5. [65] Nakamine H, Masih AS, Sanger WG, et al. Richter's syndrome with different immunoglobulin light chain types. Molecular and cytogenetic features indicate a common clonal origin. Am J Clin Pathol 1992;97: 656-63. [66] Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 2009;23:2210-21. [67] Jares P, Campo E. Advances in the understanding of mantle cell lymphoma. Br J Haematol 2008;142:149-65. [68] Mollejo M, Camacho FI, Algara P, et al. Nodal and splenic marginal zone B cell lymphomas. Hematol Oncol 2005;23:108-18. [69] Mozos A, Royo C, Hartmann E, et al. SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1– negative subtype. Haematologica 2009;94:1555-62. [70] Tasaki K, Shichishima A, Furuta M, et al. CD5-positive mucosaassociated lymphoid tissue (MALT) lymphoma of ocular adnexal origin: usefulness of fluorescence in situ hybridization for distinction between mantle cell lymphoma and MALT lymphoma. Pathol Int 2007;57:101-7. [71] Rymkiewicz G, Ptaszyński K, Walewski J, et al. Unusual cyclin D1 positive marginal zone lymphoma of mediastinum. Med Oncol 2006; 23:423-8. [72] Aukema SM, Siebert R, Schuuring E, et al. Double-hit B-cell lymphomas. Blood 2011;117:2319-31. [73] Colomo L, Loong F, Rives S, et al. Diffuse large B-cell lymphomas with plasmablastic differentiation represent a heterogeneous group of disease entities. Am J Surg Pathol 2004;28:736-47. [74] Vega F, Chang CC, Medeiros LJ, et al. Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles. Mod Pathol 2005;18:806-15. [75] Taddesse-Heath L, Meloni-Ehrig A, Scheerle J, et al. Plasmablastic lymphoma with MYC translocation: evidence for a common pathway in the generation of plasmablastic features. Mod Pathol 2010;23: 991-9.

T. G. Papathomas et al. [76] Qing X, Sun N, Chang E, et al. Plasmablastic lymphoma may occur as a high-grade transformation from plasmacytoma. Exp Mol Pathol 2011;90:85-90. [77] Lee CK, Ma ES, Shek TW, et al. Plasmablastic transformation of multiple myeloma. HUM PATHOL 2003;34:710-4. [78] Ouansafi I, He B, Fraser C, et al. Transformation of follicular lymphoma to plasmablastic lymphoma with c-myc gene rearrangement. Am J Clin Pathol 2010;134:972-81. [79] Robak T, Urbańska-Ryś H, Strzelecka B, et al. Plasmablastic lymphoma in a patient with chronic lymphocytic leukemia heavily pretreated with cladribine (2-CdA): an unusual variant of Richter's syndrome. Eur J Haematol 2001;67:322-7. [80] Foo WC, Huang Q, Sebastian S, et al. Concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine: a dimorphic presentation of iatrogenic immunodeficiency-associated lymphoproliferative disorder with evidence suggestive of multiclonal transformability of B cells by Epstein-Barr virus. HUM PATHOL 2010;41:1802-8. [81] Carlotti E, Wrench D, Matthews J, et al. Transformation of follicular lymphoma to diffuse large B-cell lymphoma may occur by divergent evolution from a common progenitor cell or by direct evolution from the follicular lymphoma clone. Blood 2009;113:3553-7. [82] Valera A, Balagué O, Colomo L, et al. IG/MYC rearrangements are the main cytogenetic alteration in plasmablastic lymphomas. Am J Surg Pathol 2010;34:1686-94. [83] Bogusz AM, Seegmiller AC, Garcia R, et al. Plasmablastic lymphomas with MYC/IgH rearrangement: report of three cases and review of the literature. Am J Clin Pathol 2009;132:597-605. [84] Hao S, Sanger W, Onciu M, et al. Mantle cell lymphoma with 8q24 chromosomal abnormalities: a report of 5 cases with blastoid features. Mod Pathol 2002;15:1266-72. [85] Reddy K, Ansari-Lari M, Dipasquale B. Blastic mantle cell lymphoma with a Burkitt translocation. Leuk Lymphoma 2008;49:740-50. [86] Au WY, Horsman DE, Viswanatha DS, et al. 8q24 translocations in blastic transformation of mantle cell lymphoma. Haematologica 2000;85:1225-7. [87] Orchard J, Garand R, Davis Z, et al. A subset of t(11;14) lymphoma with mantle cell features displays mutated IgVH genes and includes patients with good prognosis, nonnodal disease. Blood 2003;101: 4975-81. [88] Fernàndez V, Salamero O, Espinet B, et al. Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res 2010;70:1408-18.