Malignant lymphoma of follicular center origin is one

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1 Resident Short Reviews Pediatric Follicular Lymphoma Follicular lymphoma, although common in adults, is rare in children. Pediatric follicular lymphoma has a more favorable prognosis than adult follicular lymphoma, even though it is often of higher grade. Children with follicular lymphomas are generally at a lower clinical stage, respond well to less aggressive therapy, and have a better survival than adults. Follicular lymphoma must be distinguished from reactive follicular hyperplasia, which it may mimic. Immunohistochemical and molecular markers serve to facilitate this distinction, as well as careful attention to clinical and morphologic details. It is important to recognize pediatric follicular lymphoma as a unique clinicopathologic entity to properly diagnose and manage these patients. It may represent a subset of follicular lymphoma with a particularly good prognosis. (Arch Pathol Lab Med. 2009;133: ) Malignant lymphoma of follicular center origin is one of the most common types of non-hodgkin lymphoma (NHL). It accounts for approximately 20% to 30% of NHL in adults, occurring predominantly in middle and older age groups. 1 However, it is extremely rare in the pediatric population, the most common pediatric NHLs being lymphoblastic lymphoma, diffuse large B-cell lymphoma, anaplastic large cell lymphoma, and Burkitt lymphoma. Most pediatric follicular lymphomas (FLs) have been documented as single case reports with only a few collected series, including those reported by Finn et al 2 (4 cases), Frizzera and Murphy 3 (8 cases), Winberg et al 4 (12 cases), Pinto et al 5 (20 cases), and Lorsbach et al 6 (23 cases) (Table). CLINICAL FEATURES Pediatric FL comprises less than 6.5% of childhood lymphomas, with a median age range of 7.5 to 11.7 years, a male-female ratio of 4:1, and occasionally occurring in children as young as 3 years (Table). 1,3 9 One study showed a conspicuous male preponderance, with a male-female Accepted for publication June 12, From the Department of Pathology and Laboratory Medicine, Loma Linda University Medical Center, Loma Linda, Calif. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Renuka Agrawal, MD, Department of Pathology and Laboratory Medicine, Loma Linda University Medical Center, Loma Linda, CA ( reagrawal@llu.edu, renuagra@yahoo.com). A Rare Clinicopathologic Entity Renuka Agrawal, MD; Jun Wang, MD ratio of 11:1. 4 It occurs most commonly in the tonsils or lymph nodes of the head and neck region, with occasional extranodal occurrence at a variety of sites, including the gastrointestinal tract, parotid gland, kidney, epididymis, skin, and testis. 3,6,8 10 There are several recent reports of extranodal pediatric FL with a striking propensity for testicular involvement. 1,2,11,12 In many of these cases, testicular involvement was the initial manifestation of clinically occult nodal disease rather than true primary extranodal disease. 1 Ghislanzoni et al 10 recently reported the first case of primary cutaneous follicular center cell lymphoma arising on the nose and the left nasolabial fold of a 16-yearold adolescent boy. HISTOPATHOLOGIC FINDINGS Strict criteria must be used in the diagnosis of FLs in children, to differentiate them from the much more frequently occurring reactive follicular hyperplasia (Figure 1, A and B). Frizzera and Murphy 3 based their diagnosis of FL on the following architectural and cytologic features: (1) total or extensive replacement of nodal structure; (2) even distribution of nodules throughout the node or lesion, as opposed to the predominantly cortical distribution of follicles in reactive hyperplasia; (3) crowding of nodules with little interposed lymphoid tissue; (4) overall uniformity in size and shape of nodules as compared with that seen in follicles of reactive hyperplasia; (5) paucity of reactive lymphoid cells (immunoblasts and plasma cells) in the interfollicular areas, strikingly demonstrable by immunoperoxidase staining; and (6) the cytologic composition of the nodules. Winberg et al 4 found that the most helpful features were effacement of nodal architecture, the presence of cytologically atypical cells in the interfollicular areas identical to those in the neoplastic follicles, and the monomorphous appearance of these cells in the follicles. The number of histiocytes containing tingible bodies was felt not to be a reliable feature for distinguishing reactive from neoplastic follicular proliferations in both adults and children. An increase in the number of follicles per unit surface area may also serve as a helpful parameter for distinguishing reactive from malignant follicular proliferation. 13 It must be remembered that neoplastic follicles can sometimes coexist with benign follicles within the same lymph node (Figure 2). Hence, care should be taken not to overlook FL when some other areas show only reactive changes. As in adults, pediatric FLs contain both small cleaved cells (centrocytes) and large cells (centroblasts) in varying 142 Arch Pathol Lab Med Vol 133, January 2009 Pediatric Follicular Lymphoma Agrawal & Wang

2 Figure 1. A, Benign reactive follicles show polarization of the mantle zone and a polymorphous lymphoid population in the germinal center with conspicuous tingible body macrophages (hematoxylin-eosin, original magnification 200). B, In contrast to reactive follicles, neoplastic follicles show a somewhat effaced architecture and appear monomorphous. Cytologically atypical cells identical to those in the neoplastic follicles are seen in the interfollicular areas as well (hematoxylin-eosin, original magnification 100). Figure 2. Reactive follicles (on the left) may coexist with neoplastic follicles (on the right) within the same lymph node (hematoxylin-eosin, original magnification 50). Figure 3. Cytologically, both small centrocytes and larger centroblasts are seen in varying proportions within the neoplastic follicles (hematoxylineosin, original magnification 400). proportions (Figure 3). Although in adults they are often grade 1 and generally considered incurable, in children they are more often grade 2 or 3, and most are apparently curable. 7 In both children and adults, the tumor may progress from a follicular to a diffuse architectural pattern and may show transformation from small lymphocytic cells to the more aggressive larger or histiocytic cells (Table). 4 Bone marrow involvement is relatively common in FL, present in about 40% of patients overall. 14 In a series of 450 NHL cases with bone marrow involvement, which included both pediatric and adult patients, Arber and George 15 found FL to be the most common NHL to involve the bone marrow (37%), with grade 1 FL predominating. A pure paratrabecular pattern or mixed patterns with components of both paratrabecular involvement and follicular structures were the most typical of FL and highly correlated with FL as opposed to other types of NHL, although not entirely specific. MOLECULAR PATHOGENESIS AND IMMUNOPHENOTYPIC FEATURES The pathogenesis and biologic behavior of FL in children is less well understood than in adults. 6 More than 85% of FLs in adults demonstrate a characteristic translocation, t(14;18)(q32;q21), involving the bcl-2 gene, 16 whereas most pediatric FLs are negative for bcl-2 protein and lack bcl-2/immunoglobulin heavy chain (IgH) translocations. 7 This has led to the belief that in most instances the pathogenesis of FL in children might be different from its adult counterpart and in the pediatric group, detection of FL by identifying t(14;18) may not be helpful, due to the low positive rate (Table). However, up to about 30% of pediatric FLs may express bcl-2 protein and a smaller proportion may have bcl-2 translocations. These cases with bcl-2 abnormalities are usually seen in older children ( 12 years) with disseminated disease and are associated with a more adverse outcome. 6,9 Pediatric FLs lacking bcl-2 ex- Arch Pathol Lab Med Vol 133, January 2009 Pediatric Follicular Lymphoma Agrawal & Wang 143

3 Series Comparison of Major Published Series on Pediatric Lymphoma* No. of Cases Age Range, y Male/Female Site Predominant Histology Finn et al, /0 Testes F (1 case F D) Frizzera et al, /2 LN F/F D Winberg et al, /1 LN F/F D Pinto et al, /5 LN/tonsil F/F D Lorsbach et al, /7 LN/tonsil/extranodal F/F D * IHC indicates immunohistochemistry; IgH, immunoglobulin heavy chain; F, follicular; D, diffuse; LC, large cell; -ve, negative; LN, lymph node; ND, not done; and SCC, small cleaved cell. bcl-2 gene rearrangement and IgH were done in 3 of 4 cases. bcl-2 immunohistochemistry and gene rearrangement were done in 16 of 23 cases. pression are typically associated with limited-stage disease and excellent disease-free survival when treated with multiagent chemotherapy. 6 Although bcl-2 expression is not diagnostic of any particular type of lymphoma, immunohistochemistry to detect bcl-2 is still often helpful in those cases in which the distinction between FL and florid follicular hyperplasia is problematic, as reactive germinal centers are negative for bcl-2. 17,18 Given the unclear role and low frequency of bcl-2 expression in pediatric FLs, methods other than conventional cytogenetics and immunohistochemistry are needed to establish monoclonality and to determine IgH receptor gene rearrangement. These could include Southern blot analysis and polymerase chain reaction. There are limited data in the literature on techniques used specifically for pediatric FL. For confirmation of clonality in their series of primary testicular FL in childhood, Finn et al 2 used flow cytometric findings, immunohistochemical demonstration of light-chain restriction, and/or detection of clonal IgH gene rearrangement by polymerase chain reaction. Gong et al 19 compared the accuracy in detecting FL and diffuse large B-cell lymphoma of follicular center cell origin by interphase fluorescence in situ hybridization versus flow cytometry on fine-needle aspirations of 84 patients who were possibly not limited to the pediatric population. Although flow cytometry is a useful ancillary study and can support a diagnosis of FL by detecting the characteristic monoclonal B-cell proliferation with coexpression of CD19 and CD10, at least 2 million cells are required for a diagnostic panel. In their study, interphase fluorescence in situ hybridization for the t(14;18)(q32;q21) translocation provided high overall accuracy in detecting FLs in fineneedle aspirations and Gong et al concluded that it could be used for diagnosing or monitoring FL in fine-needle aspirations when cellularity is limited or when flow cytometry results are noncontributory. 19 A new method, combining seminested polymerase chain reaction with heteroduplex analysis, was used by Oehadian et al 20 to detect FL cells in peripheral blood. This method, based on the detection of IgH rearrangements in DNA, detected the presence of monoclonal B cells in FL patients with a high frequency in their study. As in adults, several other findings can be used as valuable tools in the assessment of pediatric FLs. bcl-6 gene rearrangement appears to play a role in the pathogenesis of FL, and like with diffuse large B-cell lymphoma, it may correlate with a favorable prognosis. 21,22 Follicular lymphomas express bcl-6 and often CD10 as well, both of which are immunophenotypic features consistent with a follicular center cell origin. 23,24 In their series of 23 pediatric FL cases, Lorsbach et al 6 found that all cases expressed CD20 and bcl-6 (Table), and 80% of these were positive for CD10. Immunostaining for CD21 may show follicular dendritic cells within the nodules of many tumors, including extranodal cases, further supporting a follicular center cell origin. A minority of cases may be CD43 positive. 7 The Ki-67 staining pattern effectively allows the distinction of benign versus neoplastic follicular lesions. 25 Most neoplastic follicles are easily recognized by their low proliferative rate. Ki-67 cells are randomly distributed in the follicles. They do not show any tendency to polarize and show no sharp demarcation along the edge. In contrast to reactive follicles, which typically vary from one to another according to the plane of sectioning through their polarized structures, malignant follicles tend to be monotonous and uniform across the slide. 25 Thus, Ki-67 is a helpful tool to differentiate FL from follicular hyperplasia, especially in lower grade FL. However, used alone, it is not enough to distinguish between these 2 entities. Mutations or deletions of the p53 tumor suppressor gene have been implicated in the progression of adult FL. Expression of p53 protein is significantly increased in follicular large cell lymphoma (grade 3) compared with follicular small cleaved cell lymphoma (grade 1) in adults. 26 Immunohistochemical detection of p53 protein correlates with the presence of p53 mutations in FL. 27,28 Absence of p53 staining, however, does not exclude the possibility of nonproductive p53 mutations or deletions. 2 These observations have been largely based on outcome noted in the adult population and the role of p53 in the progression of pediatric FL remains unclear. DIFFERENTIAL DIAGNOSIS Given the difficulties in differentiating FL from reactive follicular hyperplasia on morphologic grounds, care must be taken to exclude the many other common causes of reactive lymphadenopathy in childhood. A rigorous clinical and laboratory evaluation and an expert opinion from a hematopathologist are ideal. A careful physical examination and detailed clinical history are important in facilitating the recognition of reactive hyperplasia due to recent vaccinations or inflammatory processes in adjacent areas, systemic infections, autoimmune processes, or hypersensitivity reactions to drugs or other agents. 3,29 Pediatric marginal zone lymphoma and pediatric FL may have similar clinical features (male predominance, localized disease, good prognosis) and morphologic features (progressive transformation of germinal center like areas, follicle lysis-like areas). Additionally, the presence of follicular colonization and nodular growth pattern in marginal zone lymphoma may simulate FL. Immunophenotypic studies are often useful in this differential diagnosis. 144 Arch Pathol Lab Med Vol 133, January 2009 Pediatric Follicular Lymphoma Agrawal & Wang

4 Extended Predominant Cytology Clinical Stage bcl-2 (IHC) bcl-2 (Gene Rearrangement) bcl-6 IgH All LC All are stage I -ve in all -ve in 3/3 3 /4 2 /3 Mixed/LC Mostly I, II/IV also ND ND ND ND SCC/LC Mostly I, II IV also ND ND ND ND LC/SCC/mixed Mostly I, II/III also ND ND ND ND Mixed LC and SCC Mostly I, II IV also 5 /16 2 /16 All ND Marginal zone lymphomas usually lack the germinal center-associated markers bcl-6 and CD10 seen in FLs. Also, although most marginal zone lymphomas coexpress CD43, its aberrant coexpression is not a common feature of FL. 30 When testicular involvement is the initial presentation, distinction from chronic orchitis becomes important. The histologic features of classic FL and demonstration of B- cell clonality in at least some cases help confirm that these testicular follicular lesions are true malignant lymphomas, even if the patients seem to do very well. 7 PROGNOSIS AND TREATMENT Most cases of childhood FL present as low-stage disease (particularly in patients younger than 10 years), and therapy usually results in complete remission, with progression to high-grade lymphoma being unusual. This is in contrast to adults with FL, who commonly present with high-stage disease and run an indolent but progressive clinical course that is refractory to current chemotherapeutic approaches, including bone marrow transplantation. 6 Advanced stage disease with extranodal involvement at presentation is uncommon in children, but when present appears to correlate with a poor prognosis. 3 5,8,9 Winberg et al 4 found involvement of bone, lung, pleura, gonads, meninges, or disseminated skin involvement by FL to correlate with shorter survival, although bone marrow, liver, and localized skin involvement did not. Failure to achieve a complete response to initial therapy has also been associated with a poorer outcome. 4 Combination chemotherapy is typically used in the treatment of FL with predominantly good results. Some series report an adverse outcome in as few as 15% of patients, with the remainder surviving disease free and without recurrence. 6,9 Atra et al 9 found that the long-term prognosis in children was generally excellent, and although most of the children in their study received combination chemotherapy, some had no evidence of disease following surgical excision alone, prompting the authors to suggest that conservative management may be justified for children with localized disease. Given the acute toxicities and late effects associated with chemotherapy, the potential of surgical resection alone as adequate therapy in selected patients with stage I (or possibly stage II) disease is indeed intriguing. However, studies with a larger group of patients in controlled clinical trials will be necessary to confirm the most optimal therapeutic approach, and there currently remains no single established therapeutic paradigm for this rare disease. 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5 tool in the evaluation of lymphoproliferative disorders. Histopathology. 2006;48: Nguyen PL, Zukerberg LR, Benedict WF, Harris NL. Immunohistochemical detection of p53, bcl-2 and retinoblastoma proteins in follicular lymphoma. Am J Clin Pathol. 1996;105: Sander CA, Yano T, Clark HM, et al. p53 mutation is associated with progression in follicular lymphomas. Blood. 1993;82: Lo Coco F, Gaidano G, Louie DC, Offit K, Chaganti RS, Dalla-Favera R. p53 mutations are associated with histologic transformation of follicular lymphoma. Blood. 1993;82: Zuelzer WW, Kaplan J. The child with lymphadenopathy. Semin Hematol. 1975;12: Taddesse-Heath L, Pittaluga S, Sorbara L, Bussey M, Raffeld M, Jaffe ES. Marginal zone B-cell lymphoma in children and young adults. Am J Surg Pathol. 2003;27: Prepare Now for the CAP 09 Abstract Program Plan now to submit abstracts and case studies for the CAP 09 meeting, which will be held October 11th through the 14th in Washington, DC. Submissions for the CAP 09 Abstract Program will be accepted from: Monday, February 2, 2009, through Friday, March 27, Accepted submissions will appear in the October 2009 issue of the Archives of Pathology & Laboratory Medicine. Visit the CAP 09 Web site at for additional abstract program information. 146 Arch Pathol Lab Med Vol 133, January 2009 Pediatric Follicular Lymphoma Agrawal & Wang