Hodgkin

L. Jeffrey Medeiros, MD MD Anderson Cancer Center James J. Butler, MD

Robert J. Lukes, MD Cancer Research 26; 1063, 1966 Classification of Hodgkin Little Change Over Time Lukes & Butler Rye WHO - 2008 Lymphocytic Lymphocytic Nodular and/or histiocytic predominance lymphocyte Nodular predominant HL Diffuse Lymphocyte-rich classical HL Nodular sclerosis Nodular Nodular sclerosis sclerosis classical HL Mixed Mixed cellularity Mixed cellularity classical HL Diffuse fibrosis Lymphocytic Lymphocyte- Reticular depletion depleted classical HL Mercedes Benz

Same name – different cars

2019

1934 Criteria for HL Diagnosis

Criteria have shifted from purely histologic to histologic and immunophenotypic The shift has lead to: Reclassification of disease Change in disease frequencies Change in criteria for diagnosis of HL overall Impact of Immunophenotype Are RS Cells Needed for Dx of HL ?

Old Formula RS cells + appropriate = milieu Immunophenotype has changed this NLP LP cells NS Lacunar cells MC RS+ mononuclear variants LD RS+ anaplastic variants Impact of Immunophenotype Small Biopsy Specimens

Reed-Sternberg cells not required for diagnosis Need mononuclear cells with appropriate immunophenotype Hodgkin Lymphomas Frequency

HL ~ 12% lymphomas in USA (~9,000 cases)

Nodular sclerosis 62% Mixed cellularity 27% Nodular lymphocyte predominant 5% Lymphocyte-rich classical 4% Lymphocyte depleted 1%

J Clin Oncol 23: 5739, 2005 Nodular Lymphocyte Predominant HL

Male predominance Peak incidence 30-50 years age group Localized peripheral LNs (cervical #1) B-symptoms unusual Mediastinum, spleen and bone marrow rarely involved Frequent relapses (late) Nodular LPHL Immunophenotype of Neoplastic Cells in HL Classical NLP HRS Cells LP Cells T-cell - - CD15 +/- - CD20 -/+ ++ CD30 + - CD45/LCA - + PAX-5 + dim + OCT-2 - + BCL-2 +/- - BCL-6 -/+ + EBV +/- - Nodular LPHL – CD20

LP cells are of B-cell lineage

Many reactive cells are also B-cells Nodular LPHL

Reactive cells also important for Dx

A follicle-based tumor CD21

CD57 CD3 Patterns of NLPHL – CD20

A. B-cell rich nodular B. Serpiginous nodular CD3 CD20 C. Nodular with extranodular LP cells D. T-cell rich nodular E. Diffuse T-cell-rich (TCRBCL-like) F. Diffuse moth-eaten

Am J Surg Pathol 27: 1350, 2003 Pattern is Prognostic in NLPHL

Blood 122: 4246, 2013 NLPHL Pattern E

Nodular areas are required to recognize pattern E in NLPHL

Is pattern E = T-cell/histiocyte rich large B-cell lymphoma ?

Patients tend to do better than patients with DLBCL

No criteria to distinguish pattern E from true THRLBCL

OK to use clinical criteria in this Bone lesions, BM involvement Hepatosplenomegaly High serum LDH

If treatment is R-CHOP (or CHOP) the distinction may not matter NLPHL Can Transform into Diffuse Large B-cell Lymphoma

NLPHL DLBCL NLPHL pts have 3-5% increased risk of DLBCL Same or different anatomic sites Synchronous or metachronous Not true for classical HL Lymphocyte-rich Classical HL

Median age, 43 yrs Male predominance (70%) Most commonly stage I or II disease Peripheral LNs typically involved Mediastinum (15%) Spleen (15%) B-symptoms (10%) Late relapses uncommon Lymphocyte-rich Classical HL Nodular variant Lymphocyte-rich Classical HL Nodular Variant

CD20 CD20

CD30 CD3 Immunophenotype of Neoplastic Cells in HL Classical NLP HRS Cells LP Cells T-cell - - CD15 +/- - CD20 -/+ ++ CD30 + - CD45/LCA - + PAX-5 + dim + OCT-2 - + BCL-2 + - BCL-6 -/+ + EBV +/- - Lymphocyte Predominant HL vs. Lymphocyte-rich Classical HL

Overall Survival Failure-free Survival

German Hodgkin Study Group J Clin Oncol 17:776, 1999 Nodular Lymphocyte Predominant HL versus Lymphocyte-rich Classical HL

Can look very similar

Immunophenotyping is mandatory for differential diagnosis

If you don’t do it you will be sorry about 30-40% of the time Is LRCHL a Real Type of Classical HL ?

We have seen evidence of nodular sclerosis in cases that otherwise looks like LRCHL

At relapse, a subset of cases of LRCHL resemble nodular sclerosis CHL

My opinion

About 25% of LRCHL cases are “early” NS

Other cases are likely “true” LRCHL Nodular Sclerosis HL

Median age 28 years

No male predominance

Stage II disease in most patients

Peripheral lymphadenopathy (cervical #1) Mediastinal involvement in 80% Spleen and/or lung 10% Bone marrow uncommon (3%)

B-symptoms 40% Nodular Sclerosis Classical HL Any degree of fibrosis supports NS

Diagnostic triad Nodules Sclerosis Lacunar cells Nodular Sclerosis HL Lacunar cells Nodular Sclerosis HL Syncytial Variant Nodular Sclerosis HL Syncytial Variant

CD15 LCA

CD20 PAX5 Differential Diagnosis of NSHL

Other HL Fibrosis is not dense and does not polarize types with LN fibrosis DLBCL, nos Nodularity and sclerosis can mimic HL Sheets of large cells CD20+ CD45+ CD15- Primary Sheets of large cells without inflammatory mediastinal background; sclerosis common LBL CD20+ CD45+ CD15- CD30 +/- Gray zone Can look like HL or DLBCL or mixture lymphoma HL-like: CD45+ B-cell+ (strong) EBV- DLBCL-like: CD15+ CD30+ CD45- DLBCL with Sclerosis

CD20 Mediastinal Large B-cell Lymphoma

CD20

CD30 A B-lineage lymphoma that demonstrates overlapping clinical, morphological and/or immunophenotypic features between classical Hodgkin lymphoma and DLBCL.

2017 WHO book p.342 Gray Zone Lymphoma Two Variants

Resembles HL but has immunophenotype more like DLBCL Resembles DLBCL but has immunophenotype more like HL

In other words, there is discordance between morphology and immunophenotype

2017 WHO book, p.342 Gray Zone Lymphoma Clinical Features

Young, 20-40 years Male > Female Anterior mediastinal mass is common Most reported cases from Western countries

2017 WHO book, p.342 Gray Zone Lymphoma Intermediate between Classical HL and DLBCL

HL-like Gray Zone Lymphoma Intermediate between Classical HL and DLBCL

CD15 CD30 LCA

CD20 PAX5 Gray Zone Lymphoma Intermediate between Classical HL and DLBCL

CD15

CD20

DLBCL-like CD30 CD45LCA What is Best Therapy for Gray Zone Lymphoma ? 24 pats treated with DA-EPOCH-R

PMBL MGZL

Median age = 33y (14-59) 63% male 46% mass >10 cm 50% high LDH Blood 124: 1563, 2014 Diagnosis of Gray Zone Lymphoma What Are Stakes For Patient?

Recommended Therapy

Classical HL ABVD +/- IF XRT (standard) DLBCL R-CHOP + XRT (standard) DA-EPOCH-R (emerging) Gray Zone DA-EPOCH-R Lymphoma Mixed Cellularity HL

Median age 37 Male predominance Stage III or IV and B-symptoms more frequent than in nodular sclerosis Peripheral LNs common Mediastinal LNs uncommon Spleen (30%), bone marrow (10%) and liver (3%)

EBV+ (75%) Increased in HIV+ patients and developing countries Mixed Cellularity HL

EBV-LMP Mixed Cellularity HL Granulomatous Variant

CD30 Mixed Cellularity HL Interfollicular Pattern

CD15 Lymphocyte-depleted HL

Advanced age B-symptoms (80%) Stage III or IV disease (IV) Extensive disease below diaphragm Abdominal LNs Spleen, liver and BM Most aggressive form of HL Lymphocyte-depleted HL

CD30 EBER1 Criteria for Dx of CHL Are Evolving

RS-H cells can occur in many settings Infectious mononucleosis Transformed B-cell lymphomas T-cell lymphomas (AITL) Post-transplant LPDs Histiocytic tumors

The essential question (for me): Is standard HL therapy likely to work?

If the answer is no, I try to avoid calling a case HL Single Cell PCR in NLPHL

All cases are of B-cell lineage

IgH gene rearrangements

High level of somatic mutations

Ongoing somatic mutations are present

These results support origin from “functional” B-cells Single Cell PCR in Classical HL

>98% of cases have IGH rearrangements High level of somatic mutations ~25% have “crippling” mutations Rare ongoing mutations

These results support origin from “non- functional” germinal center B-cells

Rare cases are reported to be T-cell Really HL ? Nodular Sclerosis HL T-cell Antigen + Nodular Sclerosis HL T-cell Antigen +

CD15 CD30 PAX5

CD2 CD3 T-cell antigens expressed by RS-H cells classical HL

T-cell antigens expressed in 10-15% of classical HL cases Most are PAX5+ and IgH rearranged Blood 95: 3020, 2000

Does T-cell HL even exist? (I think not) I call PTCL with HL-like features Most common in NSHL

At MDACC, T-cell antigen expression does not influence treatment plan

Blood 121: 1795, 2013 RS+H Cells in HL are “Sick”

Evidence of “sickness” in RS-H cells Many Ig gene mutations Crippling mutations in ~25% B-cell program is highly defective Promoter hypermethylation Inhibitors RS+H cells should undergo apoptosis in GC Why don’t they ? Frequency of EBV Infection in HL Latency Type II Pattern

Nodular LP 0% Nodular sclerosis 10-20% Lymphocyte-rich classical 50-60% Mixed cellularity 60-70% Lymphocyte depletion 60-70% Classical Hodgkin lymphoma Cross talk between RS+H and reactive cells

Promotes survival of RS+H cells

Allows RS+H cells to escape cytotoxic T/NK- cells

J Clin Invest 122: 3439, 2012 Classical HL Pathogenesis Major Pathways

NF-κB

JAK-STAT

Escape from immune surveillance PD1-PD-L1/L2 axis NF-κB Pathway Activation is Common in Classical HL

EBV provides signals bypassing RS+H apoptosis LMP2a mimics B-cell receptor LMP1 mimics CD40 activating NF-κB

TNFAIP3 is mutated in ~40% of classical HL Encodes A20 protein = suppressor of NF-κB

EBV infection and TNFAIP3 mutations are mutually exclusive JAK-STAT Pathway Activation is Common in Classical HL

Amplification of JAK2 Located at chromosome 9p24.1

Mutations of SOCS1 and PTPN1 Inhibitors of JAK-STAT pathway Mutated in 20-30% of cases

Chromosome 9p24.1 is also site of PD-L1 / PD-L2 108 cases of classical HL assessed by FISH Abnormalities of chromosome 9 Polysomy = 5 cases (5%) Copy gain = 61 cases (56%) Amplification = 39 cases (36%) Amplification of PD-L1 or PD-L2 associated with advanced stage and shorter progression-free survival

PD-L1 / PD-L2 by IHC correlates with genetics

J Clin Oncol 34: 2690, 2016

Progression-Free Survival by Decade Hodgkin Lymphoma

n = 3216 1.0 2000s 0.8 1990s, BM transplant 0.6 1980s, ABVD 1970s, wide 0.4 field XRT and MOPP 0.2

Cummalative survival 1960s

10 20 30 40

Years Courtesy of J. Connors, MD How is HL Treated Today? NLPHL Low stage disease Recent trends are to do as little as possible

Blood 133:2121, 2019

High stage disease R-CHOP is better than ABVD

Blood 130: 472, 2017 How is HL Treated Today? Classical HL

Early stage favorable (stage I + IIA) 2-4 cycles of ABVD Involved field XRT (20-35 Gy)

Early stage unfavorable 4-6 cycles of ABVD Involved field XRT (30-35 Gy) How is HL Treated Today? Classical HL

Advanced/unfavorable 4-6 cycles of ABVD Some use: BEACOPP (Europe)

Refractory or Relapsed Disease High-dose chemotherapy + autologous stem cell transplant (ASCT)

Relapse after ASCT New agents (developed or in trials) Hodgkin Lymphomas New Therapeutic Strategies

Target RS + H cells directly Target cells in microenvironment Reverse suppression of immune response Blood 125: 1236, 2015

Monomethyl Auristatin E Peptide Anti-CD30 linker B-AVD Better outcomes with less therapy and toxicities

Blood 2019 [Epub] 23 pretreated patients with relapse 78% post ASCT and 78% post anti-CD30 20 patients had objective response (4 CR)

N Engl J Med 372: 311, 2015 Nivolumab (N) followed by N + doxorubicin, vinblastine and dacarbazine (N-AVD)

84% objective response 67% complete remission 92% overall survival at 9 months

J Clin Oncol 2019 [Epub]