1010 Letters J AM ACAD DERMATOL

MAY 2016

Although considerable overlap remains, our study 3. Feinstein A, Ackerman AB, Ziprkowski L. Histology of auto-
refines and identifies histopathologic features that somal dominant ichthyosis vulgaris and X-linked ichthyosis.
Arch Dermatol. 1970;101:524-527.
may help distinguish XLRI from ARCI. 4. Wells RS, Jennings MC. X-linked ichthyosis and ichthyosis
The authors thank Oliver Chang, MD, PhD, for his vulgaris. Clinical and genetic distinctions in a second series of
assistance in procuring the histopathology images and families. JAMA. 1967;202:485-488.
5. Williams ML, Elias PM. Heterogeneity in autosomal recessive
acknowledge Jorge Toro, MD, and his lab for performing
ichthyosis. Clinical and biochemical differentiation of lamellar
the transglutaminase gene sequencing and sharing their
ichthyosis and nonbullous congenital ichthyosiform erythro-
data with this group. IRB approved by the University of derma. Arch Dermatol. 1985;121:477-488.
Washington for human subjects research (HSD #27188)
and met criteria for Rhode Island Hospital IRB exemption. http://dx.doi.org/10.1016/j.jaad.2015.12.027
a b
Catherine S. Yang, MD, Hyemin Pomerantz, MD,
Kathleen A. Mannava, MD,c Jessica Corwin, Expression of PD-L1 in mastocytosis
MD,d Martin A. Weinstock, MD, PhD,a,b Philip
Fleckman, MD,e John J. DiGiovanna, MD,f and To the Editor: Immunologic checkpoint blockade by
Leslie Robinson-Bostom, MDa antibodies that target programmed cell death protein
1 pathway (PD-1/PD-L1) are efficacious against
Department of Dermatology,a Alpert Medical School various malignancies.1 The PD-1 receptor is
of Brown University; Dermatoepidemiology Unit,b expressed on T and B lymphocytes, while its ligand
VA Medical Center, Providence, RI; Department of (PD-L1) is expressed on tumor cells. Tumor cells may
Pathology,c Wake Forest School of Medicine, evade the immune response by abrogating this
Winston-Salem, NC; Department of Dermatology,d signaling.
Vacaville Medical Center, Vacaville, CA; Division of Mastocytosis is a clonal myeloproliferative
Dermatology,e University of Washington, Seattle, neoplasm characterized by abnormal accumulation
WA; Dermatology Branch,f Center for Cancer of mast cells (MCs) with a heterogeneous clinical
Research, National Cancer Institute, National In- presentation. The World Health Organization
stitutes of Health, Bethesda, MD has developed a classification based on clinical
Funding sources: This publication was partially manifestations and disease severity. Cutaneous MC
supported by funds from the Foundation for disorders include solitary mastocytomas, urticaria
Ichthyosis and Related Skin Types, the National pigmentosa, and diffuse cutaneous mastocytosis.
Institutes of Health award N01-AR-1-2252, and Skin-limited disease is typically indolent and seen
the National Center for Advancing Translational in younger patients and may rarely transform to
Sciences of the National Institutes of Health systemic disease. Systemic mastocytosis is typically
award UL1TR000423. The content is solely the more aggressive and may be associated with
responsibility of the authors and does not neces- multiorgan involvement with increased mortality.2,3
sarily represent the official views of the National Patients with systemic disease may develop
Institutes of Health. hematologic disorders, such as myeloid leukemia
and mast cell sarcoma, with a median survival of 2
Conflict of interest: None declared. months.
Correspondence to: Catherine S. Yang, MD, Depart- The histopathologic features of MCs include oval
ment of Dermatology, Alpert Medical School of to fusiform morphology. Mastocytosis is commonly
Brown University, 593 Eddy Street APC 1018, associated with the activating c-Kit mutation
Providence, RI, 02903 (D816V); this mutation is common in all MC
disease, suggesting that accumulated mutations
E-mail: [email protected] may contribute to disseminated disease and may
account for heterogeneity and decreased efficacy of
c-Kit-targeted therapy in systemic disease.
In addition to various tumor cells, PD-L1 is
REFERENCES
1. Ross R, DiGiovanna JJ, Capaldi L, et al. Histopathologic
expressed on MCs and dendritic cells. Here we
characterization of epidermolytic hyperkeratosis: a systematic examine PD-L1 immunohistochemical expression
review of histology from the National Registry for Ichthyosis in patients with mastocytosis. Mastocytosis was
and Related Skin Disorders. J Am Acad Dermatol. 2008;59: diagnosed clinically and histopathologically in
86-90.
16 specimens from 12 patients with MC disease
2. Herman ML, Farasat S, Steinbach PJ, et al. Transglutaminase-1
gene mutations in autosomal recessive congenital ichthyosis: (Table I). Immunohistochemistry for PD-L1, CD117,
summary of mutations (including 23 novel) and modeling of and/or mast cell tryptase (MCT) was performed in all
TGase-1. Hum Mutat. 2009;30:537-547. cases. Of the 12 patients identified with mastocytosis,
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Table I. Clinical and immunohistochemical characteristics of mastocytosis cohort

Age at PD-L1
Patient diagnosis Gender Biopsy/resection site Clinical diagnosis Treatment staining
1 17 months M Right back Urticaria pigmentosa Topical and oral antihistamines Positive
2 6 months M Left foot Solitary mastocytoma Excision Positive
3 8 years M Left shoulder None Excision Positive
4 70 years F Left hip; left inner Telangiectasia macularis Oral antihistamines and steroids Positive
thigh eruptiva perstans
5 61 years F Right upper thigh Systemic mastocytosis Oral antihistamine and cromolyn Positive
6 86 years M Umbilicus Mastocytosis Unknown Positive
7 51 years F Left lower abdomen; Diffuse cutaneous Oral antihistamines Positive
right posterior thigh mastocytosis vs
indolent systemic
mastocytosis
8 3 months M Left wrist Solitary mastocytoma Topical steroids Positive
9 46 years M Right flank Cutaneous mastocytosis Oral antihistamines, epinephrine Positive
10 11 years F Left posterior thigh; Mastocytomas Excision Positive
right anterior thigh
11 3 days M Right upper arm Diffuse cutaneous Oral antihistamines, topical Positive
mastocytosis cromolyn, topical steroids
12 75 years M Right back; left back Cutaneous and systemic Montelukast, oral antihistamines, Positive
mastocytosis epinephrine

Fig 1. PD-L1 expression in mastocytosis and normal skin. A, Mast cells highlighted by mast cell
tryptase staining in normal skin. (Original magnification: 310.) B, PD-L1 demonstrates weak
staining of mast cells within normal skin. (Original magnification: 310.). C, Mast cells
highlighted by CD117 staining in mastocytosis. (Original magnification: 310.). D, Strong and
diffuse staining of PD-L1 demonstrated by immunohistochemical staining in mastocytosis.
(Original magnification: 310.)

8 were male and 4 were female. Age ranged from 3 mastocytomas, 1 with urticaria pigmentosa, 2 with
days to 86 years old (average age, 34 years old). diffuse cutaneous mastocytosis, 2 with telangiectasia
Three patients were diagnosed with solitary macularis eruptiva perstans, 1 with systemic
1012 Letters J AM ACAD DERMATOL
MAY 2016

mastocytosis, and 3 were not specified. We also Expression of T-bet and GATA-3 in early
stained normal skin (n ¼ 17) for mast cell tryptase mycosis fungoides and spongiotic dermatitis
and PD-L1 for comparison. To the Editor: T helper (Th) cells play a major role in
The finding of strong, diffuse PD-L1 staining was the immune response through collaboration be-
identified in all mastocytosis specimens (n ¼ 16) tween T and B lymphocytes. Th1 and Th2 CD41T
(Fig 1). Additionally, staining of MC was strong for all cells are differentiated by cytokines that they secrete.
cases of mastocytosis, regardless of subtype. In 3 Th1 lymphocytes produce IFN and IL2, while Th2
biopsies (25%), the MC appeared to be darker along cells secrete IL4, IL5, IL6, IL10 and IL13. CD81T
the leading edge of the infiltrate. Normal skin bi- cytotoxic (Tc) cells were also found to be subdivided
opsies displayed very weak to no staining for PD-L1. into Tc1 and Tc2, and their activation results in the
Here we demonstrate increased expression of PD- production of INF.1 T-bet is a Th1 lineage commit-
L1 in MC proliferations. PD-L1 is expressed on various ment transcription factor required for na€ıve CD81
tumor cells, such as melanoma and lung cancer, and T cells differentiation. In contrast, GATA-3 is a Th2
enhances immune evasion.4 PD-L1 expression in lineage commitment transcription factor. Both T-bet
melanoma demonstrated a worse prognosis and and GATA-3 expression affect the balance of Th1/
blockade of the PD-1/PD-L1 interaction diminished Th2 cells.2
tumors.5 Therefore, antiePD-L1 blockade may be Early mycosis fungoides (MF) demonstrates an
therapeutic in treatment-resistant mast cell disease. increase in IL2 and INF, which is a Th1 profile,3
In conclusion, our findings provide evidence of whereas in contact dermatitis, both Th1 and Tc1
expression of PD-L1 in MC proliferations of mastocy- play a rule in pathogenesis.4 The diagnostic utility
tosis. Blockade of the PD-1/PD-L1 interaction may of T-bet and GATA-3 specific markers in MF and
prove to be a useful therapeutic modality in advanced inflammatory dermatosis mimics was recently
MC disease. The most common adverse reactions of investigated,5 and it was suggested that a predom-
antiePD-1 pathway therapy identified include mild inance of T-bet T cells in the epidermis supports a
fatigue, rash, and pruritus. Additional studies are diagnosis of patch stage MF over dermatitis. In an
required to evaluate the role of PD-L1 in MC disease. attempt to validate their findings, we assessed the
Lawrence F. Kuklinski, BA,a and Jinah Kim, MD, ratio of T-bet and GATA-3 expression via immuno-
PhDa,b histochemical staining, using both dual staining
CD3/T-bet and CD3/GATA-3 and single staining for
Department of Pathologya and Department of T-bet and GATA-3 in 10 consecutive cases each of
Dermatology,b Stanford University, California spongiotic dermatitis and patch-stage MF retrieved
Funding sources: None. from the files of Ackerman Academy. The MF cases
were typical of patch stage disease clinically and
Conflicts of interest: None declared. histologically. They were characterized by the
Correspondence to: Jinah Kim, MD, PhD, Stanford presence of band-like and superficial epidermo-
University, Department of Pathology and Derma- tropic lymphocytes of hyperchromatic atypical
tology, MC 5324, Stanford, CA 94305 lymphocytes with underlying papillary dermal
fibrosis. In contrast to the prior report, we found
E-mail: [email protected] no significant differences between the groups or in
staining of the epidermotropic T cells and the
REFERENCES
1. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of
underlying dermal infiltrate within each group
anti-PD-L1 antibody in patients with advanced cancer. N Engl J (Fig 1). Both T-bet and GATA-3 were strongly
Med. 2012;366:2455-2465. expressed in both spongiotic dermatitis and MF,
2. Akin C, Metcalfe DD. Systemic mastocytosis. Annu Rev Med. with higher expression in microabcesses in cases of
2004;55:419-432. MF for both markers. Both T-bet and GATA-3 did
3. Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342
consecutive adults: survival studies and prognostic factors.
not distinguish between spongiotic dermatitis and
Blood. 2009;113:5727-5736. patch-stage MF (Table I). However, within the
4. Dong H, Strome SE, Salomao DR, et al. Tumor-associated cases of spongiotic dermatitis, we found signifi-
B7-H1 promotes T-cell apoptosis: a potential mechanism of cantly higher expression of GATA-3/CD3 compared
immune evasion. Nat Med. 2002;8:793-800. with T-bet/CD3 (P ¼ .011; Friedmann test-
5. Hino R, Kabashima K, Kato Y, et al. Tumor cell expression of
programmed cell death-1 ligand 1 is a prognostic factor for
Bonferroni corrections) but this differential staining
malignant melanoma. Cancer. 2010;116:1757-1766. was not noted in MF. We found single staining
easier to interpret, compared with dual staining
http://dx.doi.org/10.1016/j.jaad.2015.09.029 with CD3. The bright red CD3 stain made it more