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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
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
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
Am J Dermatopathol. 2017
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
Small molecule inhibitors
(Nibs)• Inflammatory
– Lichenoid
– Granulomatous/sarcoid-like
Checkpoint Inhibitors
(Mabs)• Inflammatory
– Lichenoid
– Granulomatous/sarcoid-like
Dermatologic Toxicities to Nibs and Mabs:
Pathology Similarities and Differences
Small molecule inhibitors
(Nibs)• Inflammatory
– Lichenoid
– Granulomatous/sarcoid-like
• Reactions on keratinocytes
– Proliferative
• Verruca
• Actinic keratosis
• Keratoacanthoma
• Squamous cell
Checkpoint Inhibitors
(Mabs)• Inflammatory
– Lichenoid
– Granulomatous/sarcoid-like
Dermatologic Toxicities to Nibs and Mabs:
Pathology Similarities and Differences
Small molecule inhibitors
(Nibs)• Inflammatory
– Lichenoid
– Granulomatous/sarcoid-like
• Reactions on keratinocytes
– Proliferative
• Verruca
• Actinic keratosis
• Keratoacanthoma
• Squamous cell
Checkpoint Inhibitors
(Mabs)• Inflammatory
– Lichenoid
– Granulomatous/sarcoid-like
• Immunobullous
– Bullous pemphigoid
– Paraneoplastic pemphigus
Dermatologic Toxicities to Nibs and Mabs:
Pathology Similarities and Differences
Small molecule inhibitors
(Nibs)
• Inflammatory
– Lichenoid
– Granulomatous/sarcoid-like
• Reactions on keratinocytes
– Proliferative
• Verruca
• Actinic keratosis
• Keratoacanthoma
• Squamous cell
• Reactions on melanocytes
– Vitiligo
– Changes nevi
– Melanoma
Checkpoint Inhibitors
(Mabs)
• Inflammatory
– Lichenoid
– Granulomatous/sarcoid-like
• Immunobullous
– Bullous pemphigoid
– Paraneoplastic pemphigus
• Reactions on melanocytes
– Vitiligo
– Changes nevi
– Melanoma
Dermatologic Toxicities to Nibs and Mabs:
Pathology Similarities and Differences
Small molecule inhibitors
(Nibs)
• Inflammatory
– Lichenoid
– Granulomatous/sarcoid-like
• Reactions on keratinocytes
– Proliferative
• Verruca
• Actinic keratosis
• Keratoacanthoma
• Squamous cell
• Reactions on melanocytes
– Vitiligo
– Changes nevi
– Melanoma
• Cutaneous deposits– Calcinosis cutis
Checkpoint Inhibitors
(Mabs)
• Inflammatory
– Lichenoid
– Granulomatous/sarcoid-like
• Immunobullous
– Bullous pemphigoid
– Paraneoplastic pemphigus
• Reactions on melanocytes
– Vitiligo
– Changes nevi
– Melanoma
Dermatologic Toxicities to Nibs and Mabs:
Pathology Similarities and Differences
Small molecule inhibitors
(Nibs)
• Inflammatory
– Lichenoid
– Granulomatous/sarcoid-like
Checkpoint Inhibitors
(Mabs)• Inflammatory
– Lichenoid
– Granulomatous/sarcoid-like
Inflammatory
Dermatologic Toxicities to Nibs and Mabs:
Pathology Similarities and Differences
Small molecule inhibitors
(Nibs)
• Inflammatory
– Lichenoid
– Granulomatous/sarcoid-like
Checkpoint Inhibitors
(Mabs)• Inflammatory
– Lichenoid
– Granulomatous/sarcoid-like
Inflammatory reactions:
•Most frequent type of dermatologic toxicity
•~75% patients treated with vemurafenib
•~40% patients treated with checkpoint inhibitors
Lichenoid Dermatologic Toxicity
Associated Checkpoint Inhibitors
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
Am J Dermatopathol. 2017
Associated with Dabrafenib
Ramani, Torres Cabala et. al. Tetzlaff et. al. J Cutan Pathol. 2017
Granulomatous Panniculitis
Associated with Ipilimumab + Nivolumab
Am J Dermatopathol. 2017
Associated with Dabrafenib
BRAF Inhibitor Immune Checkpoint
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
Sarcoidosis Prednisone
(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
Sarcoidosis Prednisone
(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
epithelioid granulomata
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
epithelioid granulomata
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
epithelioid granulomata
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 to Nibs and Mabs:
Pathology Similarities and Differences
Small molecule inhibitors
(Nibs)
• Reactions on keratinocytes
– Proliferative
• Actinic keratosis
• Keratoacanthoma
• Squamous cell
Checkpoint Inhibitors
(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
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
Dermatologic Toxicities to Nibs and Mabs:
Pathology Similarities and Differences
Small molecule inhibitors
(Nibs)
Checkpoint Inhibitors
(Mabs)
• Immunobullous
– Bullous pemphigoid
– Paraneoplastic pemphigus
Immunobullous
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
Ipilimumab 21 Grovers-like reaction with
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
Ipilimumab 21 Grovers-like reaction with
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
Ipilimumab 21 Grovers-like reaction with
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
3 Grovers-like reaction with
focal acantholytic
dyskeratosis
ND Prednisone NR No
11 74 M NSCLC EM-like Anti-PD-1 +
anti-CTLA-4
47 Grovers-like reaction with
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
Associated Checkpoint Inhibitors
• Median onset 4 weeks (range 1 – 28)
• Serology and immunofluorescence
studies may be necessary
Chen, Diwan et al. 2018
Dermatologic Toxicities to Nibs and Mabs:
Pathology Similarities and Differences
Small molecule inhibitors
(Nibs)
• Reactions on melanocytes
– Vitiligo
– Changes nevi
– Melanoma
• Cutaneous deposits
– Calcinosis cutis
Checkpoint Inhibitors
(Mabs)
• Reactions on melanocytes
– Vitiligo
– Changes nevi
– Melanoma
Much more!
Dermatologic Toxicities to Nibs and Mabs:
Pathology Similarities and Differences
Small molecule inhibitors
(Nibs)
• Reactions on melanocytes– Vitiligo
– Changes nevi
– Melanoma
Checkpoint Inhibitors
(Mabs)
• Reactions on melanocytes
– Vitiligo
– Changes nevi
– Melanoma
•Damage of junctional melanocytes
•Alteration in color and size
•Involute-regress
•Development of new nevi
•Development of melanoma
Reactions on Melanocytes
Associated with Vemurafenib
• 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
Dermatologic Toxicities to Nibs and Mabs:
Pathology Similarities and DifferencesSmall molecule inhibitors
(Nibs)
• Reactions on melanocytes
– Vitiligo
– Changes nevi
– Melanoma
• Cutaneous deposits
– Calcinosis cutis
Checkpoint Inhibitors
(Mabs)
• Reactions on melanocytes
– Vitiligo
– Changes nevi
– Melanoma
Much more!
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
Pyu 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