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\begin{document}

\title{Subcutaneous panniculitis-like T-cell lymphoma of the breast in an
adolescent female: An Uncommon presentation}



\author[1]{Neetika Gupta}%
\author[2]{Reza Vali}%
\author[2]{Amer Shammas}%
\author[2]{Farshid Gheisari}%
\author[2]{Cathryn Sibbald}%
\author[2]{Rose Chami}%
\author[2]{Elena Pope}%
\author[2]{Oussama Abla}%
\author[2]{Ahmed Naqvi}%
\affil[1]{Children's Hospital of Eastern Ontario}%
\affil[2]{The Hospital for Sick Children}%


\vspace{-1em}



  
  \date{May 22, 2024}


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\selectlanguage{english}
\begin{abstract}
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of
peripheral T-cell lymphomas (PTCL) and is extremely uncommon in the
pediatric population. We present a case of a 15-year-old girl with SPTCL
and an unusual involvement of the breast. The FDG-PET/CT showed avid
uptake of 18F-FDG in the breast predominantly involving the subcutaneous
tissue that improves post treatment. To our knowledge, this is the first
case of breast SPTCL reported in pediatric patient. A study published by
Goto-et-al in 2019 {[}(1){]}(\#ref-0001), found only 27 cases of SPTCL
under 15 years, including four infants and none of them shown breast
involvement.%
\end{abstract}%



\sloppy


\emph{TITLE PAGE}

\textbf{Title} : Subcutaneous panniculitis-like T-cell lymphoma of the
breast in an adolescent female: An Uncommon presentation

\textbf{Authors \& affiliations}

\begin{enumerate}
\tightlist
\item
  Neetika Gupta, Clinical Fellow Pediatric Radiology, Department of
  Medical Imaging; CHEO; University of Ottawa
\item
  Dr Reza Vali, Associate Professor of Nuclear Medicine; Department of
  Diagnostic Imaging; The Hospital for Sick Children, University of
  Toronto
\item
  Dr Amer Shammas, Head of the Division of Nuclear Medicine; Department
  of Diagnostic Imaging; The Hospital for Sick Children, University of
  Toronto
\item
  Dr Farshid Gheisari, Clinical Fellow Nuclear Medicine, Department of
  Diagnostic Imaging; The Hospital for Sick Children, University of
  Toronto
\item
  Dr Cathryn Sebbald, Assistant Professor, Division of Dermatology,
  Department of Paediatrics, The Hospital for Sick Children, University
  of Toronto
\item
  Dr Rose Chami, Assistant Professor, Department of Laboratory Medicine
  \& Pathobiology, The Hospital for Sick Children, University of Toronto
\item
  Dr Elena Pope, Professor \& Division Head, Paediatric Dermatology, The
  Hospital for Sick Children, University of Toronto
\item
  Dr Oussama Abla, Staff Hematologist and Oncologist, Director,
  Paediatric Histiocytosis Program, Division of Haematology/Oncology,
  The Hospital for Sick Children, University of Toronto
\item
  Dr Ahmed Naqvi, Staff Hematologist and Oncologist, Co-Director
  Histiocytosis Program, The Hospital for Sick Children, University of
  Toronto
\end{enumerate}

\textbf{Corresponding author:}

Neetika Gupta,

CHEO, 401 Smyth Road, Ottawa, On, Canada

3435425577

drneetikagupta@gmail.com

\textbf{Word Count:}

a) Abstract: 100 words b) Main Text (excludes title page, abstract,
Conflicts of Interest, Acknowledgments, References, Tables, Figures, and
Legends): 1215 words

\textbf{Figures:} Two

\textbf{Short running title:} Subcutaneous panniculitis-like T-cell
lymphoma of the breast in an adolescent female: An Uncommon presentation

\textbf{Keywords:} Peripheral T-cell lymphoma, Non-Hodgkin lymphoma,
Breast lymphoma, Panniculitis, PET-CT

\textbf{Abbreviations key:}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Number & Abbreviations & Full form\tabularnewline
\midrule
\endhead
1 & SPTCL & Subcutaneous panniculitis-like T-cell
lymphoma\tabularnewline
2 & PTCL & Peripheral T-cell lymphoma\tabularnewline
3 & ALCL & Anaplastic large cell lymphoma\tabularnewline
4 & NHL & Non-Hodgkin lymphoma\tabularnewline
5 & EORTC & European Organization for Research and Treatment of
Cancer\tabularnewline
\bottomrule
\end{longtable}

\textbf{No previous} publication or presentation.

\emph{Abstract} :

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of
peripheral T-cell lymphomas (PTCL) and is extremely uncommon in the
pediatric population. We present a case of a 15-year-old girl with SPTCL
and an unusual involvement of the breast. The FDG-PET/CT showed avid
uptake of 18F-FDG in the breast predominantly involving the subcutaneous
tissue that improves post treatment. To our knowledge, this is the first
case of breast SPTCL reported in pediatric patient. A study published by
Goto-et-al in 2019 (1), found only 27 cases of SPTCL under 15 years,
including four infants and none of them shown breast involvement.

\emph{Case Report:}

A 15-year-old female presented to family physician with a 4-months
history of left breast swelling. According to the patient, she felt a
lump in the left breast that was slowly increasing in size causing some
discomfort and burning sensation. There was no complaint of pruritus or
discharge from the nipple. On examination, a violaceous thickened
cutaneous plaque was noted without any excoriation or ulceration. The
patient was referred to the breast clinic where an ultrasound-guided
biopsy of the breast parenchyma and axillary node was performed, that
revealed chronic inflammatory changes (mixed infiltrate of lymphocytes,
histiocytes, and occasional plasma cells with stromal hyalinization)
with negative histology for bacterial/fungal stains. A diagnosis of
morphea profunda was favored, and patient was referred to the morphea
clinic at our hospital. After a thorough evaluation, it was concluded
that her symptoms and presence of histiocytes on biopsy were not
consistent with morphea and possibility of non-specific inflammation was
entertained, particularly in view of a preceding covid vaccination in
the ipsilateral arm. Clarithromycin was prescribed and inflammatory
markers (ESR, CRP, ANA) were done and found to be non-diagnostic.
Ultrasound was repeated to assess any interval change and revealed
extensive soft tissue edema of the left breast and enlarged axillary
lymph nodes, concerning for lymphoproliferative disorder (Fig-1a). In
view of the ultrasound findings and interval progression, an MRI of the
breast was done that revealed marked and diffuse inflammation of the
left breast predominantly involving the subcutaneous soft tissue with
questionable nipple retraction (Fig-1b). Repeat MRI with contrast after
2 weeks (Fig-1c) demonstrated mild interval progression with predominant
subcutaneous enhancement and enhancing axillary lymph nodes without any
discrete parenchymal mass. The right breast and axilla were normal.

An ultrasound-guided punch biopsy of the subcutaneous soft tissue of the
left breast (Fig-1d) demonstrated fibroadipose tissue with lobular
panniculitis-like lymphoid cell infiltrate, background fat necrosis,
karyorrhexis, and histiocytes containing karyorrhectic debris. Atypical
lymphoid cells were mildly enlarged and have irregular and
hyperchromatic nuclei. A helpful diagnostic feature was the rimming of
atypical lymphoid cells surrounding the individual adipocytes (Fig-1e).
By immunohistochemistry, the atypical/alipotropic lymphoid cells
expressed TCR beta-F1, CD8, and cytotoxic molecules (TIA1 and
granzyme-B) were negative for CD4 and CD56. Epstein-Barr-encoding region
in-situ hybridization was negative. PCR analysis showed TCRD gene clonal
rearrangement. The overall findings were in keeping with a diagnosis of
SPTCL. The expression of beta-F1 by the atypical cells and negative
staining for CD56 facilitated the distinction from primary cutaneous
gamma/delta (\selectlanguage{greek}γ/δ\selectlanguage{english}) T-cell lymphoma. Additionally, the negative staining
for CD30 together with morphology didn't support diagnosis of primary
cutaneous-Anaplastic large cell lymphoma (ALCL).

Subsequently, the patient developed a new lesion in the right breast.
FDG PET-CT (Fig-2a,b,c) was performed and revealed asymmetrical
increased activity predominantly affecting the subcutaneous soft tissue
of the left breast (SUVmax-8.7) and left axilla (SUVmax-10.5) as well as
hypermetabolic axillary lymph nodes. Some patchy subcutaneous soft
tissue activity was also noted in the medial aspect of the right breast,
concerning for bilateral disease.

The oncology team discussed the diagnosis and management plan with the
patient and family and started immunosuppressive therapy with prednisone
(60mg/m2/day PO divided BID) and cyclosporin (6mg/kg/day PO divided
BID). CT scan of the neck and chest was repeated after four weeks of
therapy showed resolving left breast cutaneous and subcutaneous
thickening and inflammatory-like changes as well as resolved left
axillary lymphadenopathy. The prednisone dose was tapered to 30mg/m2/day
divided BID. Repeat FDG-PET/CT (Fig 2c,d,e) for response assessment at
8-weeks of the therapy revealed significant improvement, SUV max falls
from 8.7 to 3.5 in the left breast and from 10.5 to 3.02 in the left
axilla. No activity was perceived in the right breast. Currently, the
patient is on tapering doses of prednisone with a goal to decrease it to
2.5 mg daily to complete one year of therapy.

\emph{Discussion:}

SPTCL is one of the rarest subtypes of non-Hodgkin lymphoma (NHL) in
children, constituting less than 1\% of the NHL and the cutaneous
lymphomas (2,3) with limited literature in the pediatric population
(4,5). No definite gender predilection is noticed, but a slight female
predilection is reported by a few studies and is usually associated with
good outcomes (5).

Historically, the SPTCL has two subtypes based on T-cell phenotypes --
alpha/beta (\selectlanguage{greek}α/β\selectlanguage{english}) with better prognosis and gamma/delta (\selectlanguage{greek}γ/δ\selectlanguage{english}) with poor
outcome (3). The European Organization for Research and Treatment of
Cancer (EORTC) classification (2005) modified this categorization and
advocated the use of \selectlanguage{greek}α/β \selectlanguage{english}T-cell phenotype for SPTCL only and described
\selectlanguage{greek}γ/δ \selectlanguage{english}T-cell phenotype as a distinct cutaneous T-cell lymphoma (6). On
immunochemistry, the malignant T-cells in SPTCL are CD8+ve, CD3+ve,
beta-F1+ve, CD4-ve, and CD56-ve. The \selectlanguage{greek}γ/δ \selectlanguage{english}T-cell phenotype cutaneous
T-cell lymphoma is CD56+ve, while beta-F1-ve, and CD4 and CD8 are
negative in most cases (3). Histopathology with immunohistochemistry is
the gold standard for the diagnosis and is confirmatory in almost all
cases (5).

The histological findings include T-cells and macrophages infiltrating
subcutaneous fat lobules with relative sparing of the dermis and
epidermis simulating panniculitis. The malignant T-cell infiltration of
the hypodermic soft tissue in SPTCL incites an inflammatory response
very similar to panniculitis (7,8). The inflammatory change can involve
a single site or be multicentric, presenting as soft tissue nodules,
plaques, edema, discoloration, and itch (5). Compared to young infants,
older children with SPTCL present frequently with fever and weight loss
(90\% vs 40\%) and have a higher association with HLH (45.5\% vs 20\%)
(1).

Ultrasound is the initial imaging modality of choice owing to the
superficial location and typically demonstrates vague inflammatory
changes with or without regional lymphadenopathy (9). CT/MRI may help to
determine the extent of inflammatory changes, evaluate deeper
structures, underlying masses, and loco-regional lymphadenopathy (3,10).
FDG-PET is considered the most useful imaging modality, integrating both
anatomical and functional assessment. (11,12). FDG-PET demonstrates the
distribution and uptake of the FDG at the primary site and any
involvement of the distant sites, visceral organs, and lymph nodes,
allowing for accurate pre-treatment staging (3,11). It can also help to
guide the optimal biopsy site based on the metabolic activity and FDG
avidity (12). Post-therapy FDG-PET is useful in determining the
treatment response, degree of residual disease, and any signs of
recurrence (3,11,12).

The management of SPTCL in the pediatric population is variable and
largely depends on the histopathological diagnosis and institutional
preferences. Potential treatment modalities include observation,
immunosuppression, chemotherapy, and radiotherapy (4,13). Similar to the
adults, pediatric case series have shown good treatment outcomes with
dual immunosuppression (cyclosporin-A and prednisolone) in childhood
SPTCL, particularly in the absence of HLH (4). One of the largest
reviews of pediatric PTCL shows the best treatment outcome in SPTCL with
maximum 5-years survival compared to the other pediatric PTCL (14).

\emph{Conclusion} :

Clinically, the SPTCL often mimics the panniculitis from a benign
dermatological disease; initial imaging and histopathological findings
can also be non-diagnostic and a high index of suspicion is required to
reach an accurate diagnosis. FDG-PET has emerged as an excellent imaging
tool that can provide a road map for the diagnosis and management of the
SPTCL by accurately guiding the biopsy site, eluding false-negative
examinations, and by identifying the multicentricity of the disease. Our
case represents the first case of breast SPTCL in the pediatric
population and describes the role of FDG-PET in the evaluation of the
lesion, determining the multicentricity of the disease, and
loco-regional lymphadenopathy.

\emph{Conflict of Interest statement:} No affiliations to any
organization.

\emph{Acknowledgements} : None

\emph{References} :

1. Goto H, Hirano N, Kadowaki H, Suenobu S, Ihara K. Clinical features
of infantile subcutaneous panniculitis-like T-cell lymphoma. Pediatr
Int. 2019 Dec;61(12):1261--2.

2. Bradford PT, Devesa SS, Anderson WF, Toro JR. Cutaneous lymphoma
incidence patterns in the United States: a population-based study of
3884 cases. Blood. 2009 May 21;113(21):5064--73.

3. Schramm N, Pfluger T, Reiser MF, Berger F. Subcutaneous
panniculitis-like T-cell lymphoma with breast involvement: functional
and morphological imaging findings. Br J Radiol {[}Internet{]}. 2010 May
{[}cited 2022 Sep 9{]};83(989):e090--4.

4. Bairagi A, Whyte M, Kimble R. Subcutaneous panniculitis-like T-Cell
lymphoma in a child presenting as an abdominal wall mass. Journal of
Pediatric Surgery Case Reports {[}Internet{]}. 2020 Sep 1 {[}cited 2022
Sep 9{]};60:101556.

5. Hu ZL, Sang H, Deng L, Li Z. Subcutaneous Panniculitis-Like T-Cell
Lymphoma in Children: A Review of the Literature. Pediatr Dermatol. 2015
Aug;32(4):526--32.

6. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et al.
WHO-EORTC classification for cutaneous lymphomas. Blood. 2005 May
15;105(10):3768--85.

7. Ohtsuka M, Miura T, Yamamoto T. Clinical characteristics,
differential diagnosis, and treatment outcome of subcutaneous
panniculitis-like T-cell lymphoma: a literature review of published
Japanese cases. Eur J Dermatol. 2017 Feb 1;27(1):34--41.

8. Kawachi Y, Furuta J ichi, Fujisawa Y, Nakamura Y, Ishii Y, Otsuka F.
Indolent subcutaneous panniculitis-like T cell lymphoma in a 1-year-old
child. Pediatr Dermatol. 2012 Jun;29(3):374--7.

9. Sy ANL, Lam TPW, Khoo US. Subcutaneous panniculitislike T-cell
lymphoma appearing as a breast mass: a difficult and challenging case
appearing at an unusual site. J Ultrasound Med. 2005
Oct;24(10):1453--60.

10. Lee HJ, Im JG, Goo JM, Kim KW, Choi BI, Chang KH, et al. Peripheral
T-Cell Lymphoma: Spectrum of Imaging Findings with Clinical and
Pathologic Features. RadioGraphics {[}Internet{]}. 2003 Jan {[}cited
2022 Sep 9{]};23(1):7--26.

11. Kim JS, Jeong YJ, Sohn MH, Jeong HJ, Lim ST, Kim DW, et al.
Usefulness of F-18 FDG PET/CT in subcutaneous panniculitis-like T cell
lymphoma: disease extent and treatment response evaluation. Radiol
Oncol. 2012 Dec;46(4):279--83.

12. Jiang M, Zhao L, Zheng J, Zhang J, Chen P, Zhou W. Report of Eleven
Patients of Subcutaneous Panniculitis-Like T-Cell Lymphoma:
Clinicopathologic Features, 18F-FDG PET/CT Findings and Outcome. Front
Oncol {[}Internet{]}. 2021 Jul 1 {[}cited 2022 Sep 9{]};11:650822.

13. Nagai K, Nakano N, Iwai T, Iwai A, Tauchi H, Ohshima K, et al.
Pediatric subcutaneous panniculitis-like T-cell lymphoma with favorable
result by immunosuppressive therapy: a report of two cases. Pediatr
Hematol Oncol. 2014 Sep;31(6):528--33.

14. Mellgren K, Attarbaschi A, Abla O, Alexander S, Bomken S, Bubanska
E, et al. Non-anaplastic peripheral T cell lymphoma in children and
adolescents-an international review of 143 cases. Ann Hematol. 2016
Aug;95(8):1295--305.

\emph{Figures \& Legends}

Figure 1: Ultrasound of the left breast (a) shows diffuse inflammatory
changes predominantly affecting the subcutaneous soft tissue. No
definite mass or focal lesion noted. Axial FS-T2W MR image (b) shows
marked and diffuse hyperintensity and inflammatory changes of the left
breast predominantly involving the subcutaneous soft tissue. Repeat MRI
with contrast (c) after 2 weeks demonstrates mild interval progression
of the disease with prominent subcutaneous enhancement and enhancing
left axillary lymph nodes. No focal mass noted. Histology revealed
adipocytes rimmed by mildly enlarged lymphoid cells with irregular and
hyperchromatic nuclei (d). Karyorrhexis and histiocytes containing
nuclear debris in background. Mitotic figures are evident. Hematoxylin
and eosin stain, X200 (e): CD8 staining highlights the atypical lymphoid
cells rimming the adipocytes. Immunohistochemistry for CD8, X40

\textbf{Hosted file}

\verb`image1.emf`  available at \url{https://authorea.com/users/563471/articles/610673-subcutaneous-panniculitis-like-t-cell-lymphoma-of-the-breast-in-an-adolescent-female-an-uncommon-presentation}

Figure-2: Pre-treatment whole-body FDG-PET/CT (a,b,c) reveals
asymmetrical increased activity mostly affecting the subcutaneous soft
tissue of the left breast and axilla with hypermetabolic axillary lymph
nodes (black arrows in a,b). Some patchy soft tissue activity also noted
along the medial aspect of the right breast (yellow arrow in a).
Follow-up whole-body FDG-PET/CT (d,e,f) reveals significantly decreased
activity in the subcutaneous soft tissue of the left breast and axillary
lymph nodes (black arrows in d,e). There is near complete resolution of
the activity in the right breast.

\textbf{Hosted file}

\verb`image2.emf`  available at \url{https://authorea.com/users/563471/articles/610673-subcutaneous-panniculitis-like-t-cell-lymphoma-of-the-breast-in-an-adolescent-female-an-uncommon-presentation}

\selectlanguage{english}
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