dermatologic toxicities from nibs and mabs - final_final_hscp_curry_4_14_18.pdf · slide courtesy...

Dermatologic Toxicities from

Nibs and Mabs:Inflammatory, neoplastic, immunobullous, and

much more!

Jonathan L. Curry, MD

Associate Professor of Pathology and Dermatology

University of Texas-MD Anderson Cancer Center

Houston, Texas

Outline

• Nibs and Mabs in cancer therapy

• Dermatologic toxicities– Pathology

– Classification

– Histologic patterns

• Conclusion

• Patients receiving Nibs and Mabs will

become the largest category of cancer

patients

• Dermatologic toxicities are a consequence to

cancer therapy with Nibs and Mabs

• Adverse reactions will be encountered by

practicing pathologists

• Recognition of the diverse types dermatologic

toxicities for appropriate patient care

Dermatologic Toxicities from

Nibs and Mabs

Cancer Therapy

• Small molecule inhibitors (Nibs)

–Signal transduction pathway

• MAPK

• FGFR

• Monoclonal antibodies (Mabs)

– Immune checkpoint

• CTLA-4

• PD-1/PD-L1

Types of Nibs and Mabs

Small molecule inhibitors

(Nibs)

– Tyrosine kinase receptor• Sorafenib

– BrafV600E• Vemurafenib

– MEK • Selumetinib

– Fibroblast growth factor receptor (FGFR)

Monoclonal antibody

(Mabs)

– Immune checkpoint

• Anti-CTLA4

– Ipilimumab

• Anti-PD-1

– Nivolumab

– Pembrolizumab

• Anti-PD-L1

– Atezolizumab

months

Melanoma Therapy%

overa

ll surv

iva

l

Ugurel. Euro J Cancer. 2017

Clinical Trials with Combined Therapy

• AntiPD-1/PDL-1 as

blue circles

• Size of circle

corresponds to the #

of clinical trials for

each therapy

• Connecting nodes to

combination product

• Colors related to class

of treatment

Clinical Trials with Combined Therapy

• AntiPD-1/PDL-1 as

blue circles

• Size of circle

corresponds to the #

of clinical trials for

each therapy

• Connecting nodes to

combination product

• Colors related to class

of treatment

Currently over 370 combined therapy

Slide courtesy of Dr. Diab

Therapeutic Targets NibsKIT

Proliferation, cell survival, differentiation

PI3K/AKT

RAS

RTK

RAF

MEK

MAPK/ERK Inhibition of apoptosis

proliferation

Inhibition of apoptosis,

cell cycle progression,

differentiation

PTEN

CDKN2A p16/Rb BAP1

Nibs

Sorafenib

Sunitinib

Vemurafenib

Dabrafenib

Non-selective

Selective Selu

metin

ib

Tra

metin

ib

G-protein

GNAQ/GNA11

T-cell

TCR MHC

PD-1 PD-L1

Anti-PD-1 (Nivolumab)

(Pembrolizumab)

CTLA-4

Ipilimumab

Immune Checkpoint Antibodies

Melanoma

Cellular effects

T-cell activation

Remove immune suppression

Cellular effects

Restore T-cell response

Immune detection of cancer cells

Organs Affected from

Immune Checkpoint Toxicities

Skin

Eye

Pituitary

Lung

Liver

Adrenal

Kidney

Muscle

CNS

Thyroid

Heart

Pancreas

Blood

Vessels

Spectrum of Dermatologic Toxicities

to Nibs and Mabs

Lacouture et al. 2013

Am J Dermatopathol. 2017

Curry et al. 2017

Spectrum of Dermatologic Toxicities

to Nibs and Mabs

Lacouture et al. 2013


Curry et al. 2017

1. Inflammatory

2. Immunobullous

3. Reaction on keratinocytes

4. Reaction on melanocytes

5. Cutaneous deposits

Dermatologic Toxicities to Nibs and Mabs:

Pathology Similarities and Differences


(Nibs)• Inflammatory

– Dermal hypersensitivity reaction

(DHR)

– Lichenoid

– TEN/SJS

– Granulomatous/sarcoid-like

Checkpoint Inhibitors

(Mabs)• Inflammatory

– Dermal hypersensitivity reaction (DHR)

– Lichenoid

– TEN/SJS







(DHR)

– Lichenoid

– TEN/SJS


• Reactions on keratinocytes

– Proliferative

• Verruca

• Actinic keratosis

• Keratoacanthoma

• Squamous cell




– Lichenoid

– TEN/SJS







(DHR)

– Lichenoid

– TEN/SJS



– Proliferative

• Verruca


• Keratoacanthoma

• Squamous cell




– Lichenoid

– TEN/SJS


• Immunobullous

– Bullous pemphigoid

– Paraneoplastic pemphigus






– Lichenoid

– TEN/SJS


• Reactions on keratinocytes– Proliferative

• Verruca


• Keratoacanthoma

• Squamous cell

• Reactions on melanocytes– Vitiligo

– Changes nevi

– Melanoma




– Lichenoid

– TEN/SJS


• Immunobullous



• Reactions on melanocytes

– Vitiligo

– Changes nevi

– Melanoma




(Nibs)

• Inflammatory


– Lichenoid

– TEN/SJS



– Proliferative

• Verruca


• Keratoacanthoma

• Squamous cell


– Vitiligo

– Changes nevi

– Melanoma

• Cutaneous deposits– Calcinosis cutis




– Lichenoid

– TEN/SJS


• Immunobullous




– Vitiligo

– Changes nevi

– Melanoma




(Nibs)

• Inflammatory– Dermal hypersensitivity reaction

(DHR)

– Lichenoid

– TEN/SJS





– Lichenoid

– TEN/SJS


Inflammatory




(Nibs)

• Inflammatory– Dermal hypersensitivity reaction

(DHR)

– Lichenoid

– TEN/SJS





– Lichenoid

– TEN/SJS


InflammatoryInflammatory reactions:

•Most frequent type of dermatologic toxicity

•~75% patients treated with vemurafenib

•~40% patients treated with checkpoint inhibitors

Dermal Hypersensitivity Reaction

(DHR)

Associated with Ipilimumab

Toxic Epidermal Necrolysis (TEN)

Wantz et. al. Ann Dermatol Venereol, 2014

Associated with Vemurafenib

Lichenoid Dermatitis

Associated with Pembrolizumab

Lichenoid Dermatologic Toxicity

Associated Checkpoint Inhibitors

Tetzlaff et. al.

Lichenoid Dermatologic Toxicity


Tetzlaff et. al.

• Lesions may histologically appear like lichen planus

• spongiosis, parakeratosis, eosinophils of may

not be prominent

• Lichenoid dermatitis associated with CPI may show

morphologic variation in multiple biopsies

Ramani, Torres Cabala et. al. Tetzlaff et. al. J Cutan Pathol. 2017

Granulomatous Panniculitis

Associated with Ipilimumab + Nivolumab


Associated with Dabrafenib

Ramani, Torres Cabala et. al. Tetzlaff et. al. J Cutan Pathol. 2017

Granulomatous Panniculitis

Associated with Ipilimumab + Nivolumab


Associated with Dabrafenib

BRAF Inhibitor Immune Checkpoint

Mimic Disease Recurrence

Case Age

(yrs)

Sex Primary Disease Site of Metastasis Clinical Presentation Sites of Sarcoidosis and/or

Panniculitis

Anti-PD-1 Antibody Therapy

(dose)

Onset of sarcoid reaction after

initiation of anti-PD-1 antibody

therapy

(months)

Histologic features Diagnosis based on clinical and

radiographic

± tissue pathology

Treatment of sarcoid-reaction

(dose)

Outcome of sarcoid-like reaction Disease response to immune

checkpoint blockade

Follow up since initiation of

immune checkpoint therapy

(months)

1

Anderson, 2014 [7]

44 M Melanoma Kidney, lungs, mediastinal and

retroperitoneal LN, brain, bone,

muscle, subcutis

Routine surveillance Spleen Ipilimumab

(3 mg/kg Q3WKS)

Completed 4 cycles

20 Spleen biopsy: non-caseating

epithelioid granulomata

Sarcoidosis None Resolution of splenic lesion Stable disease 33

2

Firwana,

2016 [15]

41 M Melanoma

Colorectal carcinoma

Axillary LN Bilateral, occipital neck pain,

axillary and cervical LAD

Bilateral cervical, axillary, hilar,

mediastinal, iliac and inguinal LNs

Ipilimumab

(NR)

NR Not available Sarcoidosis Ipilimumab withheld

Opioids and NSAIDs

Resolution of LAD NR NR

3

Firwana,

2016 [15]

57 F Melanoma Chest wall Flu-like symptoms, fatigue, skin with

erythematous, painful nodules on

lower extremity

Hilar, mediastinal LNs Ipilimumab

(NR)

NR Hilar lymph node biopsy: poorly

formed epithelioid granulomata with

focal necrosis

Sarcoidosis Prednisone

(1 mg/kg)

NR NR NR

4

Eckert,

2008 [16]

67 F Melanoma Axillary, supraclavicular, spinal,

LNs, subcutis, liver

Low-grade dyspnea, skin lesion on

face

Facial skin, mediastinal LNs Ipilimumab

(0.3, 3, or 10 mg/kg Q3WKS

+ 10 mg/kg 3WKS)

7 Face and bronchial biopsy: non-

caseating granulomata

Sarcoidosis Ipilimumab withheld Partial resolution of LAD Stable disease 11

5

Seve,

2009 [17]

62 F Melanoma Skin, liver NR NR Ipilimumab

(0.3, 3, or 10 mg/kg Q3WKS)

7 Consistent with sarcoidosis Sarcoidosis Ipilimumab withheld Resolution Stable disease 54

6

Vogel,

2012 [18]

49 M Melanoma Bilateral inguinal, pulmonary,

mediastinal LNs, bilateral legs

Routine surveillance Mediastinal and bilateral hilar LAD Ipilimumab

(3 mg/kg Q3WKS)

5 Endobronchial biopsy: non-caseating

granulomatous inflammation

Sarcoidosis None Resolution of LAD Complete remission ~8

7

Wilgenhof, 2012 [19]

48 F Melanoma Bilateral lungs, mediastinum, axilla,

retroperitoneal, breast

Dry cough, shortness of breath,

fatigue

Skin of neck, axilla, mediastinum,

and retroperitoneal LAD, lung,

spleen

Ipilimumab

(3 mg/kg Q3WKS)

1 Transbronchial biopsy: non-

necrotizing epithelioid granulomata

Sarcoidosis Completed 4 doses of Ipilimumab

Methylprednisolone (48 mg)

Decrease in size of LAD and spleen Progression of disease 9

8

Berthod

2012 [20]

63 M Melanoma Lung, liver, mediastinal LNs Dry cough and dyspnea Lung, pleura, perihilar tissue Ipilimumab

(3 mg/kg Q3WKS)

3.25 Bronchial and lung biopsies: well-

formed granulomata with giant cells

and occasional necrosis


(1.5 mg/kg)

Resolution of lung infiltrates Progression of disease ~ 6

9

Tissoot

2013 [21]

57 M Melanoma Axilla Subcutaneous nodules on arm Skin, lung, bilateral hilar LNs Ipilimumab

(10 mg/kg Q3WKS for 4 doses,

followed by 10 mg/kg Q12WKS)

9 Skin and mediastinal biopsy: non-

caseating granulomata

Sarcoidosis Ipilimumab withheld Skin and pulmonary lesions resolved,

decreased size of mediastinal LNs

Remission 12

10

Reule

2013 [22]

55 M Melanoma Axilla Grouped erythematous papules Skin, lung, hilar and mediastinal LNs Ipilimumab

(10 mg/kg Q3WKS)

1.5 Subcarinal lymph node biopsy:

negative for malignancy

Skin biopsy: sarcoidal granulomata

Sarcoidosis Prednisone Rapid improvement Progression of disease NR

11

Murphy

2014 [23]

37 M Melanoma Inguinal, pelvic LNs, vertebrae Routine surveillance Bilateral hilar and mediastinal LNs,

brain

Ipilimumab

(3 mg/kg Q3WKS)

6.25 Transbronchial biopsy: non-caseating

granulomata

Sarcoidosis Prednisolone

(40 mg)

Resolution of LAD Stable disease 12

12

Toumeh

2016 [24]

26 F Melanoma Axilla, adrenal gland, subcutis Intermittent abdominal pain Skin, mediastinal LNs, lung,

peritoneal surface of liver

Ipilimumab

(3 mg/kg Q3WKS)

1 Mediastinal LN biopsy: cohesive

clusters of epithelioid histiocytes and

multinucleated giant cells

Skin biopsy: non-necrotizing

granulomata associated with tattoo

pigment


(60 mg)

Near complete resolution of

Mediastinal LAD

Enlargement of peritoneal nodules,

confirmed as melanoma

Progression of disease 4

13

Current report

Patient 2

33 F Melanoma Axilla Routine surveillance/staging studies Skin of bilateral lower extremities,

mediastinal and hilar LNs

Ipilimumab

(3 mg/kg Q3WKS)

3 Skin biopsy: collection of epithelioid

histiocytes

Sarcoidosis None Improvement of LAD Remission 8

14

van den Eertwegh

2012 [25]

NR NR Prostate adenocarcinoma NR Surveillance studies Lung Ipilimumab

(5 mg/kg Q4WKS)

2 Lung biopsy: small, non-compact

granulomata

Sarcoidosis Ipilimumab withheld

Prednisone

(NR)

Improvement NR NR

15

Suozzi

2016 [8]

60 F Lung adenocarcinoma LNs, Brain Nausea, vomiting, aphasia, confusion Skin with multiple pink firm papules

and annular plaques

Ipilimumab

(1 mg/kg Q6WKS)

+

Nivolumab

(1 mg/kg Q2WKS)

7 Skin biopsy: dermal granulomatous

inflammation

Sarcoidosis Clobetasol ointment (0.05%) Some improvement Progression of disease 10

16

Birnbaum

2017 [9]

63 F Lung adenocarcinoma Pleura N/A Skin of neck, face, and periorbital,

pruritic waxing and waning,

erythematous papules and plaques

Nivolumab

(3 mg/kg Q2WKS)

4.5 Skin biopsy: nodular collection of

epithelioid histiocytes with

multinucleated giant cells

Sarcoidosis Methylprednisolone (24 mg)

Hydroxychloroquine

(200 mg)

Complete resolution Stable disease 6

17

Montaudie

2016 [27]

56 M Melanoma Axilla, hilar, mediastinal LNs, liver,

lung,

Dry cough and dyspnea Bronchi, lung, parotid glands,

cervical LNs

Nivolumab

(3mg/kg Q2WKS)

0.75 Bronchial biopsy: non-caseating


Sarcoidosis Prednisone (75mg) Resolution of lung nodules Progression of disease 3

18

Danlos

2016 [26]

57 M Melanoma Skin, nasolabial fold Surveillance studies Cutaneous lip, subcutaneous tissue

near prior scar, bilateral hilar,

mediastinal LNs

Nivolumab

(3mg/kg Q2WKS)

10 Biopsy of subcutaneous nodule: non-

necrotizing epithelioid granulomata

with giant cells and some

birefringent material

Sarcoidosis None Resolution of granulomata Remission 12

19a

Cotlier

2016 [28]

72 F Hodgkin lymphoma N/A Enlarging asymptomatic nodules Skin of upper extremities, axial

skeleton, eye, lung, bilateral hilar

and mediastinal LNs

Pembrolizumab

(200 mg Q3WKS)

6 Biopsy of skin nodule: focal dermal


Sarcoidosis Pembrolizumab withheld

Prednisone

Complete resolution of

Skin nodules, LAD, and FDG-avid

lesions

Remission 13

20

Firwana,

2016 [15]

37 F Melanoma Spleen, radius Joint pain, cough, granulomatous

lesions in the arm near surgical scar

and bilateral skin nodules of lower

extremity

Cervical, axillary, mediastinal,

retroperitoneal LAD

Pembrolizumab

(Not reported)

NR Right lung wedge resection:

sarcoidosis

Sarcoidosis Pembrolizumab withheld Partial resolution of LAD NR NR

21

Current

report

Patient 1

79 M Melanoma Hilar, mediastinal LNs, liver, adrenal Subcutaneous nodules Skin, mediastinal, hilar, peritracheal,

retroperitoneal

Pembrolizumab

(2 mg/kg)

20 Biopsy of skin nodule: non-caseating


Sarcoidosis Pembrolizumab withheld

Intralesional triamcinolone

Persistence of skin nodules, stable

LAD

Remission 25

22

Current report

Patient 3

68 M Melanoma LNs, skin, humerus, brain Surveillance studies Mediastinal, peritracheal LAD Pembrolizumab

(2 mg/kg)

6 Biopsy of peritracheal lymph nodes:

“negative for melanoma”

Sarcoidosis None Resolution of LAD Remission 24

23

Current report

Patient 4

78 F Melanoma LNs, skin Surveillance studies Skin nodules Pembrolizumab

(2 mg/kg)

13 None Sarcoidosis None Improvement Partial response 16

24

Brahmer

2012 [29]

NR NR Melanoma Lymph node NR NR Anti-PD-L1

(10 mg/kg Q2WKS)

NR NR Sarcoidosis NR NR NR NR

25

Burillo-Martinez

2017[10]

60 F Melanoma Peritoneal Plaques, nodules Skin of upper and lower extremity,

bilateral hilar and mediastinal LAD

Pembrolizumab

(2 mg/kg Q3WKS)

1.2 Lobular granulomatous panniculitis Panniculitis Pembrolizumab withheld

Prednisone

Complete resolution Complete remission 6

26

Tetzlaff

2017[11]

57 F Ovarian cancer Liver, peritoneum Tender subcutaneous nodules Skin of upper and lower extremities Nivolumab

(3 mg/kg Q2WKS)

+

Ipilimumab

(1 mg/kg Q6WKS)

10 Septal and lobular panniculitis with

giant cells and septal fibrosis

Panniculitis None Complete resolution No evidence of disease 16

27

Tetzlaff

2017[11]

39 F Melanoma Axillary LNs Tender subcutaneous nodules Skin of lower extremities, buttock Neoadjuvant setting:

Nivolumab, 3 doses

(1 mg/kg Q3WKS)

+

Ipilimumab , 3 doses

(3 mg/kg Q3WKS)

Adjuvant setting:

Nivolumab

(3 mg/kg Q2WKS)

7 Septal and lobular panniculitis with

giant cells and septal fibrosis

Panniculitis All melanoma therapy withheld

Systemic steroids

Hydroxychloroquine

Nodules dissipated No evidence of disease 12

Total Median

(range)

57

(26-78)

M:Fb

11:14

Melanoma=21

Other =6c

Skin, lung, and hilar/mediastinal

LNs = 10

Lung, hilar/mediastinal LNs = 9

Skin only = 5

Other = 6d

Ipilimumab = 14

Nivolumab = 3

Pembrolizumab = 6

Anti-PD-L1 = 1

Combined ipilimumab + nivolumab

= 3

Median

(range)

6

(0.75-20)

Sarcoidosis = 24

Panniculitis = 3

Immune checkpoint therapy withheld

= 10

Systemic steroids = 12

Resolution =14

Improvement = 10

Stable = 1

NR =2

Stable = 5

Remission = 10

Partial response =1

Progression =6

NR =5

Median

(range)

12

(3-54)

• Median onset 24 weeks (3-85)

• Mimic disease recurrence

• Marker of therapeutic response in

¾ of patients reviewed

Granulomatous/sarcoid-like Lesions

Associated with Checkpoint Inhibitor

Tetzlaff et. al. J Immuother Cancer, 2018

Dermatologic Toxicities




(Nibs)


– Proliferative


• Keratoacanthoma

• Squamous cell


(Mabs)

Neoplastic

• Cutaneous epithelial

proliferations

– Invasive squamous

cell carcinoma (with

KA features)

• 64% of lesions

– Actinic keratosis

• 2% of lesions

Dubauskas, Prieto et. al. Clin Genitourin Cancer. 2009

Squamous Cell Carcinoma

Associated with Sorafenib

Vemurafenib Associated Keratinocyte

Reactions are Clinically Distinct

A B C

D E F

G H I

* *

*

SCC SCC SCC

SCC KA VV

HAK VV SCC

• SCC/KA differ from VV

• Size

• Location

• Morphology

• Dermoscopic features

84% abnormality of follicle

Median thickness 2.6 mm

Squamous cell in situ not prominentCurry et al. Am J Dermatopathol. 2014

Paradoxical Activation of

Keratinocytes with Wild Type BRAF

BRAF

V600ECRAF

MEK 1/2

ERK

MAPK

BRAF V600E Mutant

BRAF

V600ECRAF

MEK 1/2

ERK

Vemurafenib

MAPK

BRAF Wild type

BRAFCRAF

MEK 1/2

ERK

Vemurafenib

MAPK




(Nibs)


(Mabs)

• Immunobullous



Immunobullous

Bullous Pemphigoid

Associated with Nivolumab

anti-Type IV

Bullous Pemphigoid

Associated with Nivolumab

anti-IgG

Jour et al. J Cutan Pathol. 2016

Paraneoplastic Pemphigus-like


Elisa studies:

Serum IgG auto-antibodies

to BP230 at 11.34 units)

(normal < 9.0 units)

Chen, Diwan et al. 2018

Suprabasal Acantholytic Reactions


Grovers-like

• Autoimmune dermatologic toxicities

– Paraneoplastic pemphigus-like

• Non-autoimmune dermatologic toxicities

– Lichenoid dermatitis with acantholysis

– Grovers-like

Suprabasal Acantholytic Dermatoses

Associated with Checkpoint Inhibitor

Case Age

(yrs)

Sex Primary Malignancy Clinical presentation Immune checkpoint

inhibitor

Onset of suprabasal

acantholytic

dermatologic toxicity

Histologic features Immunologic

findings

Treatment of

dermatologic

toxicity

Dermatologic

toxicity response to

treatment

Checkpoint

therapy

18 63 M Melanoma Annular, hyperkeratotic, eczematous

plaques on back, legs, glans penis

Pembrolizumab +

ipilimumab

36 Lichenoid inflammation

with eosinophils and

suprabasal and

intraepidermal blister with

acantholysis involving

epidermis and follicular

epithelium

DIF negative Methylprednisolone aceponate

(0.1%, BID)

Persist with improved with

therapy at 4 month follow-

up

NR

28 62 M Melanoma Erythematous papules and plaques on back

and leg

Nivolumab 120 Lichenoid inflammation

with eosinophils and

suprabasal and

intraepithelial blister and

acantholysis

ND Betamethasone valerate

(0.02% BID)

Resolved at 4 week follow

up

NR

38 55 M Melanoma Disseminated, pruritic, erythematous

papules on trunk and upper extremities

Pembrolizumab +

ipilimumab

7 Lichenoid inflammation

with suprabasal blister

ND Betamethasone valerate

(0.02% BID) cream with 10%

glycerine

Improvement at 4 weeks

follow up, few persistent

lesion which resolved after

cessation of CPI

Yes

48 70 F NSCL Maculopapular, erythematous, violaceous

plaques on arms, back, buttock

Nivolumab 30 Spongiosis and interface

dermatitis with rare

eosinophils and small

intraepidermal vesicle

ND None Improvement of skin lesions Yes

522 53 M Melanoma Papulokeratotic eruption with pruritus on

trunk and proximal extremities

Ipilimumab 10 Grovers-like reaction with

suprabasal acantholysis with

dyskeratosis

ND Moisturize cream,

antihistamines

Relieved with treatment No

623 65 F Melanoma Papular rash with excoriations with pruritus

on abdomen and chest


suprabasal, focal

acantholysis with

dyskeratosis

ND Topical therapy (emollients

with or without steroids),

antihistamines,

dermocosmetics

Skin lesions controlled NR

79 73 M Melanoma Papulovesicular rash with pruritus on chest,

back and upper extremities


suprabasal acantholysis

ND Methylprednisolone tapered to

topical steroids

Improvement of pruritus,

rash persisted

Yes

824 73 M Melanoma Multiple, erythematous, 2-7 mm scaly

papules and fragile vesicles on chest,

abdomen, back, and proximal arms


Suprabasal acantholysis

with dyskeratotic cells

DIF negative Hydrocortisone butyrate (0.1%)

lotion with menthol (1%)

Improvement with persistent

lesions

No

9 60 M Melanoma Erythematous papules Anti-PD-1 +

anti-CTLA-4

9 Grovers-like reaction with

focal acantholytic

dyskeratosis

ND Prednisone, triamcinolone NR No

10 51 F Melanoma Erythematous to hyperpigmented papules Anti-PD-1 +

anti-CTLA-4


focal acantholytic

dyskeratosis

ND Prednisone NR No

11 74 M NSCLC EM-like Anti-PD-1 +

anti-CTLA-4


focal acantholytic

dyskeratosis

ND Prednisone, triamcinolone NR No

12 75 M SCC of tongue Erythematous urticarial plaques, tense

blisters with erosions

pembrolizumab 82 Suprabasal acantholysis,

rare necrotic keratinocytes,

spongiosis, lymphocytic

inflammation with

eosinophils

DIF positive IgG and IgA

at BMZ and intercellular

deposits of IgG and C3 in

the epidermis, Serum

BP230 (11.34 units )

Prednisone, triamcinolone Improvement of blisters,

persistence of some plaques

Yes

13 64 M Melanoma Maculopapular rash with pustules pembrolizumab 210 Grovers-like with

suprabasal acantholysis with

dyskeratosis containing

corps ronds and corps

grains, lymphocytic

inflammation with

eosinophils

ND Prednisone, doxycycline Minimal improvement Yes

Total Medi

an

64

(51-

75)

M:F

10:3

Melanoma = 10

NSCLC = 3

SCC tongue =1

Ipilimumab = 4

Nivolumab = 2

Pembrolizumab = 2

Combined CPI therapy = 5

Median

21

(7-210)

Lichenoid with suprabasal

acantholysis/vesicle = 4

Grovers-like = 8

PNP-like = 1

DIF negative Topical therapy alone = 6

Systemic steroids = 6

No therapy = 1

Persist with improved with

therapy at 4 month follow-

up

Yes = 5

No = 5

NR = 3

Suprabasal Acantholytic Dermatoses


• Median onset 4 weeks (range 1 – 28)

• Serology and immunofluorescence

studies may be necessary




(Nibs)


– Changes nevi

– Melanoma

• Cutaneous deposits– Calcinosis cutis


(Mabs)


– Vitiligo

– Changes nevi

– Melanoma

Much more!




(Nibs)


– Changes nevi

– Melanoma


(Mabs)


– Vitiligo

– Changes nevi

– Melanoma

•Loss of junctional melanocytes

•Alteration in color and size

•Involute-regress

•Development of new nevi

•Development of melanoma

Reactions on Melanocytes Associated

with Vemurafenib

Invasive Melanoma and Nevus


Reactions on Melanocytes


• Paradoxical

activation of wild

type BRAF

melanocytes

• BRAFV600E -

• Cytologic atypia

• New melanoma

Mudaliar et. al.

Reactions on Melanocytes Associated

with Checkpoint Inhibitors

Disappearing pigmented lesions

-nevi

-seborrheic keratosis

-lentingines


Regressed Nevi


Regressed Nevi

• Marker of therapy response

• Vitiligo

• Regressed nevi

Mauzo, et al. Int J Dermatol. 2017.


Pathology Similarities and DifferencesSmall molecule inhibitors

(Nibs)


– Vitiligo

– Changes nevi

– Melanoma

• Cutaneous deposits

– Calcinosis cutis


(Mabs)


– Vitiligo

– Changes nevi

– Melanoma

Much more!

FGFR inhibitor

Calcinosis Cutis

Aruda, Nelson et al. 2018.

Time to Onset of Dermatologic Toxicities Associated with Vemurafenib

• >85% of adverse cutaneous reaction

occurred within 16 weeks

• Median time (in weeks)

– Inflammatory reaction “rash” ~2

–Verruca, hyperplastic actinic keratosis

~2–5

–Squamous cell carcinoma and KA ~7–11

Lacouture, Duvic, Hauschild et al. The Oncologist, 2013 Belum, Pulitzer, Busam et al. Cancer. 2015

Time to Onset of Any Type and Grade Immune Checkpoint Associated Skin Toxicities

Weber et al. JCO. 2017

Bullous

pemphigoid

(~11 weeks)Lichenoid

dermatitis

(~12 weeks)

Granulomatous/sarcoid

osis

(~24 weeks)

Time to Onset of Dermatologic Toxicities Associated with Immune Checkpoint

Conclusion

• Dermatologic toxicities are a consequence of Nibs and Mabs

• Diverse morphologies, clinically and histologically

• Similarities and differences

• Knowledge of the types of dermatologic toxicities

– Mimic disease recurrence

– Therapeutic response

– Management of toxicity

Victor Prieto

Carlos Torres-Cabala

Michael Tetzlaff

Doina Ivan

Phyu Aung

Priya Nagarajan

Ignacio Wistuba

Luisa Solis

Celia Garcia-Prieto

Beatriz Sanchez-Espiridion

Sarah Fayle

E. Parra-Cuentas

J. Rodriguez-Canales

Suzanne Davis

Courtney Hudgens

Ronald Rapini

Kelly Nelson

Saira George

Sharon Hymes

Madeleine Duvic

Carol Drucker

Omar Pacha

Anisha Patel

Saira George

Richard Janhan-Tigh

Kudakwashe Maloney

Patrick Hwu

Adi Diab

Dan Johnson

Roda Amaria

Wen-Jen Hwu

Isabella Glitza

Jen Wargo

Alexandre Reuben

Robert Szczepaniak

Acknowledgments

Thank you

dermatologic toxicities from nibs and mabs - final_final_hscp_curry_4_14_18.pdf · slide courtesy...

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