How I treat patients whose biopsies are reported descriptively Youn H Kim, MD

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1 How I treat patients whose biopsies are reported descriptively Youn H Kim, MD Director, Multidisciplinary Cutaneous Lymphoma Group Stanford Cancer institute & School of Medicine NCCN NHL Panel Member

2 Disclosure statement Youn Kim, MD Steering Committee Eisai, Kyowa, Millennium/Takeda Consultant or Advisory Board Actelion, Innate, Seattle Genetics, Forty Seven, Medivir, Takeda Investigator Kyowa, Merck, Millennium/Takeda, Seattle Genetics, Eisai, Tetralogic, Innate, Neumedicine, Soligenix, miragen, Forty Seven, Horizon, Portola

3 Multidisciplinary Teamwork for Optimal Comprehensive Care Diagnosis Pathology (Dermpath/Hemepath/ molecular diagnostics) Dermatology (Cutaneous Oncology) Cutaneous Lymphoma Clinical Care Providers Support Staff Medicine (Medical/Hematology Oncology, BMT) Radiation Oncology Other (Pediatric Onc, Radiology/Nuclear Med)

4 Evaluation and management in CTCL Clinical Integrative/correlative Management determined by Specific diagnosis Type & extent of dz Biologic behavior Histologic Diagnosis Prognostication Treatment Laboratory Imaging Molecular (primarily TCRR) Chromosomal aberrations Gene expression patterns Genomic alterations by NGS Epigenetic alterations/profiles MicroRNA profiles NOT ready for clinical use Other key factors Age Comorbidities, PS Availability & accessibility

5 Evaluation and management in CTCL Clinical Histologic descriptive Uncertain diagnosis Laboratory Imaging Molecular (primarily TCRR)

6 Evaluation and management in CTCL Clinical Histologic descriptive +/- More biopsies Uncertain diagnosis Prognostication? How to treat? Laboratory Imaging Molecular (primarily TCRR)

7 Commonly occurring descriptive sign-outs of T-cell process Atypical lymphoid infiltrate (ALI) Atypical granulomatous and lymphocytic infiltrate or lymphohistiocytic infiltrate CD4+ T-cell proliferation, lymphoid neoplasm, or lymphoma CD30+ T-cell proliferation, lymphoproliferative disorder, or lymphoma CD8+ epidermotropic atypical T-cell infiltrate or proliferation Epidermotropic cytotoxic T-cell lymphoma or cutaneous cytotoxic T cell lymphoma, not otherwise specified Atypical lymphocytic (or lymphohistiocytic or lymphoplasmacytic) lobular panniculitis or atypical subcutaneous panniculitic lymphoid infiltrate CTCL with TCR-g expression or dual TCR-b and TCR-g expression CTCL or skin PTCL, not otherwise specified

8 Commonly occurring descriptive sign-outs of T-cell process Atypical lymphoid infiltrate (ALI) Atypical granulomatous and lymphocytic infiltrate or lymphohistiocytic infiltrate CD4+ T-cell proliferation, lymphoid neoplasm, or lymphoma CD30+ T-cell proliferation, lymphoproliferative disorder, or lymphoma CD8+ epidermotropic atypical T-cell infiltrate or proliferation Epidermotropic cytotoxic T-cell lymphoma or cutaneous cytotoxic T cell lymphoma, not otherwise specified Extranodal NK-/T-cell lymphoma, nasal type Atypical lymphocytic (or lymphohistiocytic or lymphoplasmacytic) lobular panniculitis or atypical subcutaneous panniculitic lymphoid infiltrate CTCL with TCR-g expression or dual TCR-b and TCR-g expression CTCL or skin PTCL, not otherwise specified 2016 WHO Mature T and NK neoplasms Mycosis fungoides and variants/subtype Sézary syndrome Cutaneous CD30+ T-cell lymphoproliferative disorders Lymphomatoid papulosis Cutaneous anaplastic large cell lymphoma Subcutaneous panniculitis-like T-cell lymphom Cutaneous g/d T-cell lymphoma Hydroa vacciniforme-like lymphoproliferative disorder* Adult T-cell leukemia/lymphoma Cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma Cutaneous acral CD8+ T-cell lymphoma* Cutaneous CD4+ small/medium T-cell lymphoproliferative disorder* Follicular T-cell lymphoma* Peripheral T-cell lymphoma, NOS *Changes from 2008 classification; provisional entities are in italics, Blood 2016

9 How I treat patients whose biopsies are reported descriptively What is the BEST CLINICAL FIT? Optimize clinical-pathologic correlative interpretation (not limited to descriptive cases, important in confident sign-outs) Review the slides directly with your pathologist whenever possible More skin biopsies? Type of biopsies: punch vs shave vs incisional vs excisional Heterogeneity of skin lesions and pathology, more the better, compare TCR profile Would any other tests help to be more specific? Consider the high yield tests to sort out ddx (e.g., molecular diagnostics) Don t forget to check the blood Sézary flow, HTLV1 If significant lymphadenopathy, order imaging and consider sampling LN Watch & wait Confirms regressing or benign course (e.g., CD4+, CD30+ or g/d LPD spectrum) Reevaluate, rebiopsy as indicated

10 Clinical case examples

11 70F skin eruption x 8 yrs of extremities and trunk, many annular, managed as dermatitis, drug rxn, SCLE; TS, excimer, MTX, acitretin, hydroxychloroquine; remote h/o patch-type MF Prior path diagnosis: psoriasiform lichenoid dermatitis with cytotoxic changes +/- eos in several biopsies over 8 yrs; prior TCR PCR (biomed2) failed to support clonal process Initial visit at Stanford 2016: Clinical appearance very suspicious for MF (polymorphic lesions with background of poikilodermatous change) How should we manage this patient? Given strong clinical suspicion, pursue more supportive tests to confirm clinical impression New biopsies from left upper back and right flank and review of prior forearm biopsies (she refused more forearm bx): Atypical lymphoid infiltrate variable psoriasiform hyperplasia, exocytosis, CD4 predominant infiltrate with partial loss of CD7, some features of MF but also with dyskeratotic cells in epidermis, atypical and not diagnostic for MF

12 70F skin eruption x 8 yrs of extremities and trunk, many annular, managed as dermatitis, drug rxn, SCLE; TS, excimer, MTX, acitretin, hydroxychloroquine; remote h/o patch-type MF Prior path diagnosis: psoriasiform lichenoid dermatitis with cytotoxic changes +/- eos in several biopsies over 8 yrs; prior TCR PCR (biomed2) failed to support clonal process Initial visit at Stanford 2016: Clinical appearance very suspicious for MF (polymorphic lesions with background of poikilodermatous change) How did I manage the patient? Given strong clinical suspicion, pursue more supportive tests to confirm clinical impression! New biopsies from left upper back and right flank and review of prior forearm biopsies (she refused more forearm bx): Atypical lymphoid infiltrate variable psoriasiform hyperplasia, exocytosis, CD4 predominant infiltrate with partial loss of CD7, some features of MF but also with dyskeratotic cells in epidermis, atypical and not diagnostic for MF Sent for TCR HTS (high throughput sequencing) Dominant TCR sequence identical in all specimens Final clin-path/molecular integrated diagnosis of MF

13 MF stage IB (T2bN0M0B0), patch/plaque dz, >10% BSA: mostly patches with few areas of plaques => forearm progressed to thicker plaques Forearm plaques worsened with clobetasol ointment Low-dose (12 Gy) localized RT 6 months later, maintaining response Before low-dose Localized e-beam therapy 6 mo after low-dose Localized e-beam therapy

14 Importance of close collaboration in diagnosis, continued conversations with your pathologist for optimal sampling, tests, and outcome Suspect MF/SS Skin biopsy: select site, size, process Suspect other than MF/SS > 2 sites, off skin tx Adequate size/depth Essential for Dx: Dermatopathology review of all slides Ancillary studies: immunophenotyping molecular studies As indicated Essential for proper dx Clinical-pathologic correlation for final interpretation Re-evaluate, resample with time

15 Variability of CD30 expression in lesional skin FDA approval of brentuximab vedotin (anti-cd30 ADC) in CD30+ MF CD30, 10% CD30, 35% CD30, 0% CD30, 10% CD30 min = 0% CD30, 5% CD30 min = 10% CD30, 10% CD30 max = 90% CD30 max = 35% CD30 min <10% CD30, 90% CD30 min >10% CD30, 20%

16 Intra- and inter-patient variability in baseline CD30 expression of enrolled MF patients (N=100) Baseline CD30 expression, % positive 100 CD30 expression from individual biopsies at baseline % cut-off for enrolment Individual patients Each box represents intra-patient range of baseline CD30 expression Top and bottom dots represent the maximum and minimum CD30 expression from the individual patient; the horizontal bar within each box represents median CD30 expression among all biopsies tested For individuals with only 2 biopsies the top and bottom of each box overlap with the maximum and minimum CD30 values whereas those with >2 biopsies the ends of the boxes represent 75 th and 25 th percentiles Prince HM, Kim YH, et al. Lancet 2017;390:555

17 Baseline CD30 expression, % positive Response lasting 4 months observed with brentuximab vedotin across variable profiles of baseline CD30 expression levels (N=50 MF) 100 CD30 expression from individual biopsies at baseline % cut-off for enrollment Individual patients Response lasting 4 months achieved Response lasting 4 months not achieved Prince HM, Kim YH, et al. Lancet 2017;390:555

18 Variability in CD30 expression: inter-lesional, intra-lesional in a patient CD30= 100% CD30 = 5% Tumor on the L upper arm CD30= 30% Plaque on the L lateral chest CD30= 20% Stanford investigator-initiated trial of BV in MF/SS Kim et al. J Clin Oncol 2015;33:3750 Rahbar et al. J Invest Dermatol 2018, in press

19 63 F with 4 yr h/o progressive erythroderma, keratoderma; multiple biopsies Pursue clinical suspicion with blood evaluation Lichenoid, spongiotic dermatitis with cytotoxic changes, atypical lymphoid infiltrate How should we manage this erythrodermic patient with descriptive biopsies? Given clinical suspicion of Sézary syndrome (no drug or other etiologies), blood for Sézary flow cytometry and TCR HTS Blood flow showed expanded CD4+ T cells, CD4+CD26-85% of lymphs, abs cnt of 3,570 /mm3 TCR HTS with dominant TCR sequence identical in blood and skin Confirms Sézary syndrome (skin biopsies are often not-diagnostic) ECP + IFN => MTX => CR with mogamulizumab (anti-ccr4 mab) x 3 yrs Bex + IFN => romidepsin => near CR with anti-kir3dl2 mab x 1 yr

20 65 yo Asian healthy M itchy rash x 3 months, no new meds; mildly scaly small patches, not classic for MF Outside pathology Biopsy interpretation, atypical lymphoid infiltrate concerning for early MF Initial Stanford visit: Mildly scaly small sized patches; clinical ddx included small plaque parapsoriasis or digitate dermatosis, lymphomatoid drug, atypical MF, derm NOS Additional skin biopsies L arm, L thigh, R flank: Focal PK, mild spongiosis, mixed CD4: CD8 ratio Atypical lymphoid infiltrate, favor reactive Absence of dominant TCR sequence in all 3 sites Final interpretation c/w reactive/inflammatory ddx such as small plaque parapsoriasis or digitate dermatosis Rebiopsy if skin lesions become larger, polymorphic

21 65 yo Asian healthy M itchy rash x 3 months, no new meds; mildly scaly small patches, not classic for MF Outside pathology Biopsy interpretation, atypical lymphoid infiltrate concerning for early MF Initial Stanford visit: Mildly scaly small sized patches; clinical ddx included small plaque parapsoriasis or digitate dermatosis, lymphomatoid drug, atypical MF, derm NOS Additional skin biopsies L arm, L thigh, R flank: Focal PK, mild spongiosis, mixed CD4: CD8 ratio Atypical lymphoid infiltrate, favor reactive Absence of dominant TCR sequence in all 3 sites Final interpretation c/w reactive/inflammatory ddx such as small plaque parapsoriasis or digitate dermatosis Rebiopsy if skin lesions become larger, polymorphic

22 65 yo Asian healthy M itchy rash x 3 months, no new meds; mildly scaly small patches, not classic for MF Outside pathology Biopsy interpretation, atypical lymphoid infiltrate concerning for early MF Initial Stanford visit: Mildly scaly small sized patches; clinical ddx included small plaque parapsoriasis or digitate dermatosis, lymphomatoid drug, atypical MF, derm NOS Additional skin biopsies L arm, L thigh, R flank: Focal PK, mild spongiosis, mixed CD4: CD8 ratio Atypical lymphoid infiltrate, favor reactive Absence of dominant TCR sequence in all 3 sites Final interpretation c/w reactive/inflammatory ddx such as small plaque parapsoriasis or digitate dermatosis Rebiopsy if skin lesions become larger, polymorphic Management: Treated with fluocinonide cream with prompt improvement 6 mo f/u, no progression

23 21 yo F asymptomatic rash x 2 yrs started of R abdomen and gradually "wrapped" around the flank to the lower R back, all confined to R side Biopsy of R back and R abd: Atypical lymphocytic infiltrate, CD3+, CD4+, CD8-, CD7-; routine TCR PCR fail to support clonal process CD3 CD4 CD8 Coutesy K Rieger

24 21 yo F asymptomatic rash x 2 yrs started of R abdomen and gradually "wrapped" around the flank to the lower R back, all confined to R side Biopsy of R back and R abd: Atypical lymphocytic infiltrate, CD3+, CD4+, CD8-, CD7-; routine TCR PCR fail to support clonal process TCR HTS identified dominant TCR sequence identical at both sites Final diagnosis of Zosteriform or dermatomal MF Clobetasol cream with clearing Recurred year later, same area Biopsy showed same TCR sequence Retreated with clobetasol, again CR

25 45 yo F, 20+ yr h/o patches/plaques, clinically classic for MF 2002 presented with 10 yr h/o patch/plaques, 40-50% BSA, with bx showing classic features of MF, no IHC done, treated with topical NM. Lost to f/u. Seen at Stanford 12 years later 2014: Recent bx reviewed outside as MF with majority of atypical cells CD4-, CD8- Additional biopsies showed band-like infiltrate with papillary dermal fibrosis; epidermotropism with atypical lymphs. Epidermotropic lymphs CD3+, CD4-, CD8-, CD56-, TCRgamma+, TCR-beta-; TIA-1 and GB neg. Epidermotropic CTCL with TCR-gamma expression suspicious for pc G/D TCL => path sign-out How should we manage this patient? Given such indolent course (20+ yrs of similar lesions), clinically managed as MF with atypical TCR-g expression Alternatively indolent G/D TCL with MF-like presentation nbuvb with CR Topical NM, initial PR Oral bexarotene, good PR

26 67 yo F slow growing small red papule of nasal tip; no other skin lesions Dermatologist biopsied 4 mm papule for? BCC Nose bx 10/2014: Atypical T-cell infiltrate suspicious for a TCL Epidermotropic and folliculotropic atypical T-cell infiltrate. CD3+, CD4-, CD8-, dual expression of TCR-b and TCR-g, loss of CD5, low-ki-67, CD56-, TIA-1- and GB-. Dominant TCR seq+ Additional biopsies nose/cheek: Atypical lymphoid infiltrate, favor TCR-g expressing TCL PET/CT and flow negative, localized (nose/left cheek) skin-limited disease How should we manage this patient? Indolent, localized disease => conservative management with local RT (24 Gy) => CR, sustained New R lower leg lesion, biopsy 8/2016: Atypical lymphoid infiltrate, favor TCR-g and TCR-b expressing T- cell lymphoma TCR HTS of nose, cheek, both leg lesions show same dominant TCR sequences in all samples Updated imaging negative, cont to manage conservatively

27 54 yo F several months h/o asymptomatic nodules upper arms, back, chest; ROS negative for lupus or HLH symptoms Incisional biopsies: Atypical panniculitic lymphohistiocytic infiltrate, ddx of LEP vs SPTCL All rheumatologic w/u negative except ANA 1:320 homogeneous pattern; no systemic symptoms Initial Stanford visit: seen by rheum/derm, CL Clinical-path ddx extensive LEP vs SPTCL (indolent) How should we manage this patient? TCR HTS variable results, lack of clear dominant TCR seq shared in all samples Dx remained unclear, pt desired treatment MTX (can address either dx) Oral bexarotene Additional biopsies and multiple consults: Path features more supportive of LEP Managed as LEP by rheum/derm

28 71 yo M, 5 mo h/o red/violaceous nodules of neck, scalp, chest; absence of patch/plaque type lesions Biopsy of R neck 6/2015: Dense dermal infiltrate with a Grenz zone; absent epidermotropism or folliculotropism. T-cell process with mostly medium-sized T-cells that express CD3 and CD4. PD-1 neg. TCR beta+, TCR gamma-. No evidence of B cell process. Ki-67 5%-10%. CD30 <5% of the infiltrate. TCR HTS shows dominant TCR sequence => CD4+ T-cell lymphoma not otherwise specified PET/CT and blood flow negative, skin-only process How should we manage this patient? Given skin-only disease with overall indolent nodules, treat conservatively Local low-dose RT to selected sites, lasting CR Cont slow growing new lesions Oral bex, ater added peg-ifn (acute hearing loss) Clinical trial with anti-kir3dl2 mab, SD Brentuximab, PR Local RT to selected lesions as needed

29 71 yo M, 5 mo h/o red/violaceous nodules of neck, scalp, chest; cont to develop indolent nodular lesions without any patches/plaques 2 yrs later remains indolent Continue conservative management; modify if change in behavior of lesions

30 Clinical vs pathologic finding misfits: Worsening lichenoid dermatitis cases that do not look like inflammatory process clinically 2 case examples discussed A management dilemma

31 When path descriptive with uncertain dx, attempt to refine Clinical Optimal Integrative/correlative Management determined by Specific diagnosis Type & extent of dz Biologic behavior Histologic +/- More biopsies Diagnosis Prognostication Treatment Laboratory Imaging Molecular (primarily TCRR) Other key factors Age Comorbidities, PS Availability & accessibility

32 Diagnosis remains descriptive/uncertain despite more attempts Clinical Management determined by Clinical suspicion Category of dz Extent of dz, Biologic behavior Reassess with change Histologic +/- More biopsies Uncertain diagnosis How to treat? Prognostication? Laboratory Imaging Molecular (primarily TCRR) Other key factors Age Comorbidities, PS Availability & accessibility

33 Take Home: How to treat pts with descriptive path sign-outs Importance of clinical-path correlative optimal interpretation Consider more or different type of sampling to ensure adequate material for the pathologist Work closely with pathologist to consider appropriate ancillary tests Be cognizant of IHC variability and shifts; false +/- of tests Avoid being cornered to give a definitive diagnosis when clin-path remains uncertain Re-evaluate, re-sample with time If treatment is needed to alleviate symptoms, select safe treatments Consider the biology (indolent vs aggressive) of the disease when selecting treatments Continue to re-evaluate and resample if behavior/response changes Consider additional input from centers/programs with expertise (clinical/path evaluations)