![Follicular lymphoma (FL)
• Mutational landscape better understood but
clinical impact remains to be determined
• Mutations in chromatin regulator/modifier
genes [CREBBP, KMT2D (MLL2)] and
EZH2: early event and potential treatment
targets](https://image.slidesharecdn.com/who2016updatedclassificationoflymphoidneoplasm-170326220329/85/Who-2016-updated-classification-of-lymphoid-neoplasm-5-320.jpg)
![Nodular lymphocyte predominant
Hodgkin lymphoma
• Variant growth patterns, if present, should be noted in
diagnostic report: “classic” (B-cell-rich) nodular
(patter A), serpiginous/interconnected nodular (B),
nodular with prominent extranodular L&H cells (C),
T-cell-rich nodular (D), diffuse with a T-cell-rich
background (T-cell-rich B-cell lymphoma [TCRBCL]-
like) (E), and a (diffuse) B-cell-rich pattern (F)
• Presence of many extranodular L&H cells (pattern C)
predicts for progression to a diffuse pattern](https://image.slidesharecdn.com/who2016updatedclassificationoflymphoidneoplasm-170326220329/85/Who-2016-updated-classification-of-lymphoid-neoplasm-56-320.jpg)
Who 2016 updated classification of lymphoid neoplasm
- 1. WHO 2016 update of lymphoid neoplasms Medical Director, Hematopathology and Molecular Pathology Program Director, International Hematopathology/Molecular Pathology Fellowship, Florida Hospital Professor of Pathology, University of Central Florida, College of Medicine E-mail: c.jeff.chang.md@flhosp.org Phone: 407-303-1879
- 2. • Updated diagnostic categories and criteria to current entities (some with new names) and a limited number of new provisional entities • Expanding the genetic/molecular landscape and the biologic and clinical correlates • Development of targeted therapeutic strategies
- 3. Monoclonal B-cell lymphocytosis (MBL) • Up to 12% healthy individuals (DO NOT ORDER FLOW CYTOMETRY FOR FUN) • Must distinguish low count (< 0.5 x109/l), extremely limited chance of progression, no follow-up needed, from high count (> 0.5 x109/l) MBL, need yearly follow-up (annual progression rate: 1 to 2%). • Non-CLL type MBL: related to splenic MZL • A lymph node equivalent of MBL exists: preserved nodal architecture, with cells of MBL phenotype, <1.5 cm, no proliferation center (be careful with FNA specimen)
- 4. CLL/SLL • Cytopenias or disease-related symptoms are now insufficient to make a diagnosis of CLL with < 5 x109/l PB CLL cells. • Large/confluent (broader than a 20x field) and/or highly proliferative proliferation centers (PC) (either >2.4 mitoses or Ki-67 >40%/PC) are adverse prognostic indicators. • PC may express weak cyclin D1, increase MYC protein expression • Mutations of TP53, NOTCH1, SF3B1, ATM, and BIRC3: adverse prognostic factors, targeted therapy (del TP53 for Ibrutinib).
- 5. Follicular lymphoma (FL) • Mutational landscape better understood but clinical impact remains to be determined • Mutations in chromatin regulator/modifier genes [CREBBP, KMT2D (MLL2)] and EZH2: early event and potential treatment targets
- 6. In situ follicular neoplasia • New name for in situ follicular lymphoma (FL) reflecting low risk of progression to lymphoma • May associated with prior or synchronous overt lymphoma, requiring clinical assessment • Strong BCL2 expression, CD10+/BCL6+ cells predominantly restricted inside follicle (no spilling out) • Flow cytometry showing clonal B-cells with FL phenotype: be careful with FNA specimen • Must be distinguished from partial involvement by FL
- 7. Pediatric-type FL • A localized (most stage 1) clonal proliferation with excellent prognosis; excision alone may be sufficient • Occurs in children and young adults, rarely in older individuals • Blastoid cells more frequent than centroblasts/or centrocytes • “Starry sky” follicles, no diffuse areas (foci of DLBCL) • BCL2 protein -/+, CD10+, BCL6+, MUM1-/+ (+ in Waldeyer’s ring cases), MIB1 high (> 30%) • IGH clonal rearrangement • BCL2, BCL6, MYC rearrangement: absent, IRF4 rearrangement: some Waldeyer’s ring cases (overlapping with LBL-IRF4)
- 8. Am J Surg Pathol. 2013 Mar; 37(3): 333–343.
- 9. Large B-cell lymphoma with IRF4 rearrangement • New provisional entity to distinguish from pediatric-type FL and other DLBCL • Children and young adult • Localized disease, often involves cervical lymph nodes or Waldeyer ring • Low stage, treatment usually required • Follicular (Grade 3B, D/D CD10-, MUM1+ FL in older patients; pediatric-type FL, may need FISH), follicular and diffuse, or pure diffuse pattern • Strong MUM1+, BCL6+, high MIB1, BCL2 +/- (NO BCL-2 rearrangement), CD10+/-
- 10. IRF4/MUM1 BCL6
- 11. Duodenal-type FL • Localized process with low risk for dissemination, excellent outcome • Overlap with ISFN
- 12. Predominantly diffuse FL with 1p36 deletion • Grade 1 to 2 • Presents as localized mass, often inguinal • Lacks BCL2 rearrangement • CD10+, CD23+, BCL2+/- • 1p36 deletion not specific, seen in other lymphomas, including classical FL • Appearing to have good prognosis (13% recurred and 6% progressed after chemo/radiotherapy in 29 cases reported)
- 14. Mantle cell lymphoma (MCL) • Two MCL subtypes: different clinicopathological manifestations and molecular pathogenetic pathways • Classical: Largely with unmutated/minimally mutated IGHV and mostly SOX11+, nodal and extranodal site • largely with mutated IGHV and mostly SOX11- (indolent leukemic non-nodal MCL with PB, BM, ±splenic involvement, may become more aggressive with additional mutations, such as p53). • Mutations of potential clinical importance, such as TP53, NOTCH 1/2, recognized in small proportion of cases. • CCND2 rearrangements in approximately half of cyclin D1 negative MCL.
- 16. In situ mantle cell neoplasia • New name for in situ MCL, reflecting low clinical risk • Cyclin D1+ cells in the inner mantle zone of follicles with preserved nodal architecture • D/D: overt MCL with a mantle zone growth pattern Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/257780134_fig7_Fig-8-Session- 32-Mantle-cell-lymphoma-'-in-situ-'-Case-431-P-Browne-a-At-low
- 17. Lymphoplasmacytic lymphoma (LPL) • MYD88 L265P mutation in vast majority (90%) of LPL and significant portion of IGM MGUS (more closed to LPL/B-cell lymphoma than PCM) • CXCR4: 30% of LPL (higher extent of BM infiltration and lower leucocyte counts, haemoglobin and platelet counts, resistant to Ibrutinib) • Not specific for LPL: small proportion of other small cell lymphoma (MZL, CLL); 30% non-GC DLBCL; 50% primary cutaneous DLBCL, leg type; but not PCM, even of IGM type • Morphology: monotony of lymphoplasmacytic proliferation (lack of monocytoid cells, large transformed cells), sometimes follicular colonization
- 18. Hairy cell leukemia • BRAF V600E mutations in vast majority of cases • MAP2K1 mutations in most cases that that use IGHV4-34 and lack BRAF mutation
- 19. Diffuse large B-cell lymphoma, NOS • Distinction of GCB versus ABC/non-GC type required with use of immunohistochemical algorithm acceptable, may affect therapy. • Co-expression of MYC (> 40% cells) and BCL2 (> 50% of cells) considered new prognostic marker (20 to 35% of DLBCL, double expressor lymphoma, most do not have MYC/BCL2 rearrangement) • Double expressor worse outcome than other DLBCL, NOS but better than the DHLs • CD30 expression may be tested for new antibody-based (anti-CD30) treatment
- 20. • GCB-DLBCL: mutations in histone methyl transferase EZH2, cell motility regulator GNA13, BCL2 translocation • ABC-DLBCL: BCR/TLR and NFkB pathway (MYD88, CD79A, CARD11, TNFSIP3) Diffuse large B-cell lymphoma, NOS
- 21. EBV+ DLBCL, NOS • Replaceing EBV-positive DLBCL of the elderly (worse prognosis) since it may occur in younger patients (with better outcome) • Not including EBV+ B-cell lymphomas that can be given a more specific diagnosis (e.g. LYG)
- 22. EBV+ mucocutaneous ulcer • New provisional entity associated with iatrogenic immunosuppression or age-related immunosenescence. • Self-limited growth potential • Conservative management • Isolated sharply circumscribed ulcers involving oropharyngeal mucosa, skin, and gastrointestinal tract • Polymorphous infiltrate and atypical large B-cell blasts often with Hodgkin/Reed-Sternberg (HRS) cell-like morphology • B cells showed strong CD30 and EBER positivity • CD15 -/+, CD20+/-
- 23. Modern Pathology (2013) 26, S42–S56 Blood 2011;117(18):4726-4735
- 24. Burkitt lymphoma • TCF3 or ID3 (negative regulator of TCF3) mutations in up to approximately 70% of sporadic and immunodeficiienty related cases and 40% of endemic cases • TCF3 activating BCR/PI3K pathway promoting survival and proliferation of lymphoid cells
- 25. Burkitt-like lymphoma with 11q aberration • New provisional entity that closely resembles Burkitt lymphoma but lacks MYC rearrangement • Clinical course and gene expression profile similar to BL • Interstitial gains including 11q23.2-q23.3 and telomeric losses of 11q24.1-qter • More complex karyotypes, lower level of MYC expression, certain degree of cytological pleomorphism, sometimes a follicular patten, frequently nodal presentation
- 26. CD20 BCL6MIB1
- 27. High grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 translocations • New category for all ‘double/triple hit’ lymphomas other than FL or lymphoblastic lymphomas.
- 28. High grade B-cell lymphoma, NOS • Together with the new category for the ‘double/triple hit’ lymphomas, replacing the 2008 category of B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (BCLU) • Includes blastoid-appearing large B-cell lymphomas and cases lacking MYC and BCL2 or BCL6 translocations that would formerly have been called BCLU
- 29. MYC R
- 31. Peripheral T-cell lymphoma (PTCL), NOS • Subsets based on phenotype and molecular abnormalities being recognized that may have clinical implications but are mostly not a part of routine practice at this time. • GATA3 overexpression subtype: inferior prognosis, high levels of Th2 cytokines • Mutations of epigenetic mediators: KMT2D, TET2, KDM6A, ARID1B, DNMT3A, CREBBP, MLL AND ARID2. • Mutations in signaling pathway: TNFAIP3, APC, CHD8, ZAP70, NF1, TNFRSF14, TRAF3 • Mutations in tumor suppressors: TP53, FOXO1, ATM
- 32. Node-based EBV+ PTCL • Considered a variant of PTCL, NOS • EBV in the majority of neoplastic cells • Monomorphic, lack of angioinvation and necrosis • Older pateints, post-transplant setting, other immunodeficiency states
- 33. Nodal T-cell lymphomas with T follicular helper (TFH) phenotype • A new umbrella category created to highlight the spectrum of nodal lymphomas with a TFH phenotype : angioimmunoblastic T-cell lymphoma, follicular T-cell lymphoma and other nodal PTCL with TFH phenotype (specific diagnoses to be used due to clinicopathologic differences) • TFH phenotype: at least 2 or 3 of TFH-related antigens: CD279/PD1, CD10, BCL6, CXCL13, ICOS, SAP, CCR5 • Overlapping recurrent molecular/cytogenetic abnormalities: TET2, IDH2, DNMT3A, RHOA, CD28 mutations; ITK-SYK OR CTLA4-CD28 fusion
- 34. • AITL and FTCL: EBV+ B-cell blasts, progression to EBV+ (rarely EBV-) BCL • FTCL: localized disease, fewer systemic symptoms Nodal T-cell lymphomas with T follicular helper (TFH) phenotype
- 35. ALK-negative anaplastic large cell lymphoma • Now a definite entity • Convergent mutations and kinase fusions leading to activation of JAK/STAT3 pathway • Including cytogenetic subsets with prognostic implications: • 6p25 rearrangements at IRF4/DUSP22 locus: relatively monomorphic, lack cytotoxic granules, superior prognosis, also occurring in LYP, primary cutaneous ALCL • TP63 rearrangement: very aggressive
- 37. Breast implant-associated anaplastic large cell lymphoma • New provisional entity distinguished from other ALK-negative ALCL • Seroma fluid between the implant and surrounding fibrous capsule. • Both saline and silicone implants • Median time interval: 10 years • If no invasion of the capsule, removal of implant and capsule • If invasion through the capsule, systemic chemotherapy due to risk of LN involvement and systemic spray
- 41. Primary cutaneous acral CD8+ T-cell lymphoma • New provisional entity • Indolent, originally described as originating in the ear, almost always localized to a single site • Clonal CD8+ cytotoxic T-cells • Dense, diffuse proliferation of monomorphous medium-sized T cells throughout the dermis and subcutis; no epidermotropism • CD3+, CD8+, CD4−, TIA1+, granzyme B− • Conservative management only • D/D: primary cutaneous CD8+ aggressive epidermotrophic cytotoxic T-cell lymphoma
- 42. CD8 haematologica | 2014; 99:1421
- 43. T-cell large granular lymphocyte leukemia • New subtypes recognized with clinicopathologic associations. • STAT3 mutations common (also in NK-LGL) • STAT5B mutations in a subset, associated with more clinically aggressive disease.
- 44. Systemic EBV+ T-cell Lymphoma of childhood • Name changed from lymphoproliferative disorder to lymphoma due to its fulminant clinical course and desire to clearly distinguish it from chronic active EBV infection (CAEBV). • CAEBV: from indolent/localized forms (hydroa vacciniforme-like LPD, severe mosquito bite allrgy ) to a more systemic form with fever, hepatosplenomegaly, lymphadenopathy, w/wo skin manifestations. • D/D: EBV associated HLH, may response to HLH 94 protocol, not neoplastic
- 45. Hydroa vacciniforme-like lymphoproliferative disorder • Name changed from lymphoma to lymphoproliferative disorder. • Relationship with CAEBV and a spectrum in terms of its clinical course.
- 46. Enteropathy associated T-cell lymphoma (EATL) • Diagnosis only to be used for cases formerly known as type I EATL • Typically associated with celiac disease • Predominantly occurring in patients of northern European origin
- 47. Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) • Formerly type II EATL • Lack of association with celiac disease • Asians and Hispanic population • Monomorphic, expression of CD8, CD56 and MAPK, most are GD-T cells, • STAT5B mutation • Gains in 8q24 involving MYC
- 48. Indolent T-cell lymphoproliferative disorder of the GI tract • New provisional entity • diffuse, band-like monoclonal intestinal T- cell infiltration of the lamina propria, and, focally, the submucosa by lymphoid infiltrate • Clonal cytotoxic T-cells: CD8+ >> CD4 • Indolent clinical course, some cases show progression
- 52. Phenotype/genotype: T-LPD • CD3+, CD2+, CD5±, CD7±, CD56-, TCRβ+, TCRγ-, EBER-, CD30-. • Ki-67 up to 5-10%. • CD8+ cases (majority): TIA1+, granz B- • CD4+ cases: cytotoxic marker negative • Clonal TCRγ rearrangements (1 oligoclonal)
- 53. D/D: Histologically/ immunophenotypically Indolent T-LPD: nondestructive, involving the lamina propria and muscularis mucosae, small mature cells. EATL : large and destructive infiltrate. medium- to large-sized pleomorphic cells with prominent nucleoli; the intestinal mucosa adjacent to the main tumor mass frequently shows evidence of enteropathy (Not indolent T- LPD)
- 54. MEITL: destructive infiltrate, monotonous and small to medium-sized cells, florid infiltration of the intestinal crypt epithelium and adjacent intestinal mucosa by lymphoma cells (Not indolent T-LPD). MEITL: CD3+, CD8+, CD56+, often TCR- G+, CD4-. CD56- in indolent T-LPD also aids in the distinction from NK cell enteropathy.
- 55. Primary cutaneous CD4+ small medium T-cell lymphoproliferative disorder • Remains a provisional entity. • No longer to be diagnosed as an overt lymphoma due to limited clinical risk, localized disease, and similarity to clonal drug reactions.
- 56. Nodular lymphocyte predominant Hodgkin lymphoma • Variant growth patterns, if present, should be noted in diagnostic report: “classic” (B-cell-rich) nodular (patter A), serpiginous/interconnected nodular (B), nodular with prominent extranodular L&H cells (C), T-cell-rich nodular (D), diffuse with a T-cell-rich background (T-cell-rich B-cell lymphoma [TCRBCL]- like) (E), and a (diffuse) B-cell-rich pattern (F) • Presence of many extranodular L&H cells (pattern C) predicts for progression to a diffuse pattern
- 58. • Histopathologic NLPHL variants (pattern C, D, E, F) are associated with advanced disease and a higher relapse/progress rate. • Cases associated with synchronous or subsequent sites indistinguishable from THRLBCL without a nodular component should be designated THRLBCL-like transformation.
- 59. Erdheim-Chester disease • Should be distinguished from other members of the juvenile xanthogranuloma family • Often associated with BRAF mutations
- 60. Other histiocytic/dendritic neoplasms • Clonal relationship to lymphoid neoplasms (FL, CLL, T/B lymphoblastic lymphoma, PTCL) recognized in some cases. • Indicating transdifferentiaiton. • V600E in LCH, histiocytic sarcoma, disseminatied JXG, ECD, FDCS