Houston Society of Clinical Pathologists 59th Annual Spring Symposium: Dermatopathology

Hematolymphoid lesions part I (cutaneous lymphoma) Melissa Pulitzer, MD Associate Attending Pathologist Department of Pathology, Dermatopathology Division Memorial Sloan Kettering Cancer Center Weill Cornell Medical Center New York, New York 1

Houston, Texas April 14, 2018

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• No disclosures of financial relationships No unlabeled/ investigational use of a commercial product

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Xing , Cancer 2010

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How do we meaningfully classify CTCL for prognosis, and therapeutic stategizing to improve lives and reduce morbidity/mortality???

• Pian Fungoides (Alibert) 1814 • Gillot & Ranvier Lymphadenee Cutanee (4 phases) 1869 • Bazin 3 phases (1870) • Vidal and Brocq Tumor d’emblee 1885 • Pusey 1st derm to use radiation to shrink skin tumors 1902 • The New York Cancer Hosptial and General Memoral hospital for Cancer department of cancer surgery and

radiation therapy – x-ray and radium 1912

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• L. Frank Frazer • Confirmed MF to be lymphoma 1825

• Sezary – Observed Cellules Monstreuses in the

blood of patients

• Frank Barr Malloy • Nathan Brill • George Callendar • Gall and Malloy • Rappaport

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CD4+ small/medium T-cell lymphoproliferative disorder

Includes types D and E Primary cutaneous CD8+ acral T-cell lymphoma

WHO/EORTC classification is a guideline

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Physical examination Skin biopsy Chest X-ray CT abdomen Biopsy of any enlarged lymph nodes

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CD4

CD8 CD3+, CD4+ , CD45RO+ CD8- CD2,5,7 +/- BetaF1+ Granzyme/perforin/TIA-1 +/- CD30 +/-

Follicular (Pilotropic) MF

• Folliculotropic/centric/pilotropic • Worse px • Erythematous patches/plaques with

comedo-like plugs • +/- hair loss • Face, upper trunk • Small-medium sized atypical lymphocytes • Spare interfollicular epidermis • +/-Mucin, follicular plugging, cystic dilation • Large cell transformation & nodal

involvement

Patch and sparse FMF is easily notable as early (IA-IIA) stage disease Tumors with FMF is easily notable as aggressive/advanced disease This study looked at plaques with FMF and discerned 2 subgroups

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Variant MF

• Pilotropic/folliculotropic mycosis fungoides • Pagetoid Reticulosis, localized

(Woringer Kolopp Disease) • Granulomatous Slack Skin

Large cell transformation

Large cell transformation

• +/- CD30, +/- CD25 • Correlates with stage • When found in first manifestation of disease, may not be predictive of

aggressive course • Controversial if it is independently predictive of outcome

– no study to date has been perfect e.g. CLIPI study used referral diagnosis of LCT when we found that interobserver variability is exceedingly high in a 75 patient review

Findings predictive of outcome in LCT

• Age>60, LFTs • Follicular mucin • Fibrosis • Dermal CD30 absence

Patients who had LCT at presentation did not have alteration of stage-dependent prognosis.

• CD8+ MF is less common than CD4+ MF • Often characterizes hypopigmented, poikilodermatous, pagetoid

reticulosis variants of MF – Clinical course may or may not be similar – Recent suggestion to reclassify as LPD

• CD30+ CD8+ ddx favors a CD30+ LPD

CD8, 3, 2, 45RO

Can Ki-67 help us to prognosticate in MF?

AJSP 2009 •47 patients •Median epidermal Ki-67 14%; median dermal Ki-67 13% •Increased in large cell transformation, particularly in dermis •Dermal Ki-67 a/w higher stage at dx and maximum stage •Survival from 1st rash, time of biopsy or dx was worse if dermal or epidermal Ki-67> median •When evaluated as a continuous variable, both dermal and epidermal Ki-67 were associated with adverse px •On multivariate analysis, only dermal ki-67 held up as independent prognostic factor

CD20+ Mycosis Fungoides

• Dual expression of both CD3 and CD20 proteins

• CD3 is uniformly positive • Other pan-T-cell markers may be

diminished. • CD20 is dim to brightly positive in

the same cells. • Other B-cell markers CD79a and

PAX5 e.g. are negative.

CD3 CD20

CD3 CD20

• 52 year old male • CD20+ T-cell LPD • Multispectral imaging showed that 23%

of CD3+ T-cells were CD20+ • 38% of CD20+ cells were also CD3+

AJDP 2015

AJDP 2015

AJDP 2016

JID, in press (Next page)

•144 biopsy samples •36 patients at baseline

•Patch/plaque vs tumor •intratumoral

•ICC is correlation and agreement between measurements

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Pimpinelli et al, JAAD 2005

International Society of Cutaneous Lymphoma algorithm Do we need to immunophenotype MF at all?

YES If there are unusual morphologic features Cytotoxic, angiocentric or large cell features e.g. that might imply a different diagnosis YES If there is a possibility of a second lymphoma or a reaction to drug therapy YES If the findings will determine a different course of therapy (CD25, CD52L, CCR4, PD1, CD30 e.g.)

MF versus SS - Points in a disease continuum? Or separate disease? • MF- malignant T cells present in skin lesions

– Indolent course – Express markers of skin resident effector memory T cells (TEM).(phenotype

of antigen stimulated cells) • SS/L-CTCL- erythroderma, circulating clonal malignant T cells, and often

lymphadenopathy – Poor prognosis – Express central memory T-cell markers – lymph node homing molecules, L-selectin and CCR7 – A subset also co-express CLA and CCR4 and can migrate between skin and

LN – ore PD-1 expression in SS

Regarding monoclonal T-cell receptor gene rearrangements

• TCR PCR – 40-90% patients with MF – Stage dependent

• 50-70% patch, 75% plaque, 85-100% tumor (T-stage) • Positive clones in lymph node correlate with skin stage • 25-65% with certain inflammatory dermatoses may have dominant

clones by TCR PCR – Gamma and Beta chain rearrangement analysis equally specific and

sensitive, although not same • Combined use may increase sensitivity

–Especially TCR Beta in early disease • Combined use requiring both could increase specificity

Lukowsky et al JID 2000, Schiller et al Arch derm res 2000, Fraser-Andrews BJD 2006, Zhang et al, JMD 2010

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B2 patients Rarely patch/plaque MF have B2. Significance is unclear

Recommendations Use of flow cytometry to measure blood involvement at all stages of MF and SS Use absolute flow counts of CD4+/CD7- or CD4+/CD26- to set a cut off. Define SS (IVA1 and above) as erythrodermic B2 blood and a circulating T-cell clone identical to that in skin. Blood response criteria - complete response should improve from B/B2 to B0 . For PR, 50% reduction in blood tumor burden for B2 pts.. Don’t count movement between B0 and B1. Elevated number of neoplastic cells for progressive disease should be lower (1000/ml)

Prognostication

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European Journal of Cancer, 2013

Showed decreased OS and PFS in patients dependent on whether or not they had 1, 2, 3, 4 or 5 of a predetermined adverse factor (low, intermediate and high groups): • Male sex, age>60, plaques, FMF, N1/NX in early stage disease • Male sex, age>60, B1/B2, N2/N3 or M1 in late stage disease

Validation on 80 patients worked for early stage MF, but not for late stage

Differential considerations and pitfalls

Cutaneous T-cell lymphoproliferative disorders and lymphomas with T-follicular helper immunophenotype

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British Society for Hematopathology

KNOW CLINICAL PRESENTATION!!

Follicle helper T-cell phenotype LPD

• CD3+/CD4+ AND>3: – CD10, PD-1, CXCL-13, ICOS, BCL-6

• Nuclear Bcl-6 and cytoplasmic CD3 colabel • Brisk B-cell infiltrates, may be clonal • DDX:

– MF/SS – AITL – CD4+SMPTCL – Other

• PcPTCL unspecified • PTCL NOS involving skin • So called PcTFH lymphoma

67 Year old male with a nodule on his left temple

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Cd3

CD4 CD8

TIA-1

Ki67 PD-1

CD79a CD20

• 36 bx from 21 patients with MF • 9 LyP • 11ALCL • 13 SMTCL • 2 gamma delta • 8 SPTCL • 3 PTCL NOS • 1 SS • PD-1, ICOS, CXCL13, IL6, CD10

• 3/5 markers was observed in 33 biopsies (20 MF, 11 SMTCL, 1 SPTCL, ALCL)

Conclusions: The expression of TFH markers should not be used for classification of any CTCl and should only be used with other markers!

Date of download: 10/13/2013 Copyright © 2012 American Medical Association. All rights reserved.

From: Primary Cutaneous Follicular Helper T-cell Lymphoma: A New Subtype of Cutaneous T-cell Lymphoma Reported in a Series of 5 Cases Arch Dermatol. 2012;148(7):832-839. doi:10.1001/archdermatol.2011.3269

Figure Legend:

Primary cutaneous Cd4+ small/medium-sized T-cell lymphoproliferative disorder

• 5-10% ctcl • Face, neck, upper trunk, usually (but not always) solitary • Nodular infiltrates involve dermis +/- subcutis • While small-medium sized cells are the hallmark, up to 30% of the cells

may be large and atypical, per definition. • Admixed lymphs and histiocytes, B-cells, proliferative activity • Clonal TCR gene rearrangement • 60-80% 5 year survival

Primary cutaneous peripheral T cell Lymphoma, unspecified

• Heterogeneous group of T cell neoplasms that don’t fit into the other categories well

• <10% of all CTCL • CD30- • Generally aggressive

• Primary cutaneous aggressive epidermotropic cd8 positive cytotoxic t cell lymphoma

• Cutaneous gamma/delta T-cell lymphoma

• Primary cutaneous CD4+ small/medium sized pleomorphic T-cell lymphoproliferative disorders

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Gamma delta T-cells

• Gamma delta T-cells comprise about 7% of normal skin-resident T-cells • Skin and other epithelial barriers are gamma-delta T-cell rich organs • Gamma delta T-cells play a significant role in immune surveillance

AJDP2015

JCP 2015

AJDP2015

AJDP 2015

OTHER ENTITIES CAN express TCRgamma and/or Delta

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Closing messages

• Classifications will be continue to evolve, so use them as guidelines, not laws • Most mycosis fungoides can be accurately diagnosed, although false positives and

negatives are possible • Prognostic and therapeutic biomarkers are ongoing in their analysis

– Simple CD4+ T-cell lymphoma in the skin can be challenging – Make sure it really is CD4+ – Make sure that the clinical description and the histopathology fit the diagnosis

that you yield • Gamma-delta and CD8+ aggressive T-cell lymphomas are being better evaluated

over time – Continue to beware of and read about pitfalls in immunohistochemistry,

molecular testing and communications with clinicians.

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Special thanks to Dr. Prieto, Dr. Torres-Cabala and to my colleagues at MSKCC Pat Myskowski, Steve Horwitz, Allison Moskowitz, and Shamir Geller THANK YOU

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