Challenging Diagnosis in Hematopathology

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1 Challenging Diagnosis in Hematopathology S. David Hudnall, M.D. Professor of Pathology & Laboratory Medicine Chief, Division of Hematopathology Yale University School of Medicine

2 Challenging Situations Lymphoid lesions -1 Large vs. small cells in poorly fixed or thick sections Classical Hodgkin lymphoma vs. CD30+ diffuse large B cell lymphoma some cases may require a large panel of antibodies (CD45, CD30, CD15, Oct-2, Bob.1, CD20, Pax-5, LMP1, Fascin) Nodular lymphocyte predominant Hodgkin lymphoma vs. T cell-histiocyte rich large B cell lymphoma Grey zone lymphomas confusing criteria Extraosseous plasmacytoma vs. plasma cell rich extranodal marginal zone lymphoma Follicular lymphoma - problem with small biopsies grading and diffuse areas Follicular lymphoma may see aberrant loss of CD21 or CD23 on FDC Rituximab-induced loss of CD20 expression by B cell lymphoma use instead PAX-5 or CD79a Reactive vs. neoplastic MALT abnormal lymphoepithelial lesions should exhibit epithelial damage in some sites intraepithelial lymphocytes are normal - kappa/lambda may be very helpful Lymphoplasmacytic lymphoma vs. nodal marginal zone lymphoma Anaplastic myeloma vs. plasmablastic lymphoma (CD56, EBER) Subcutaneous panniculitis-like TCL vs. lupus panniculitis (absence vs. presence of plasma cells) Angio-immunoblastic T cell lymphoma diagnostic criteria for use of Tfh markers (PD1, CD10, BCL6, CXCL13) is not well defined False positive or negative gene rearrangements by PCR clonal T cells may be detected in small biopsies Flow limitations - often negative in CD34- AMoL and DLBCL always negative in Hodgkin underestimates the marrow plasma cell count sdh2014

3 Challenging Situations Lymphoid lesions 2 Kikuchi disease proliferative stage can be confused with diffuse large B cell lymphoma look for characteristic zonal necrosis Mantle cell lymphoma may be CD5 and/or CyclinD1 negative - need SOX11 IgG4 sclerosing disease criteria in flux EBV detection inappropriate reliance on LMP1 instead of EBER CD138 loss in myeloma need CD38 Rosai-Dorfman disease vs. inflammatory myofibroblastic tumor look carefully for S100+ large cells with emperipoiesis Kappa and lambda IHC high background staining use ISH instead Nodal T-PLL subtle paracortical lymphoid infiltrate with follicular sparing - difficult diagnosis if CD4+CD8- TCL1 is a helpful marker Early nodal mycosis fungoides vs. dermatopathic lymphadenitis CD7 loss and clonal TCR may be useful Lobular breast cancer in marrow or node easily missed on H&E need cytokeratin Lymphocyte-rich thymoma vs. T lymphoblastic lymphoma/leukemia - for thymoma look carefully for cytokeratin+ thymic epithelial cells flow of thymoma can be misread as T lymphoblastic lymphoma/ leukemia Hematogones (normal precursor B cells) vs. residual B lymphoblasts after transplant in B-ALL flow very helpful sometimes only time will tell sdh2014

4 Challenging Situations Myeloid disease Blastic plasmacytoid dendritic cell neoplasm vs. AML vs. reactive plasmacytoid dendritic cells in chronic myelomonocytic leukemia (CD4, CD56, CD123 markers are critical) Primary vs. secondary myelodysplasia (clinical history is critical, cytogenetics very helpful, although up to 50% of primary cases are negative) Leukemoid G-CSF response vs. residual acute leukemia following stem cell transplant for AML (clinical history is critical) Wide differential diagnosis of aplastic marrow with pancytopenia (clinical history is critical) Acute panmyelosis with myelofibrosis vs. refractory anemia with excess blasts 2 with fibrosis vs. AML (clinical history of acute fever and bone pain favors acute panmyelosis, predominance of megakaryoblasts favors AML-M7, <20% blasts favors RAEB-2) sdh2014

5 APMF vs. AML-M7 vs. RAEB-2F Abrupt onset with fever and bone pain favors APMF 20% blasts with 50% CD41/CD61+ megakaryoblasts favors AML-M7 5q- or 7q- favors AML with myelodysplasia-related changes

6 CD138 nega+ve myeloma popula+on of immature clonogenic CD45+ CD38+ CD138- plasma cells (?plasmablasts) found in all cases of myeloma range of 1-98% (median 20%) S. Reid et al. Characterisa+on and relevance of CD138- nega+ve plasma cells in plasma cell myeloma. Int J Lab Hematol 32:6;190, 2010

7 NLPHL vs. TCRLBCL NLPHL TCRLBCL Age/gender year old males year old males Extranodal disease Rare Common PaZern Nodular Diffuse Background cells Small CD8+ T cells Small B cells CD21+ FDC networks Prominent Absent IgD+ mantle zone B cells Present Absent CD57+ T cells Numerous Not increased T cell rosezes Common Absent CD20+ CD30- large B cells Mul+lobulated (popcorn) Centroblas+c / pleomorphic EBV Nega+ve Nega+ve (DLBCL if pos)

8 Plasma Cell Neoplasms MGUS <3g/dL paraprotein, <10% clonal plasma cells, no CRAB Myeloma CD19-, CD79a+, CD138+, CD56+ Symptomatic - usually >3g/dL paraprotein, usually >10% clonal plasma cells, CRAB Asymptomatic - >3g/dL paraprotein, >10% clonal plasma cells, no CRAB Plasma cell leukemia - >2x10 6 /ml or 20% in blood, may be lymphoplasmacytic, CD56 neg Plasmacytoma Solitary plasmacytoma of bone bone pain, single mass, paraprotein +/-, no evidence of myeloma Extraosseous plasmacytoma localized lesion, upper respiratory tract, paraprotein -/+ (often IgA), differential includes MALT lymphoma, LPL, plasmablastic lymphoma Monoclonal immunoglobulin deposition disease Primary amyloidosis deposition of abnormal Congo Red positive immunoglobulin protein, organomegaly, underlying disease of MGUS or myeloma Monoclonal light/heavy chain deposition diseases renal disease most common, Congo Red negative immunoglobulin protein, underlying disease of myeloma or MGUS Osteosclerotic myeloma Incomplete POEMS chronic progressive polyneuropathy is common Osteosclerotic bone lesions with lambda-restricted plasma cells Often associated with nodal Castleman disease, plasma cell variant (HHV8+) Heavy chain disease (HCD) Gamma HCD - cm+ k/l-, polymorphous infiltrate may resemble angioimmunoblastic T cell lymphoma, Hodgkin lymphoma, or plasmacytoma Mu HCD cm+ k/l+/- CLL-like infiltrate with vacuolated plasma cells, spleen/liverbm, no nodes Alpha HCD - Mediterranean IPSID MALT lymphoma type ca+ k/l- lymphoplasmacytic infiltrate

9 Extraosseous plasmacytoma vs. Marginal zone lymphoma with marked plasma cell differentiation Upper airway disease and IgA paraprotein favors plasmacytoma Gastrointestinal or nodal disease favors MZL A clonally related lymphoid population favors MZL Presence of MALT-associated cytogenetic defects favors MALT lymphoma [trisomy 3, 12, or 18; t(11;18), t(1;14), t(14;18), or t(3;14)]

10 Lymphoplasmacytic lymphoma vs. Nodal marginal zone lymphoma Residual CD21+ FDC networks favor NMZL Findings favoring LPL: IgM paraprotein IgM+ lymphoplasmacytic infiltrate with Dutcher bodies, mast cells, hemosiderin Absence of monocytoid IgG+ marginal zone B cells

11 Reactive versus Neoplastic MALT LEL-like (non-destructive) structures may be seen in reactive MALT (gastric) Neoplastic MALT favored by: Diffuse destructive extra-follicular infiltrate of IgM+/IgDmarginal zone B cells Halo-like monocytoid B cell infiltrates around LEL (parotid) CD43 B cell positivity B cell monoclonality MALT-associated cytogenetic defects [trisomy 3, 12, or 18; t(11;18), t(1;14), t(14;18), or t(3;14)]

12 predicting classical Hodgkin s lymphoma is reciprocal (inverse) to that of the markers predicting primary mediastinal large B-cell lymphoma. Classical Hodgkin lymphoma vs. Primary medias+nal large B cell lymphoma Specificity Sensitivity Cyclin E Hodgkin Lymphoma CD15 LMP-1 MUM1p CD30 CD20 Oct2 Primary medias+nal large B cell lymphoma ), CD23 (B) and p63 (C) in classical, with a positive predictive results are summarized in CD79a BOB.1 p63 CD23 100% 80% 60% 40% 20% 0% 20% 40% 60% Classical Hodgkin lymphoma 100% 80% 100% 80% 60% 40% 20% 0% 20% 40% 60% Primary mediastinal B-cell lymphoma 100% 80% Figure 4. Comparison of the sensitivities and specificities of each immunohistochemical marker studied. The marker with the highest sensitivity and specificity for classical Hodgkin s Hoeller S et lymphoma al. Histopathology cyclin 2010;56:217 E, for primary mediastinal large B-cell lymphoma, BOB.1.

13 Atypical lesions of the lung Lymphomatoid granulomatosis underlying immunodeficiency multiple lesions with lymphocytic vasculitis and necrosis Absent neutrophils CD4+ T cell rich lymphoid infiltrate with EBV+ B cells Grade 3 lesions considered DLBCL Inflammatory Pseudotumor single plasma cell rich lesion fibrosis but no necrosis no atypia, EBV negative Wegener s granulomatosis Neutrophil rich lesions with necrosis and palisading granulomas Fibrinoid vascular necrosis and capillaritis Lymphocytic interstitial pneumonitis Intact lung parenchyma Absence of necrosis and neutrophilia Allergic Angiitis and Granulomatosis (Churg-Strauss syndrome) history of asthma or allergy necrotizing vasculitis and granulomas marked eosinophilia

14 Plasmablastic Lymphoma vs. ALK+ large B cell lymphoma vs. anaplastic myeloma Site Oral cavity (HIV+) in PL (HIV- is nodal) nodes/mediastinum in ALBCL AP in marrow/bone, sometimes soft tissue Morphology Sinusoidal vs. diffuse vs. diffuse IHC Cannot be distinguished with CD45 or CD138 ALBCL is CD30neg while PL is often pos AM is CD56 is pos PL is EBV+

15 B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and Hodgkin lymphoma Young men with mediastinal mass Confluent growth of large pleomorphic cells resembling Hodgkin cells no classic RS cells Sparse inflammatory infiltrate with necrosis CD45+, CD30+, CD15+, CD20+/-, PAX5/OCT2+/-, BCL6+/-, CD10-, ALK-, EBV-/+ If NSHL-like with CD20 strong and CD15 negative most likely B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and Hodgkin lymphoma If primary mediastinal large B cell lymphoma-like with CD20 negative and either CD15 or EBV positive, consider B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and Hodgkin lymphoma

16 B cell lymphoma unclassifiable, with features intermediate between Burkitt lymphoma and DLBCL Adults with lymphadenopathy and/or extranodal disease Intermediate and large cells High Ki-67 with starry sky If blastoid, do TdT to rule out B lymphoblastic lymphoma Strong BCL2, Ki67 <90%, or presence of a double hit (MYC+ BCL2/ BCL6+) excludes Burkitt lymphoma MYC translocation with simple karyotype favors Burkitt lymphoma MYC translocation with complex karyotype (6 or more other defects) favors this grey zone diagnosis

17 DLBCL vs. BL vs. BCL- BL/DLBCL DLBCL BURKITT BL/DLBCL ONLY LARGE CELLS* COMMON NO NO Ki67 RATE >90% YES RARE COMMON STRONG BCL2 SOMETIMES NO SOMETIMES IG- MYC REARR RARE** YES SOMETIMES** BCL2/BCL6 REARR SOMETIMES NO RARE DOUBLE HIT RARE NO SOMETIMES MYC- COMPLEX KARYO RARE RARE COMMON *Grey zone lymphoma usually looks like BurkiZ but with more cellular heterogeneity (admixed large pleomorphic cells) formerly called atypical BL **cases with MYC- IG rearrangement as the sole abnormality are probably best classified as BurkiZ

18 The End