CBCL An Overview and Newer Approaches

Steven M. Horwitz M.D.Lymphoma ServiceMemorial Sloan Kettering Cancer Center

Classification of Cutaneous Lymphomas

Blood 2005;105:3768-85

CUTANEOUS T/NK LYMPHOMAS

Mycosis fungoides

Sezary Syndrome

ATLL

Primary cutaneous CD 30+

Anaplastic large cell

Lymphomatoid papulosis

Subcutaneous panniculitis-like T-cell

Extranodal NK/T-cell

Primary cutaneous peripheral T-cell

Epidermotropic CD8+ T-cell

Cutaneous T-cell

CD4+ pleomorphic T-cell

CUTANEOUS B-CELL LYMPHOMAS

Primary cutaneous marginal zone

Primary cutaneous follicle center

Primary cutaneous diffuse large cell

Leg type

Intravascular

Primary Cutaneous B Cell Lymphoma

Background

Subtypes

Prognosis

NCCN

Clinical scenarios:

Do we need to stage low grade CBCL?

Use of low dose radiation

PCFCL in nodes

Unusual cases of PC-MZL

Primary Cutaneous B Cell Lymphoma

Definition:

– Lymphoma presenting in the skin

– No evidence of extracutaneous disease on complete staging at time of diagnosis

Approximately 20-25% of all cutaneous lymphomasPrimary cutaneous B-cell lymphomas have some unique clinical features

– Indolence-slow growth-majority- MZL/FC– Relapses are common, regardless of the treatment-not assoc with

worse prognosis– Relapses are largely confined to the skin

Primary Cutaneous Marginal Zone B-cell Lymphoma

Clinical Features: M>F (1.4 :1), median age=53

• Red papules, plaques, nodules, rare ulcerations

• Upper extremities > trunk > head

• Slow growth/ spontaneous regression

• Association with Borrelia burgdorferi ? (Europe)– Anecdotal responses to antibiotics

• Therapy-observation, local, topical

• Anecdotes/small series with rituximab, antibiotics, interferon

• Topical corticosteroids, nitrogen mustard

• 5-year survival > 95%

Primary Cutaneous Marginal Zone B-cell Lymphoma

Pathology

• Non-epidermotropic

• Nodular-diffuse infiltrates

• Some large cells

• Reactive T-cells

• CD20, CD79a,

• CD5, CD10, bcl-6-negative

• Light chain restriction, IGH rearranged

• Cases showing rearrangement 14:18 – IGH on 14 and MLT gene on 18

CD20 (B-cell)

CD3 (T-cell)

Primary Cutaneous Marginal Zone Lymphoma

Kappa LambdaLight chainrestriction

PC Follicle Center Lymphoma

• Solitary, grouped, or multifocal plaques or tumor nodules

• Scalp/forehead> trunk >extremities

• Less common disseminated lesions

• Slow growth/ Spontaneous regression

• Rare extracutaneous spread

• Most common; M>F (2.1:1)median age=58

• Excellent prognosis

• 5-yr DSS 95%

Senff NJ, Noordijk EM, Kim YH, et al. Blood 2008;112:1600

WHO monogram, 4th Edition, 2008

Primary Cutaneous Follicle Center Lymphoma

In contrast:PCLBCL-LT:Monotonous diffuse centroblasts & immunoblastsExtension to subcutaneous fat; MUM-1+, Bcl-2 + Frequent mitosis

Mix of centrocytes and centroblastsEpidermal sparingVarying amounts of large cellsFollicular or diffuseFrequent reactive T-cells

Immunohistochemistry/Genetics

• Tumor cells express CD20 and CD79

• Tumor cells will express HGAL, bcl-6, and LMO2 consistently

• PC FCL do not consistently express bcl-2 or CD10

• T(14;18) and bcl-2 gene rearrangement not present in most cases of PC FCL

Weinberg O et al. Am J Surg Pathol. 2009 Apr;33(4):591-8.

Xie X et al. Mod Pathol. 2008 Jun;21(6):653-9.

Morales A et al. Am J Dermatopathol. 2008 Oct;30(5):425-30.

Cutaneous MZL/FC LymphomaIndolent histologies

Treatment N CR Relapse Relapse:EC OS

5/10y

ALL 416 90% 44% 6-11% 96/90%

XRT 217 98% 49%

Chemo +/- XRT

(Variety)

96 80% 52%

Excision 103 97% 35%

Zinzani et al. J Clin Oncol 24:1376-1382. March 2006

Cutaneous MZL/FC LymphomaLocal therapy: XRT/Excision

All DFS

Treatment N 5 year 10 year

Single 247 64% 51% p<.001

Regional 125 43% 27%

Disseminated 57 45% 36%

Zinzani et al. J Clin Oncol 24:1376-1382. March 2006Reddy et al, ASCO 2007, a8028

Indolent N Relapse

Localized 65 34 52%

Generalized 19 13 68%

Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg Type

• Rare; rapid growth

Lower extremities> anywhere else

• Especially elderly women(F>M 2:1; age >70)

• Extracutaneous involvement more common

than other lymphomas

• 5 year over-all survival 67%

Pathology• Dense diffuse infiltrate of large B cells, with obliteration of existing

adnexal structures

• Extends significantly into subcutaneous tissue

• Monomorphous large B cells, with appearance of immunoblasts

• Express CD79, CD20, MUM-1, FOXP1, IgM and IgD

• In some series, strong uniform expression of bcl-2 with variable expression of bcl-6

• Does not usually express CD10

Sundram U et al. J Cutan Pathol. 2005 Mar;32(3):227-34.Kodama K et al. Blood. 2005 Oct 1;106(7):2491-7.

MUM-1

CD20

Bcl-2

Bcl-6

Hoefnagel et al Blood 2005;105:3671-3678

Willemze et al Blood, 2005;105:3768-3785

de Leval et al Am J surg Pathol. 2001;25:732-741

Hoefnagel et al Br J Dermatol. 2003:149:1183-1191

Child et al Br J Dermatol. 2001;144:735-744

Cerroni et al J Invest Dermatol. 1994; 102:231-235

FCL LBC-L

CD20/CD 79a + +

Bcl-2 -/+ ++

Bcl-6 + +

CD10 -/+ -

MUM-1 - +

t(14:18) - -

Trans myc (fish) - +/-

ABC GC

Follicle center -Diffuse large B-cell, leg typePathology

DLBC-Leg Type

Treatment N CR Relapse Relapse:EC OS

5/10y

ALL 51 82% 55% 17% 73/47%

XRT 28 23% 52%

Chemo +/- XRT

(CHOP)

20 80% 63%

Excision 3 100% 33%

Zinzani et al. J Clin Oncol 24:1376-1382. March 2006

Senff, N. J. et al. Arch Dermatol 2007;143:1520-1526.

disease-specific survivalrelapse-free survival

Results after Primary Radiation for Cutaneous B-cell Lymphoma

Koens et al. Journal of Investigative DermatologyVolume 134, Issue 1, January 2014, Pages 290-292

JAMA Dermatol. 2014;150(11):1173-1179. doi:10.1001/jamadermatol.2014.821

MYD88 mutation was not present in 24 patients and was present in 34 patients.(P = .002).

Overall Survival of 58 Patients With Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg-Type According to the MYD88 Mutation

MarieBeylot-Barry J. Invest Derm Volume 138, Issue 9, September 2018, Pages 1982-1989

Lenalidomide for Cutaneous Diffuse Large B-Cell Lymphoma, Leg-Type

Anecdote with BTK inhibitor

6 had CR and 5 had PR

What is the utility of initial staging for low grade CBCL?

Utility of imaging in cutaneous marginal zone lymphoma and cutaneous follicle center lymphoma

Meenal Kheterpal, Shamir Geller, MD1, Julia Dai, Melissa Pulitzer , Patricia Myskowski, Alison Moskowitz, Ai Ni, Jinah Kim, MD Richard Hoppe, MD, Youn H. Kim, Steven M. Horwitz

1Memorial Sloan Kettering Cancer Center, Stanford University School of Medicine

Retrospective review:Patients with cutaneous presentation of FCL (CFCL) diagnosed between 1997-2016

evaluated at MSKCC or at Stanford UniversityPatients with cutaneous presentation of MZL (CMZL) diagnosed between 1998-2016,

evaluated at MSKCC or at Stanford University

Inclusion criteria:CMZL/CFCL confirmed by pathologists at MSKCC / StanfordSkin was the initial site of presentation of the cutaneous lymphomaImaging study (positron emission tomography scan and/or chest, abdomen and pelvic

computed tomography scan) within 12 months as part of the initial workup.

MZL

Marginal Zone LymphomaClinical characteristics of patients with systemic involvement at

presentation

45.4

63.6

36.4

0

36.4

9.1

45.536.4

18.227.3

9.10

27.3

54.5

0

10

20

30

40

50

60

70

% o

f p

atie

nts

Clinical Characteristics

FCCL

Follicular lymphoma presenting in the skinClinical characteristics of patients with systemic

involvement at presentation89.4

21.1

5.215.8

57.9

21.1 21.16.3

17.6 15.8 21.4

0

33 38.9

0102030405060708090

100%

of

pat

ien

ts

Clinical characteristics

Conclusions• 3.6% of patients with CMZL vs 8.8% of patients with CFCL histology presenting in the skin

have concurrent extracutaneous disease most consistent with systemic B-cell lymphoma

• Of the patients with systemic involvement at presentation, imaging alone detected 81.8% (9/11) of MZL cases and 89.4% (17/19) of FCL cases.

• Due to the rarity of extracutaneous disease, imaging had a low yield in CMZL in follow up

• Bcl2 positivity is suggestive of systemic nodal B-cell lymphoma in patients with CFCL Additionally, subcutaneous involvement, elevated LDH and lower extremity involvement may be associated with a higher likelihood of systemic disease.

• Large lesions with deep subcutaneous involvement in patients presenting with CMZL may be suggestive of systemic B-cell lymphoma although prospectively collected data is needed for validation

Use of low dose radiation for low grade CBCL

Boom Boom Radiation

Treatment

Karen Chau, Joanna Yang, Monica Chelius, Carla Hajj, and Joachim Yahalom

2Gy x 2 RT for Patients with Indolent Lymphomas

Background• Boom boom is 2Gy x 2 RT

– Option for patients with radiosensitive and indolent lymphomas

• Initially published in 1994 by Ganem, et al.1

– 89% of patients had a response

• Literature– Netherlands study (Haas, et al.2)

• 109 patients (304 sites)• Overall response rate was 92% (61% CR and 31% PR)• Median time to local progression: 42 months

– FORT trial (next slide)1 Ganem, GéRard, et al. "Potential role for low dose limited‐field radiation therapy (2× 2 grays) in advanced low‐grade

non‐Hodgkin's lymphomas." Hematological oncology 12.1 (1994): 1-8.2 Haas, R. L. M., et al. "High response rates and lasting remissions after low-dose involved field radiotherapy in indolent

lymphomas." Journal of clinical oncology 21.13 (2003): 2474-2480.

FORT trial• 4Gy versus 24Gy radiotherapy for patients with indolent lymphoma

(FORT): a randomized phase 3 non-inferiority trial

– Eligibility

• 18+ years old with FL or MZL and no previous treatment for at least 1 month pre-RT

– Between April 7, 2006, and June 8, 2011

• 24Gy: 299 sites

• 4Gy: 315 sites

– Median f/u: 26 months (range: 0.39 – 75.4)

FORT trial– Outcomes

• Initial response measured at 12 weeks

– 24Gy: 236 (91%) had a CR/PR

– 4Gy: 227 (81%) had a CR/PR

24Gy 4Gy

Complete response 176 (68%) 137 (49%)

Partial response (>30%) 60 (23%) 90 (32%)

Stable disease (including <30% regression) 22 (8%) 44 (16%)

Progression 2 (<1%) 10 (4%)

Total 260 281

FORT trial– Outcomes

• 91 local progressions (24Gy group: 21; 4Gy group: 70)• Time to local POD with 4Gy was not non-inferior to 24Gy• 24Gy is more effective than 4Gy but 4Gy remains useful alternative

for palliative Tx

• Difference in local progression-free interval at 3 years: 20%

Boom Boom: Retrospective Review of Our Experience at MSKCC

Patient selection• Received 2Gy x 2 RT between 2006 – 2017 at MSKCC

• ≥18 years of age at Dx

• MSKCC confirmed pathology of indolent lymphoma prior to RT

–Follicular lymphoma

–Marginal zone lymphoma

Histology65%

Follicular Lymphoma33% Marginal Zone

Lymphoma

2% Other

Cohort characteristics

54%Early stage

46%Advanced stageInitial stage (early vs. advance)

40%Stage I

13%Stage II

18%Stage III

29%Stage IVInitial stage (breakdown)

First line treatment66%

Other34%

Boom boom RT

Lesion type (nodal vs. extranodal)60%

Extranodal35%

Nodal

5% Both

Timeline

2Gy x 2

(Radiation therapy)

Follow-up at 2 months

(Evaluation of initial response)

Further treatment or

f/u

(if needed)

Response at 2 month f/u (by histology)

CR

PR

NR

Follicular Lymphoma

Response rate: 85%

111 sites

60%(n = 67)

25%(n = 28)

15%(n = 16)

CR

PR

NR

Response rate: 90%

57 sites

72%(n = 41)

18%(n = 10)

10%(n = 6)

Marginal Zone Lymphoma

CR

PR

NR

Nodal

Response rate: 75%60 sites

58%(n = 35)17%

(n = 10)

25%(n = 15)

Response at 2 month f/u (by lesion type)

CR

PR

NR

Response rate: 94%103 sites

71%(n = 73)

23%(n = 24)

6%(n = 6)

Extranodal

In-field progression (pts with initial CR/PR)

n = 109

n = 38

p < 0.001

Conclusion• Patients with FL and MZL in this series appeared to have excellent initial

response

–ORR was 87%

• A complete response is durable

–2 year FFLF: 92%

–5 year FFLF: 85%

• A partial response remains stable/disease-free approximately 50% of the time

• Very low dose radiation appears to be a viable option for pts with PCBCL

How to approach PC-FCCL when it involves lymph nodes?

Cutaneous Large B-cell LymphomaOS by Site

Grange et al J Clin Oncol 19:3602-3610, 2001

2

5

5

0

7

5

10

0

%

0 1 2 3 4 5Years

Leg

Non-Leg

80 yo M with PCFCCL• Multiple lesions – chest and abdomen, 3 mo duration

• Bx outside (1/10): PCFCCL (Large Cells, CD20+ BCL-2+/- BCL-6+ focally, MUM-1 -, CD10+), confirmed also at MSK

• Workup: PET (2/25/2010) : No evidence of FDG-avid lymphoma. CBC, LDH – wnl

• F/U – PR with topical CS, RT was given to a tumor lesion on the back. Local recurrences treated with IL CS

PC-FCCL• Indolent course whether cells large or small

• Large cells in node (same cells) will be often called DLBCL

• Unclear best way to tell whether at that point its an aggressive or indolent lymphoma

• Clinically?

Unusual presentations of PC-MZL?

CD20

CD3

Bcl-2

PC-MZL

• Antigen stimulation

• Secondary to external trauma/stimulation?

• Bicycle helmet straps

• Right leg prosthesis

• Laser hair removal

• Chandelier

Primary Cutaneous B Cell Lymphoma

Overview

Do we need to stage low grade CBCL?

Use of low dose radiation-”Boom- Boom”

PCFCL in nodes

Unusual cases of PC-MZL

MSKCC Cutaneous LymphomaAlison MoskowitzPatricia MyskowskiSarah NoorShamir GellerMeenal KhetterpalJoachim Yahalom-XRT

Dermatopathology

Melissa Pulitzer

Klaus Busam

Travis Hollman

Acknowledgements

Thank you