Hematopathology Specialty Conference Case #1
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1 Hematopathology Specialty Conference Case #1 Robert (Bob) Ohgami, MD, PhD Assistant Professor Stanford University Disclosure of Relevant Financial Relationships Disclosure of Relevant Financial Relationships USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. USCAP requires that all faculty in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. Ohgami declares he has no conflicts of interest to disclose. Case history Case history A 32 year old man presents with a 4 month history of isolated left inguinal lymphadenopathy. A physical exam demonstrates no other abnormal findings. The patient has no personal or family history of malignancy. Further workup including CBC, peripheral blood smear and bone marrow biopsy were unremarkable. CBC and Differential WBC: 6.2 K/μL HGB: 14.3 g/dl PLT: 210 K/μL Neutrophils: 65% Lymphocytes: 30% Monocytes: 3% 1
2 Case history A 32 year old man presents with a 4 month history of isolated left inguinal lymphadenopathy. A physical exam demonstrates no other abnormal findings. The patient has no personal or family history of malignancy. Further workup including CBC, peripheral blood smear and bone marrow biopsy were unremarkable. A LN biopsy was performed 2
3 CD3 CD4 CD8 CD99 3
4 What about the atypical spindled cells? CD3+/CD4+/CD8+/CD99+/+ D240 CD123 CD21 Keratin HHV8 4
5 Cytogenetic and molecular studies Normal male karyotype: 46,XY[20]. Molecular studies: Negative for T-cell and B- cell clonality. Summary Clinical Healthy male Prolonged isolated inguinal adenopathy Morphology Infiltrate of immature blastic lymphoid cells in sheets and clusters Atrophic lollipop follicles with onion skinning mantle zones Effacement by a proliferation of atypical spindled cells, some binucleate Immunophenotype Lymphoid infiltrate: CD3+, CD4+, CD8+, CD99+, + Spindled cells: D240+, CD123+, focal dim CD21 Cytogenetics/Molecular Non-clonal T-cells Normal cytogenetics Differential Diagnosis Thymoma T-lymphoblastic lymphoma Kaposi Sarcoma Castleman disease Follicular dendritic cell sarcoma Indolent T-lymphoblastic proliferation Differential Diagnosis No Keratin positive cells Thymoma T-lymphoblastic lymphoma Kaposi Sarcoma Castleman disease Follicular dendritic cell sarcoma Indolent T-lymphoblastic proliferation Differential Diagnosis Differential Diagnosis Thymoma T-lymphoblastic lymphoma No HHV8 positive staining Kaposi Sarcoma Castleman disease Follicular dendritic cell sarcoma Indolent T-lymphoblastic proliferation Thymoma T-lymphoblastic lymphoma Indolent, non-clonal, no marrow involvement Kaposi Sarcoma Castleman disease Follicular dendritic cell sarcoma Indolent T-lymphoblastic proliferation 5
6 Differential Diagnosis Thymoma T-lymphoblastic lymphoma Kaposi Sarcoma Castleman disease Follicular dendritic cell sarcoma Indolent T-lymphoblastic proliferation Final Diagnosis Indolent T-lymphoblastic proliferation Castleman disease, hyaline vascular type Follicular dendritic cell sarcoma Final Diagnosis Indolent T-lymphoblastic proliferation Castleman disease, hyaline vascular type Follicular dendritic cell sarcoma Final Diagnosis Indolent T-lymphoblastic proliferation Castleman disease, hyaline vascular type Follicular dendritic cell sarcoma Castleman disease HIV Castleman disease HHV8 Morphology Clinicopathologic Hyaline Vascular Intermediate Plasma cell Unicentric Multicentric 6
7 Follicular dendritic cell sarcomas Castleman disease Follicular dendritic cell sarcoma Spindled proliferation Plump, sometimes binucleate cells Positive for follicular dendritic cell markers (CD21, CD35, D240, CD23) Lost CD21 Express CD123 Rarely happens But I m here to talk about CD3+/CD4+/CD8+/CD99+/+ perhaps What they ^didn t teach you in fellowship Indolent T-lymphoblastic proliferation perhaps ^ What they didn t teach you in fellowship Indolent T-lymphoblastic proliferations Rules /Dogma can be broken Robert (Bob) Ohgami, MD, PhD Stanford University 7
8 What they didn t teach you in fellowship Indolent T-lymphoblastic Proliferations Indolent T-lymphoblastic proliferations Rules /Dogma can be broken Initial case in 1999 Milind Velankar, Larry Weiss et al. Described a 33 year old patient with a 16 year history of an upper aerodigestive tract proliferation of indolent non-clonal +/CD3+ T-cells H&E TDT Velankar et al., AJSP 1999 Indolent T-lymphoblastic Proliferation Indolent T-lymphoblastic Proliferation First case in 1999: Healthy patient Proliferation of blastic lymphoid cells CD3+/+ T-cells Extra thymic expansion Clinical indolence Non-clonal Similar to Malignant T-lymphoblastic lymphoma First case in 1999: Healthy patient Proliferation of blastic lymphoid cells CD3+/+ T-cells Extra thymic expansion Clinical indolence Non-clonal EXCEPT Velankar et al., AJSP 1999 Velankar et al., AJSP 1999 Since then 13 other cases in the literature Summary of cases of indolent T-lymphoblastic proliferations Age: ~40 (10-70) Male:Female 1:1 Morphology: small-medium sized cells, blastic chromatin Immunophenotype: 100% +/CD4+/CD8+/CD3+ T-cells Molecular: 100% non-clonal Velankar et al., AJSP 1999 Eun et al., J Kor Med Sci 2010 Ohgami et al., AJSP 2012 Qian et al., Leuk Lymph 2009 Strauchen et al., AJSP 2001 Wang et al., Leuk Lymph 2006 Kim et al., Hum Path 2010 Ohgami et al, AJSP 2014 You et al., AJCP 2015 Yang et al., IJCEP 2014 Kansal et al., Hum Path 2015 Woo et a., JPTM 2015 Ohgami et al., Adv Anat Pathol
9 Prethymic CD2/CD5/CD7 CD3 CD34 CD4 CD8 CD1a T-cell development Cytoplasmic Thymus Cortex Double positive Double positive Thymus Medulla Surface Single positive Single positive Summary of cases of indolent T-lymphoblastic proliferations thus far Age: ~40 (10-70) Male:Female 1:1 Morphology: small-medium sized cells, blastic chromatin Immunophenotype: 100% +/CD3+ T-cells Molecular: 100% non-clonal Velankar et al., AJSP 1999 Eun et al., J Kor Med Sci 2010 Ohgami et al., AJSP 2012 Qian et al., Leuk Lymph 2009 Strauchen et al., AJSP 2001 Wang et al., Leuk Lymph 2006 Kim et al., Hum Path 2010 Ohgami et al, AJSP 2014 You et al., AJCP 2015 Yang et al., IJCEP 2014 Kansal et al., Hum Path 2015 Woo et a., JPTM 2015 Ohgami et al., Adv Anat Pathol 2013 Summary of cases of indolent T-lymphoblastic proliferations thus far Age: ~40 (10-70) Male:Female 1:1 Morphology: small-medium sized cells, blastic chromatin Immunophenotype: 100% +/CD3+ T-cells Molecular: 100% non-clonal Associated diseases: Castleman disease, Follicular dendritic cell sarcoma Velankar et al., AJSP 1999 Eun et al., J Kor Med Sci 2010 Ohgami et al., AJSP 2012 Qian et al., Leuk Lymph 2009 Strauchen et al., AJSP 2001 Wang et al., Leuk Lymph 2006 Kim et al., Hum Path 2010 Ohgami et al, AJSP 2014 You et al., AJCP 2015 Yang et al., IJCEP 2014 Kansal et al., Hum Path 2015 Woo et a., JPTM 2015 Ohgami et al., Adv Anat Pathol 2013 Summary of cases of indolent T-lymphoblastic proliferations thus far Age: ~40 (10-70) Male:Female 1:1 Morphology: small-medium sized cells, blastic chromatin Immunophenotype: 100% +/CD3+ T-cells Molecular: 100% non-clonal Associated diseases: Castleman disease, Follicular dendritic cell sarcoma Velankar et al., AJSP 1999 Eun et al., J Kor Med Sci 2010 Ohgami et al., AJSP 2012 Qian et al., Leuk Lymph 2009 Strauchen et al., AJSP 2001 Wang et al., Leuk Lymph 2006 Kim et al., Hum Path 2010 Ohgami et al, AJSP 2014 You et al., AJCP 2015 Yang et al., IJCEP 2014 Kansal et al., Hum Path 2015 Woo et a., JPTM 2015 Ohgami et al., Adv Anat Pathol T-lymphoblastic cells are increased in Castleman disease and FDCS/FDCT + T-lymphoblastic cells are increased in Castleman disease and FDCS/FDCT /CD3+ cells per HPF +/CD3+ cells per HPF Ohgami et al., AJSP 2012 Ohgami et al., AJSP
10 + T-lymphoblastic cells are increased in Castleman disease and FDCS/FDCT + T-lymphoblastic cells are increased in angioimmunoblastic T-cell lymphoma (AITL) /CD3+ cells per HPF Ohgami et al., AJSP 2012 Ohgami et al., AJSP 2012 Association with CD, FDCS, AITL In 2013 Some have speculated interleukine/cytokines are responsible for cells Il-6 Still not understood Diagnostic Criteria Why are diagnostic criteria needed? Diagnosis Reactive Indolent T-lymphoblastic proliferation Malignant T-lymphoblastic lymphoma 10
11 Diagnostic Criteria: it-lbp Major Criteria + T cells in sheets/dense clusters primarily in interfollicular region Preservation of general follicular lymphoid architecture Small-medium sized T cells without significant morphologic atypia No aberrant antigen expression Non-clonal (TCR) No associated thymic epithelium Clinical evidence of indolence Diseases associated with Castleman disease and/or follicular dendritic cell sarcomas/tumors Concurrent angioimmunoblastic T-cell lymphoma (AITL) or history of AITL What they didn t teach you in fellowship Indolent T-lymphoblastic proliferations Rules /Dogma can be broken Ohgami et al., Adv Anat Path 2013 What they didn t teach you in fellowship Case B H&E H&E Indolent T-lymphoblastic proliferations Rules /Dogma can be broken 49 year woman Diffuse lymphadenopathy Healthy otherwise H&E H&E H&E CD3 Ki67 Ohgami et al., AJSP 2014 Expression of other antigens, including CD33 CD33 expression odd H&E H&E CD3 CD1a CD4 CD8 CD33 Ki67 TCR-b TCR-g Ohgami et al., AJSP
12 CD33 expression odd = lymphoma CD33 expression odd = lymphoma? CD33 expression odd Expression can be seen on reactive and highly activated T-cells 4 years later patient is still alive without treatment Diagnosis here: Indolent T-lymphoblastic proliferation with CD33 expression Unusual disseminated disease Since that report a second case with CD33 has been described H&E CD33 Woo et a., JPTM 2015 That s interesting But we re not done yet 12
13 A very recent case Healthy 24 year old male Isolated inguinal adenopathy Non-clonal CD8 CD56 Additional clinical information Clinical indolence: 3 months without progression No marrow or peripheral blood involvement Radiology: SUV of lymph node was very low, minimally increased. What they didn t teach you in fellowship Indolent T-lymphoblastic proliferations Rules /Dogma can be broken What they didn t teach you in fellowship Indolent T-lymphoblastic proliferations Non-clonal Rules /Dogma can be broken CD8 CD56 13
14 Is this malignant? Is this reactive? Non-clonal Prethymic T-cell development Thymus Cortex Thymus Medulla CD2/CD5/CD7 CD3 Cytoplasmic Surface CD8 CD34 CD4 CD8 CD1a Double positive Double positive Single positive Single positive CD56??CD56?? CD56 expression odd CD56 expression odd =?lymphoma? NK/T cell development NK/T cell development Stem cell NK/T cell precursor Committed NK/T cell Stem cell NK/T cell precursor Committed NK/T cell CD2 CD2 CD3 Cytoplasmic CD3 Cytoplasmic CD34 CD34 CD4 CD8 Double positive Double positive Single positive or double negative Single positive or double negative CD4 CD8 Double positive Double positive Single positive or double negative Single positive or double negative CD1a CD1a CD56 Positive or Negative CD56 Positive or Negative 14
15 More information on the case: Followup Many more months, patient is healthy, no disease, no treatment Diagnosis here? Castleman disease, hyaline vascular type Unusual CD56+ lymphoblastic proliferation Koo and Cloetingh et al., in preparation Indolent NK/T-lymphoblastic proliferation Stay tuned Summary Indolent T-lymphoblastic proliferations In the context of science and reason Rules /Dogma can be broken^ Koo and Cloetingh et al., in preparation Questions remain What is driving these proliferations? Do these indolent immature T-cells mature into functional T-cells? Why are these associated with Castleman disease? Follicular dendritic cell sarcomas? Angioimmumnoblastic T-cell lymphoma? Returning to Case 1 What did our panelists think? 15
16 Case 1 - Panelists Diagnoses Acknowledgements Indolent T-lymphoblastic proliferation in the setting of Castleman s Disease TDT+ T lymphoblastic proliferation in Castleman's disease Indolent T lymphoblastic proliferation, Castleman disease and follicular dendritic cell proliferation (recommend more stains to better define follicular dendritic cell proliferation). Stanford University Roger Warnke Yaso Natkunam Michaela Liedtke Susan Atwater Brent Tan Dita Gratzinger Jason Kurzer Colleagues Beyond Mark Fleming, CHB/Harvard Dan Arber, U Chicago Tracy George, UNM Milind Velankar, Loyola U Larry Weiss, Neogenomics 16
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