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\begin{document}

\title{Pediatric Cutaneous Gamma-delta T-cell Neoplasm and Mimics: Not Always
Aggressive}



\author[1]{Jinjun Cheng}%
\author[1]{Keri Toner}%
\author[1]{Kaiane Habeshian}%
\author[2]{Michael Cardis}%
\author[1]{Catherine Bollard}%
\author[1]{Birte Wistinghausen}%
\author[1]{Anna Kirkorian}%
\affil[1]{Children's National Hospital}%
\affil[2]{MedStar Georgetown University Hospital}%


\vspace{-1em}



  
  \date{March 14, 2025}


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\selectlanguage{english}
\begin{abstract}
Pediatric cutaneous T-cell lymphoma with \selectlanguage{greek}γδ \selectlanguage{english}immunophenotype is extremely
rare. Only a few cases of \selectlanguage{greek}γδ \selectlanguage{english}T-cell neoplasm have been reported in the
literature and therefore little is known whether \selectlanguage{greek}γδ \selectlanguage{english}T-cell neoplasms in
children are distinct from their adult counterparts with respect to the
clinicopathological presentation, behavior and prognosis. In this study,
we demonstrate three unique cases with increased \selectlanguage{greek}γδ \selectlanguage{english}T-cells in malignant
and non-malignant skin conditions of children. All cases showed an
indolent clinical course. Full integration of clinical presentation,
morphology, immunophenotype, and genetics supports the correct diagnosis
and guides the treatment.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Normal T-lymphocytes express either \selectlanguage{greek}αβ \selectlanguage{english}or \selectlanguage{greek}γδ \selectlanguage{english}T-cell receptors, while \selectlanguage{greek}γδ
\selectlanguage{english}T-cells comprise 0.5\%--10\% of total T-cells with variable distribution
in mucosa, spleen, lymph node and other sites, that play critical roles
of innate and adaptive immunity.\textsuperscript{1} The physiological
development and immunophenotype of \selectlanguage{greek}γδ \selectlanguage{english}T-cells are different from \selectlanguage{greek}αβ
\selectlanguage{english}T-cells.\textsuperscript{2} For instance, subsets of \selectlanguage{greek}γδ \selectlanguage{english}T-cells are less
dependent on thymic microenvironment and may arise
extrathymically.\textsuperscript{1-3} The \selectlanguage{greek}γδ \selectlanguage{english}T-cells express CD3,
variable CD5, variable CD56 and CD57, while they are often negative for
CD4 and CD8.

T-cell lymphomas (TCLs) account for about 12\% of the total lymphoid
tumors, and comprise over 20 distinct entities in the World Health
Organization (WHO) classifications.\textsuperscript{4} TCLs are
extremely rare in children. Aside from T-lymphoblastic and anaplastic
large cell lymphomas; the majority of TCLs originate from \selectlanguage{greek}αβ \selectlanguage{english}T-cells and
only few arise from \selectlanguage{greek}γδ \selectlanguage{english}T cells, \textsuperscript{4-6} including primary
cutaneous \selectlanguage{greek}γδ \selectlanguage{english}T-cell lymphoma (PCGDTCL), hepatosplenic T-cell lymphoma
(HSTCL), and monomorphic epitheliotropic intestinal T-cell lymphoma
(MEITL).\textsuperscript{4} Patients with these types of \selectlanguage{greek}γδ \selectlanguage{english}TCLs appear
to have an aggressive clinical course and poor outcome despite
aggressive chemotherapy and/or additional
treatments.\textsuperscript{4}Occasional \selectlanguage{greek}γδ \selectlanguage{english}T-cell lymphoma cases are
limited to the subcutis and show a less aggressive clinical
course.\textsuperscript{3,7-10} Further, some cutaneous and subcutaneous
TCLs and non-malignant skin conditions may demonstrate an increase in \selectlanguage{greek}γδ
\selectlanguage{english}T-cells, with uncertain significance.\textsuperscript{2-4,11,12}

Hence, our current knowledge of \selectlanguage{greek}γδ \selectlanguage{english}TCLs is mostly based on adult
patients; and the pathological and clinical studies of pediatric \selectlanguage{greek}γδ \selectlanguage{english}TCLs
are scarce.\textsuperscript{13} Moreover, the spontaneous regression of
cutaneous \selectlanguage{greek}γδ \selectlanguage{english}T-cell clonal proliferation has been reported in
inflammatory and in non-neoplastic disorders.\textsuperscript{14} In
this study, we report the pathological and clinical features of three
unusual patients from this unique pediatric multi-disciplinary cutaneous
lymphoma clinic.

\textbf{Case Description}

The first patient is a 14-year-old female with a clinical history of
tumid lupus (biopsy proven at age 2) on immunomodulator treatment, who
presented with a 3-year history of progressive cutaneous plaques,
subcutaneous nodules, and ulcerations on the left forearm. Serologic
studies were negative for auto-antibodies. PET/CT scans demonstrated
avidity of skin lesions and two minimally enlarged axillary lymph nodes
without additional lesions. The patient had a history of intermittent
fevers, occasional malaise and mild cytopenia, which improved without
intervention, and elevated CXCL9 on an inflammatory cytokine workup. The
biopsy of one plaque showed features of lobular panniculitis, while
another biopsy of an ulcerated skin lesion revealed an epidermal
ulceration and subcutaneous lobular panniculitic pattern with marked \selectlanguage{greek}γδ
\selectlanguage{english}T cell infiltrates rimming the adipose tissue, with a high Ki67
proliferation rate. T-cell gene rearrangements were clonal. NGS studies
for both germline and somatic pathogenic mutations were negative. The
overall findings favored a SPTCL with increased \selectlanguage{greek}γδ \selectlanguage{english}T-cells (Figure 1).
The patient received immunomodulation therapy and with close follow up,
disease progression was not observed.

The second patient was diagnosed with stage 1B hypopigmented mycosis
fungoides with a \selectlanguage{greek}γδ \selectlanguage{english}T-cell variant at approximately 5 years old. After
seven years of follow up, the patient's skin lesions did not appreciably
progress. The third patient is a 6-year-old male who presented with a
three-monthly history of extensive hyperpigmented macules on the trunk
and extremities and hypopigmented patches on the face. Skin biopsy
revealed parakeratosis, psoriasiform epidermal hyperplasia with minimal
spongiosis, exuberant lymphocyte exocytosis with epidermotropism, and a
perivascular lymphohistiocytic infiltrate in dermis. Immunohistochemical
stains revealed an atypical population of CD3+ T-lymphocytes with
diminished CD4, CD8, CD5 and CD7 expression within the epidermis.
Molecular studies for T-cell gene rearrangements were clonal. A
diagnosis of cutaneous T cell lymphoma was suspected. However,
additional immunostaining for TCR-delta highlighted that the atypical
T-cell population were \selectlanguage{greek}γδ \selectlanguage{english}T cells in nature. The overall findings
favored a diagnosis of \selectlanguage{greek}γδ \selectlanguage{english}variant of pityriasis lichenoides (Figure 2).
The skin lesions were fully resolved after PLC treatment (azithromycin
and triamcinolone ointment).

\textbf{Discussion}

Rare cases of primary \selectlanguage{greek}γδ \selectlanguage{english}cutaneous T-cell lymphoma (CTCL) have been
reported in children,\textsuperscript{5} which creates major diagnostic
and treatment challenges for pathologists and primary clinicians. Here
we describe three unusual pediatric patients with this rare condition
and its mimics.

PCGDTCL, a definitive entity in the WHO classification of lymphomas,
expresses a mature cytotoxic phenotype with frequent necrosis and/or
apoptosis and exhibits diverse histological patterns and clinical
symptoms.\textsuperscript{15} Because of the poor clinical outcome,
early diagnosis and aggressive therapy are indicated in these patients.
Most PCGDTCL have pathogenic mutations in the JAK-STAT, MAPK, and MYC
signaling pathways.\textsuperscript{16} In contrast, subcutaneous
panniculitis-like T-cell lymphoma (SPTCL) is a clonal expansion of \selectlanguage{greek}αβ
\selectlanguage{english}cytotoxic T-cells involving subcutaneous adipose tissue. Patients
typically present with subcutaneous nodules, systemic symptoms, and as
many as 20\% of cases are associated with an autoimmune
condition.\textsuperscript{17} SPTCL patients often respond to
immunomodulatory therapy. Only 10-20\% SPTCL contain somatic mutations
in epigenetic genes and rarely in JAK-STAT signaling pathways. Primary
cutaneous \selectlanguage{greek}γδ \selectlanguage{english}T-cell lymphoma is extremely rare in children. Such a
diagnosis should always be based on the integration of clinical
presentation, morphology, immunophenotype, and genetics. Our first
patient demonstrated an indolent clinical course, with negative germline
and somatic pathogenic mutations, which argues against an aggressive
PCGDTCL, and favor a SPTCL with increased \selectlanguage{greek}γδ \selectlanguage{english}T-cells. It is therefore
critical to avoid aggressive chemotherapy in these patients, and
instead, commence initial therapy with an immunomodulator.

Mycosis fungoides (MF), a non-Hodgkin T-cell lymphoma of the skin, is
the most common primary cutaneous lymphoma. Rare MF contains an increase
in \selectlanguage{greek}γ/δ \selectlanguage{english}T-cells, which may represent a subset of the malignant clone or a
background reactive population.\textsuperscript{4} These patients may
show a variety of types of MF, ranging from folliculotropic to
granulomatous, hypopigmented, pigmented purpuric dermatosis-like,
large-cell transformation, and classic patch/plaque. Due to the scarce
data in the literature, there is no solid evidence that demonstrates a
significant difference in prognosis for patients with \selectlanguage{greek}γδ \selectlanguage{english}type MF versus
\selectlanguage{greek}αβ \selectlanguage{english}type MF.\textsuperscript{16,18} A relatively aggressive disease
course for \selectlanguage{greek}γδ \selectlanguage{english}type MF has been reported in one
study,\textsuperscript{19} but not all. Our second patient of \selectlanguage{greek}γδ \selectlanguage{english}type MF
shows an indolent clinical course, similar to the \selectlanguage{greek}αβ \selectlanguage{english}type of MF.

As observed in our third patient, \selectlanguage{greek}γδ \selectlanguage{english}T cells can be increased in
non-malignant skin lesions, such as pityriasis lichenoides (PL), an
inflammatory condition of the skin characterized by waxing and waning
eroded and crusted papules.\textsuperscript{12} PL chronica (PLC) or et
variolaformis acuta (PLEVA) mostly arise from \selectlanguage{greek}αβ \selectlanguage{english}T cells, while
extremely rare lymphomas derive from \selectlanguage{greek}γδ \selectlanguage{english}T cells.\textsuperscript{12} The
histopathology of \selectlanguage{greek}γδ \selectlanguage{english}type PL appears to be not appreciably different
from \selectlanguage{greek}αβ \selectlanguage{english}type PLs. Finally, it is important to note that all three
patients show an indolent course.

In summary, our three cases demonstrated increase in \selectlanguage{greek}γδ \selectlanguage{english}T-cells in
malignant and non-malignant skin conditions of children, and all of them
showed an indolent clinical course. In borderline case like our first
patient, NGS studies may be helpful to establish the diagnosis and avoid
aggressive therapies. However, biological and collaborative studies of
these unusual and rare disorders are needed in future.

\textbf{Reference:}

1. Girardi M. Cutaneous biology of gammadelta T cells. \emph{Adv
Dermatol.} 2004;20:203-215.

2. Goyal A, Nardi V. Gamma/Delta (gammadelta) T Cells: The Role of the
T-Cell Receptor in Diagnosis and Prognosis of Hematologic
Malignancies.\emph{Am J Dermatopathol.} 2022;44(4):237-248.

3. Guitart J, Weisenburger DD, Subtil A, et al. Cutaneous gammadelta
T-cell lymphomas: a spectrum of presentations with overlap with other
cytotoxic lymphomas. \emph{Am J Surg Pathol.} 2012;36(11):1656-1665.

4. Swerdlow SH CE, Harris NL, Jaffe ES, Pileri SA, Stein H, et al.
.\emph{WHO Classification of Tumours of Haematopoietic and Lymphoid
Tissues, Revised Fourth Edition.} Vol 2. Lyon, France: IARC/WHO Press;
2017.

5. Boccara O, Blanche S, de Prost Y, Brousse N, Bodemer C, Fraitag S.
Cutaneous hematologic disorders in children. \emph{Pediatr Blood
Cancer.} 2012;58(2):226-232.

6. Kempf W, Mitteldorf C. Cutaneous T-cell lymphomas-An update
2021.\emph{Hematol Oncol.} 2021;39 Suppl 1:46-51.

7. Endly DC, Weenig RH, Peters MS, Viswanatha DS, Comfere NI. Indolent
course of cutaneous gamma-delta T-cell lymphoma. \emph{J Cutan
Pathol.}2013;40(10):896-902.

8. Galadari A, Ram-Wolff C, Al Hage J, et al. Cutaneous gamma delta
T-Cell lymphoma with indolent evolution: a series of five cases. \emph{J
Eur Acad Dermatol Venereol.} 2022;36(9):e715-e717.

9. Kempf W, Kazakov DV, Scheidegger PE, Schlaak M, Tantcheva-Poor I. Two
cases of primary cutaneous lymphoma with a gamma/delta+ phenotype and an
indolent course: further evidence of heterogeneity of cutaneous
gamma/delta+ T-cell lymphomas. \emph{Am J
Dermatopathol.}2014;36(7):570-577.

10. Magro CM, Wang X. Indolent primary cutaneous gamma/delta T-cell
lymphoma localized to the subcutaneous panniculus and its association
with atypical lymphocytic lobular panniculitis. \emph{Am J Clin
Pathol.}2012;138(1):50-56.

11. Jaffe ES, Nicolae A, Pittaluga S. Peripheral T-cell and NK-cell
lymphomas in the WHO classification: pearls and pitfalls. \emph{Mod
Pathol.} 2013;26 Suppl 1(Suppl 1):S71-87.

12. Martinez-Escala ME, Sidiropoulos M, Deonizio J, Gerami P, Kadin ME,
Guitart J. gammadelta T-cell-rich variants of pityriasis lichenoides and
lymphomatoid papulosis: benign cutaneous disorders to be distinguished
from aggressive cutaneous gammadelta T-cell lymphomas. \emph{Br J
Dermatol.} 2015;172(2):372-379.

13. Wei EX, Leventaki V, Choi JK, et al. gammadelta T-Cell Acute
Lymphoblastic Leukemia/Lymphoma: Discussion of Two Pediatric Cases and
Its Distinction from Other Mature gammadelta T-Cell
Malignancies.\emph{Case Rep Hematol.} 2017;2017:5873015.

14. Marchitto MC, Dillen CA, Liu H, et al. Clonal Vgamma6(+)Vdelta4(+) T
cells promote IL-17-mediated immunity against Staphylococcus aureus skin
infection. \emph{Proc Natl Acad Sci U S A.} 2019;116(22):10917-10926.

15. Toro JR, Liewehr DJ, Pabby N, et al. Gamma-delta T-cell phenotype is
associated with significantly decreased survival in cutaneous T-cell
lymphoma. \emph{Blood.} 2003;101(9):3407-3412.

16. Daniels J, Doukas PG, Escala MEM, et al. Cellular origins and
genetic landscape of cutaneous gamma delta T cell lymphomas. \emph{Nat
Commun.} 2020;11(1):1806.

17. Huppmann AR, Xi L, Raffeld M, Pittaluga S, Jaffe ES. Subcutaneous
panniculitis-like T-cell lymphoma in the pediatric age group: a lymphoma
of low malignant potential. \emph{Pediatr Blood
Cancer.}2013;60(7):1165-1170.

18. Merrill ED, Agbay R, Miranda RN, et al. Primary Cutaneous T-Cell
Lymphomas Showing Gamma-Delta (gammadelta) Phenotype and Predominantly
Epidermotropic Pattern are Clinicopathologically Distinct From Classic
Primary Cutaneous gammadelta T-Cell Lymphomas. \emph{Am J Surg
Pathol.}2017;41(2):204-215.

19. Pulitzer M, Geller S, Kumar E, et al. T-cell receptor-delta
expression and gammadelta+ T-cell infiltrates in primary cutaneous
gammadelta T-cell lymphoma and other cutaneous T-cell
lymphoproliferative disorders. \emph{Histopathology.}2018;73(4):653-662.

\textbf{Figure Legend:}

\selectlanguage{greek}\textbf{Figure 1: A skin biopsy of SPTCL with increased γδ T cells.}\selectlanguage{english} A
and B, the skin lesions show a spectrum of plaques, subcutaneous nodules
and so on. The skin biopsy reveals an ulcerated lesion with extensive
dermal and subcutaneous lymphoid infiltrate (C, H\&E, 20x). Repeated PCR
for T-cell gene rearrangements in multiple skin biopsies confirms a
persistent clonal gene rearrangement (D). On high power, the H\&E
sections show a adipose rimming by atypical lymphocytes (E, H\&E 200x
and F, H\&E, 400x). The atypical lymphocytes are predominantly CD3+ T
cells (G, 200X), CD8+ (H, 200x) with high Ki67 proliferation rate (I,
200x). TCR delta stains a marked increase of atypical T lymphocytes (K,
200x), although TCR BF1 also highlights substantial T lymphocytes (L,
200X). CD79a, CD123 and EBER-ISH are mostly negative (not shown).

\selectlanguage{greek}\textbf{Figure 2: A skin biopsy of γδ variant of PLC.}\selectlanguage{english} The H\&E sections
reveals parakeratosis, psoriasiform epidermal hyperplasia with minimal
spongiosis but exuberant lymphocyte exocytosis multifocally tagging
along the dermoepidermal junction and forming small clusters (A, H\&E,
200x; B, H\&E, 400X) within the epidermis. The dermis features a mildly
dense perivascular lymphohistiocytic infiltrate. Immunohistochemical
stains reveal a population of CD3+ T lymphocytes (C, 200X) with very
rare CD20+ B lymphocytes (not shown). CD5 (D, 200X) and CD7 (not shown)
expressions are diminished compared to epidermal CD3 expression. CD4 (E,
200x) and CD8 (F, 200X) expression are decreased within the epidermis.
TCR-Delta highlights an increase in \selectlanguage{greek}γδ \selectlanguage{english}T cells (G, 200x). CD30 (H, 200x)
is largely negative. Neither fungal microorganisms nor basement membrane
changes are seen with interpretation of PAS histochemical stain (not
shown). PCR for T-cell gene rearrangements were positive.

\textbf{Figure 1}\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

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\textbf{Figure 2}\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

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