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    • Surgical Pathology Criteria
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    Follicular Lymphoma

    Definition

    • B lineage lymphoma demonstrating follicular architecture and composed of varying proportions of small cleaved cells and large cleaved and non-cleaved cells

    Alternate/Historical Names

    • Centroblastic lymphoma
    • Centroblastic-centrocytic lymphoma
    • Follicular center lymphoma, follicular
    • Nodular histiocytic lymphoma
    • Nodular lymphoma
    • Nodular lymphoma, poorly differentiated (NLPD)
    • Nodular mixed lymphoma

    Diagnostic Criteria

    • Uniform, densely packed follicles
      • Frequently back to back
        • May coalesce, simulating diffuse areas
      • Median 47 follicles per 40x field (4x objective, 10x eyepiece)
        • Compare to 30 per 40x field for reactive
    • Obliterates nodal architecture
      • Compression of interfollicular stroma and vessels
        • Highlighted by reticulin stain
      • Extracapsular follicles may be seen
    • Follicular population uniformly atypical
      • Small cells have cleaved, twisted, indented, elongated, angulated nuclei
      • Large cells may be cleaved or non-cleaved
      • Interfollicular zone typically composed of small reactive cells
        • Occasionally made up of neoplastic cells
      • Epithelioid histiocytes may rarely be seen
    • Ill defined mantle zones in most cases
      • Usually indistinct borders
    • Tingible body macrophages infrequent
      • More frequent following steroid treatment
    • No polarization of follicles
      • Reactive follicles typically are polarized
        • Small cells concentrated under mantle cap
        • Large cells predominate at opposite pole
      • Follicular lymphomas typically show no such polarization
        • Occasionally seen in grade 2 follicular lymphoma
    • Mitotic figures less frequent in follicular lymphoma than reactive hyperplasia
        • Grade 3 lymphoma may have high mitotic rate
    • bcl2 and CD10 positive in 85% of cases
      • bcl2 is quite specific vs. germinal centers
      • CD10 is quite specific vs. other small B lymphomas
    • Paratrabecular nodules indicate bone marrow involvement
    • Circulating lymphoma cells have the appearance of buttock cells
    • Diffuse areas may be identified
      • Report as follicular and diffuse or follicular with diffuse areas
    • 60-80% of cases eventually transform to large cell lymphoma, usually diffuse
      • Distinguish from diffuse areas composed of same cell type as follicular areas
      • Not related to therapy
    • Occasional histologic features

      • Yasodha Natkunam MD PhD
      Robert V Rouse MD
      Department of Pathology
      Stanford University School of Medicine
      Stanford CA 94305-5342

      Original posting:: May 1, 2006

      Bone Marrow Involvement by Follicular Lymphoma

      • Paratrabecular nodules are characteristic and virtually diagnostic of involvement
        • Diagnostic of involvement if there is a prior diagnosis of follicular lymphoma
        • If no prior diagnosis we consider this to be highly suggestive
          • Node biopsy, immunologic study or genetic analysis are necessary to make a definitive diagnosis
        • Architecture frequently more useful than cytology for grade 1 cases
        • Typically increased reticulin fibers present
        • Diffuse infiltrates may also occur
      • Non-paratrabecular nodules
        • Typically non-neoplastic unless extensive or cytologically clearly atypical
        • Uniform population of cleaved cells is indicative of lymphoma
        • Light chain restriction is indicative of lymphoma
          • Immunohistochemistry infrequently useful in our experience
          • Flow staining may be useful if sufficient cells present
      • Grade 1 follicular lymphoma in marrow in a patient with grade 3 follicular lymphoma in nodes indicates a composite lymphoma
      • Grade 1 follicular lymphoma in marrow in a patient with diffuse large B cell lymphoma suggests that the large cell lymphoma is derived by transformation of the follicular lymphoma

      Peripheral Blood Involvement by Follicular Lymphoma

      • Circulating neoplastic lymphocytes can be found in many patients with follicular lymphoma
        • 18% by standard light microscopy
        • 60% by PCR
      • When leukemic this is termed "lymphosarcoma cell leukemia"
        • No published guidelines for definition of leukemic
      • Cytologic appearance on smears
        • Cleaved cells appear to have notched nuclei, termed "buttock cells"
        • Clumped chromatin
        • Scant blue cytoplasm
      • No known specific correlation between circulating cells and remission/relapse or prognosis
      • More common with Stages III and IV

      Primary Cutaneous Variant of Follicular Lymphoma

      • Same features as non-cutaneous and secondary cutaneous follicular lymphoma except:
        • Frequent floral pattern
          • 32% of cases vs 5% of secondary cases
        • Less frequent bcl2
          • 57% overall, 40% of grade 2 and 3 vs. 100% of secondary cases
        • Less frequent t(14;18) translocation
          • 31% vs. 77% of secondary cases
      • Most relapses are cutaneous

      Signet Ring Variant of Follicular Lymphoma

      • Nuclei displaced, frequently deformed by clear vacuoles or eosinophilic globules
      • Most signet cells in follicles, occasionally interfollicular
      • Clear vacuoles usually IgG positive
        • EM shows microspherules and microvesicles
      • Eosinophilic globules usually IgM positive
        • EM shows membrane bound homogeneous electron dense material
      • May mimic carcinoma
      • May be seen rarely in other types of lymphoma
      • No clinical significance

      Floral Variant of Follicular Lymphoma

      • Follicles invaded by B and T cells of mantle
        • Pale staining neoplastic follicle becomes lobulated, resembling petals of a flower
      • Most often seen in grade 3 follicular lymphoma
      • May be confused with nodular lymphocyte predominant Hodgkin lymphoma
      • Mimics progressive transformation of germinal centers
      • No clinical significance

      Variant: Follicular Lymphoma with Marginal Zone Differentiation

      • Follicles surrounded by rim of pale monocytoid cells
      • Centers of follicles have usual population of follicular lymphoma
      • Both cell populations composed of the same clone
      • May be confused with marginal zone lymphoma or reverse (inverse) variant of follicular lymphoma
      • Shorter survival has been reported in some cases

      Hyaline Vascular Variant of Follicular Lymphoma

      • Mimics Castleman disease
        • Hyalinized venules penetrate follicles
        • Concentric layers of lymphoma cells
      • Requires immunologic or genotypic analysis
      • Unknown clinical significance

      Reverse or Inverse Variant of Follicular Lymphoma

      • Dark center composed of small cleaved cells
      • Pale periphery composed of large noncleaved cells
      • Contrasts with usual follicular lymphoma in which the neoplastic follicle is paler than the surrounding normal mall lymphocytes
      • May be confused with marginal zone lymphoma or follicular lymphoma with marginal zone differentiation
      • No clinical significance

      Supplemental studies

      Immunohistology and Flow

      • B lineage (CD20 or CD79a) positive
      • Immunoglobulin 90%
        • Variably demonstrable in paraffin sections
      • bcl2 90%
        • Grade 1 nearly 100% positive
        • Specific vs. reactive follicles
        • Not specific vs. other small B cell lymphomas
      • CD10 85%
        • Specific vs. other small B cell lymphomas
      • CD5 <5%
      • CD43 7%
      • CD23 0-25% (lymphoma cells)
        • Follicular dendritic cells present in follicles
      • bcl1 negative

      Genetic Analysis

      • Immunoglobulin gene rearrangements useful in difficult cases
        • Both heavy and light chains rearranged in almost all cases
        • More than one clonal rearrangement may be detected in some patients
      • t(14;18) translocation involving bcl2 present in >85% of follicular lymphoma in USA
        • 27-67% of Europeans and Asians
        • Not specific for follicular lymphoma

       

      Differential Diagnosis

       

      Small B Cell Lymphomas
        SLL/CLL Mantle Marginal Zone Lymphoplasmacytic Follicular
      CD23 85% 2% 8% 0-30% on immunohistology but up to 60% weak positive on flow 0-25%
      CD5 80% 80% 0% 5% 0%
      bcl1 2% 85% 0% 0% 0%
      CD10 0% 2% 2% 3% 85%
      CD43 80% 85% 35% 10-30% 7%
      bcl2 95% 95% 65-90% >50% 90%

      • CD23 staining refers to lymphoid staining
        • Follicular dendritic cells stain in many processes
      • bcl1
        • Blastic mantle cell lymphoma 100%
        • Hairy cell leukemia 41%
      • CD43 stains only 2% of splenic marginal zone lymphoma

      Reactive Follicular Hyperplasia Follicular Lymphoma
      Follicles not densely packed (30/40x field) Follicles densely packed (47/40x field)
      Normal architecture retained Obliterates normal architecture
      Variable size and shape of follicles Uniform size and shape of follicles
      Well defined mantles Poorly defined mantles
      Extracapsular follicles infrequent Extracapsular follicles may be seen
      Many tingible body macrophages Infrequent tingible body macrophages
      Mixed population in follicles Uniform population of atypical cells
      Interfollicular cells bland Interfollicular cells may be small, cleaved
      bcl2 negative in follicles bcl2 positive in follicles (100% in grade 1)
      Light chains mixed (variably demonstrable in paraffin) Light chains monotypic (variably demonstrable in paraffin)
      Germ line Ig genes Ig gene rearrangement
      Not all cases will demonstrate all of the above architectural and cytologic features

       

      Castleman disease Follicular Lymphoma
      Numerous small depleted follicles Cellular follicles
      Prominent mantles with concentric layering Mantles generally indistinct
      Penetrating hyalinized vessels Penetrating vessels rare
      Immunologic and genotypic features as above. A very rare hyaline vascular variant of follicular lymphoma exists.

       

      Progressive Transformation of Germinal Centers Follicular Lymphoma
      Small number of large atypical nodules Many atypical small nodules
      Surrounding typical reactive follicles Surrounding reactive follicles unusual
      Nodules predominantly composed of small non-atypical lymphocytes Nodules composed of atypical lymphocytes
      Immunologic and genotypic features as above. Floral variant of follicular lymphoma may mimic PTGC but generally is part of a process that effaces the normal nodal architecture and is usually composed of large atypical cells.

       

      Nodular Lymphocyte Predominant Hodgkin Lymphoma Follicular Lymphoma
      Limited number of large nodules Innumerable small nodules
      Scattered large cells in background of normal small cells Nearly all cells atypical, small or large
      EMA positive large cells (variably) EMA negative
      Light chain polytypia or negative Light chain monotypia or negative
      CD57+ cells increased, with ringing around large cells No CD57 increase
      Both contain follicles composed predominantly of blc2+ B cells.

       

      Follicular Lymphoma Mantle Cell Lymphoma
      Distinct nodules composed of cleaved cells Residual germinal centers may simulate nodules
      Mantle pattern surrounding germinal center rare Mantle pattern frequent
      bcl1 negative bcl1 85%
      CD5 negative CD5 80%
      CD43 7% CD43 85%
      CD10 85% CD10 2%
      Follicular dendritic network intact FDC network disrupted or confined to germinal centers
      bcl2 92% bcl2 95%
      Floral variant of follicular lymphoma surrounds and invades follicles resulting in a lobulated follicle rather than the more even obliteration by mantle cell lymphoma

       

      Extranodal Marginal Zone Lymphoma Follicular Lymphoma
      Polymorphous population Uniform population of atypical small lymphocytes
      Centers of nodules may contain bcl2 negative residual germinal centers Centers of nodules composed of bcl2 positive small atypical lymphocytes
      Plasmacytoid differentiation frequent Plasmacytoid differentiation rare
      Lymphoepithelial lesions may be seen No lymphoepitelial lesions
      CD10 2% CD10 85%
      • Both may involve the GI tract and other mucosal sites
      • Both usually express bcl2 in the neoplastic cells
      • Cases with combined features are occasionally seen

       

      Follicular Lymphoma SLL/CLL
      Distinct nodular pattern Vague proliferation centers
      Nodules composed of cleaved cells Nodules composed of prolymphocytes and paraimmunoblasts
      Interfollicular cleaved cells common Background sheets of regular small lymphocytes
      CD23 0-38% CD23 85%
      CD5 negative CD5 80%
      CD43 7% CD43 80%
      CD10 85% CD10 0%
      bcl2 stains over 90% of both

      Clinical

      • Mean age 54 years
        • Rare under 20 years
      • Grade 1 is indolent disease but therapy rarely cures
        • 7 year median survival
      • Presence of diffuse areas may indicate worse prognosis
        • Literature is variable, but prognosis appears worse for:
          • Grade 1 and 2 if diffuse areas >25%
          • Grade 3 if any diffuse areas
      • Large cell transformation has poor prognosis
        • 10 month median survival

      Grading / Staging / Report

      Grading

      • Grading based on percent of large cells
        • Grade 1, under 25%
        • Grade 2, 25-50%
        • Grade 3, over 50%
      • Based on highest grade area present
        • If two discrete patterns present, lymphoma may be considered composite
      • WHO recommendation (Mann-Berard) entails counting 20 hpf using 40x objective
        • Record mean number of large noncleaved cells
        • Using the table below
          • Grade 1 is at the low cutoff or below
          • Grade 2 is above the low cutoff to the high cutoff
          • Grade 3 is above the high cutoff
            Microscope Type
            Eyepiece
            Low Cutoff
            High Cutoff
            American Optical
            10x
            5
            15
            American Optical
            15x
            4
            12
            Olympus
            10x
            7
            20
            Olympus
            15x
            4
            12
            Nikon
            10x
            7
            20
            Nikon
            15x
            4
            12
          • Modifications for other microscopes from Warnke et al. AFIP Fascicle
        • Reproducibility of the Mann-Berard method is subject to:
          • Interobserver consistency in recognition of large noncleaved cells
          • Variations in slide thickness and staining
          • We prefer the simpler percentage based scheme given above

      While staging is linked to prognosis, it does not usually determine therapy

      • Therapy is usually determined by clinical signs and symptoms
        • Most staging is radiographic
        • Pathologic staging is usually limited to bone marrow and biopsy of other sites to confirm clinical evidence of involvement
        • Staging laparotomy is not generally indicated
      • 40-70% present as stage III or IV

      Ann Arbor Staging System

      • Stage I
        • I if involvement of a single lymph node region
        • IE if involvement of a single extralymphatic organ or site
      • Stage II
        • II if two or more lymph node regions on same side of diaphragm
        • IIE if localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm
      • Stage III
        • III if Involvement of lymph node regions on both sides of the diphragm
        • IIIS if spleen involved
        • IIIE if extralymphatic site involved
      • Stage IV
        • Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement
      • Systemic Symptoms in 6 months preceding admission
        • Fever, night sweats, 10% weight loss
        • A = absent
        • B = present
      • Extranodal sites are also designated
        • M+ = marrow
        • L+ = lung
        • H+ = liver
        • P+ = pleura
        • O+ = bone
        • D+ = skin and subcutaneous tissue
      • Although originally designed for Hodgkin lymphoma, the Ann Arbor System is also used for non-Hodgkin lymphomas.

      The pathology report should contain the following information:

      • Diagnosis in the World Health Organization (WHO) classification
        • Equivalent diagnosis in other classifications used by relevant clinicians
      • Results of supplementary studies if performed
      • Relationship to other specimens from the same patient
      • Information relevant to staging if available

      Lists

      Types and variants of large B cell lymphoma

      Types of small B cell lymphoma

      Bibliography

      • Warnke RA, Weiss LM, Chan JKC, Cleary ML, Dorfman RF . Tumors of the Lymph Nodes and Spleen, Atlas of Tumor Pathology, AFIP Third Series, Fascicle 14, 1995
      • Jaffe ES, Harris NL Stein H, Vardiman JW eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2001
      • Harris M, Eyden B, Read G. Signet ring cell lymphoma: a rare variant of follicular lymphoma. J Clin Pathol. 1981 Aug;34(8):884-91.
      • Kim H, Dorfman RF, Rappaport H. Signet ring cell lymphoma. A rare morphologic and functional expression of nodular (follicular) lymphoma. Am J Surg Pathol. 1978 Jun;2(2):119-32.
      • Spagnolo DV, Papadimitriou JM, Matz LR, Walters MN. Nodular lymphomas with intracellular immunoglobulin inclusions: report of three cases and a review. Pathology. 1982 Oct;14(4):415-27. Review.
      • Osborne BM, Butler JJ. Follicular lymphoma mimicking progressive transformation of germinal centers. Am J Clin Pathol. 1987 Sep;88(3):264-9.
      • Goates JJ, Kamel OW, LeBrun DP, Benharroch D, Dorfman RF. Floral variant of follicular lymphoma. Immunological and molecular studies support a neoplastic process.
      • Am J Surg Pathol. 1994 Jan;18(1):37-47. Frizzera G, Gajl-Peczalska K, Sibley RK, Rosai J, Cherwitz D, Hurd DD. Rosette formation in malignant lymphoma. Am J Pathol. 1985 Jun;119(3):351-6.
      • Chan JK, Ng CS, Hui PK. An unusual morphological variant of follicular lymphoma. Report of two cases. Histopathology. 1988 Jun;12(6):649-58.
      • Goodlad JR, Batstone PJ, Hamilton D, Hollowood K. Follicular lymphoma with marginal zone differentiation: cytogenetic findings in support of a high-risk variant of follicular lymphoma. Histopathology. 2003 Mar;42(3):292-8.
      • Yegappan S, Schnitzer B, Hsi ED. Follicular lymphoma with marginal zone differentiation: microdissection demonstrates the t(14;18) in both the follicular and marginal zone components. Mod Pathol. 2001 Mar;14(3):191-6.
      • Schmid U, Cogliatti SB, Diss TC, Isaacson PG. Monocytoid/marginal zone B-cell differentiation in follicle centre cell lymphoma. Histopathology. 1996 Sep;29(3):201-8.
      • Chan JK, Ng CS, Hui PK. Follicular immunoblastic lymphoma: neoplastic counterpart of the intrafollicular immunoblast? Pathology. 1990 Apr;22(2):103-5.
      • Frizzera G, Anaya JS, Banks PM. Neoplastic plasma cells in follicular lymphomas. Clinical and pathologic findings in six cases. Virchows Arch A Pathol Anat Histopathol. 1986;409(2):149-62.
      • Chittal SM, Caveriviere P, Voigt JJ, Dumont J, Benevent B, Faure P, Bordessoule GD, Delsol G. Follicular lymphoma with abundant PAS-positive extracellular material. Immunohistochemical and ultrastructural observations. Am J Surg Pathol. 1987 Aug;11(8):618-24.
      • Mann RB, Berard CW. Criteria for the cytologic subclassification of follicular lymphomas: a proposed alternative method. Hematol Oncol. 1983 Apr-Jun;1(2):187-92. No abstract available.
      • Kim BK, Surti U, Pandya A, Cohen J, Rabkin MS, Swerdlow SH. Clinicopathologic, immunophenotypic, and molecular cytogenetic fluorescence in situ hybridization analysis of primary and secondary cutaneous follicular lymphomas. Am J Surg Pathol. 2005 Jan;29(1):69-82.
      • Arber DA, George TI. Bone marrow biopsy involvement by non-Hodgkin's lymphoma: frequency of lymphom types, patterns, blood involvement, and discordance with othe sites in 450 specimens. Am J Surg Pathol. 2005 Dec;29(12):1549-57.
      • Nathwani BN, Anderson JR, Armitage JO, Cavalli F, Diebold J, Drachenberg MR, Harris NL, MacLennan KA, Muller-Hermelink HK, Ullrich FA, Weisenburger DD. Clinical significance of follicular lymphoma with monocytoid B cells. Non-Hodgkin's Lymphoma Classification Project. Hum Pathol. 1999 Mar;30(3):263-8.
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