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\begin{document}

\title{CD30 POSITIVE NON-LEUKEMIC VARIANT OF ADULT T-CELL LEUKEMIA/LYMPHOMA,
HTLV-1 ASSOCIATED}



\author[1]{Mark Podberezin}%
\author[2]{Aliyah Sohani}%
\affil[1]{Lahey Hospital and Medical Center}%
\affil[2]{Massachusetts General Hospital}%


\vspace{-1em}



  
  \date{June 15, 2024}


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\begin{abstract}
We present a case of non-leukemic (lymphomatous) variant of HTLV-1
associated adult T-cell leukemia/lymphoma in a young woman. Tumor
demonstrated strong and diffuse CD30 and PD-1 expression which is very
unusual finding in this entity. Very good clinical response was obtained
with brentuximab-containing treatment regimen.%
\end{abstract}%



\sloppy


CD30 POSITIVE LYMPHOMATOUS (NON-LEUKEMIC) VARIANT OF ADULT T-CELL
LEUKEMIA/LYMPHOMA, HTLV-1 ASSOCIATED

Mark Podberezin\textsuperscript{1} and Aliyah R.
Sohani\textsuperscript{2}

\textsuperscript{1}Department of Anatomic Pathology, Lahey Hospital and
Medical Center, Burlington, MA; \textsuperscript{2}Department of
Pathology, Massachusetts General Hospital, Boston, MA

Corresponding author: Mark Podberezin. Lahey Hospital and Medical
Center, Pathology and Laboratory Medicine 41 Burlington Mall Rd
Burlington, MA, USA 01805-0001 Phone: (781)7441353

e-mail address: mark.podberezin@lahey.org

A 38-year-old previously healthy woman of Haitian origin presented with
splenomegaly and extensive lymphadenopathy involving cervical,
supraclavicular, axillary, mediastinal, hilar, para-esophageal,
para-aortic, mesenteric and inguinal lymph nodes.~ The largest lymph
node measured 2.9 cm in size and PET-CT scan showed maximum SUV of
approximately 32 mSv. No skin lesions were identified. Serum calcium was
normal. Peripheral blood counts were within normal range and no
circulating abnormal lymphoid cells were seen.

The patient underwent a biopsy of a cervical lymph node. The lymph node
architecture was effaced by an atypical infiltrate of large pleomorphic
lymphoid cells with moderate eosinophilic cytoplasm, irregular nuclei,
coarse to vesicular chromatin and occasional prominent nucleoli (Images
1 and 2) amid a background of rare small lymphocytes and histiocytes.

By immunohistochemistry, neoplastic cells were positive for CD3, CD4,
CD25, and negative for CD7 (Image 3), positive for CD2, CD5, and Bcl-2
(not shown). In addition, tumor cells were strongly positive for CD30
and PD1 (Image 4), CD8, CD10, CD20, Bcl-6, ALK-1, granzyme B and
CXCL-13. Neoplastic cells showed 60\% Ki67 proliferation index. CD21
highlighted rare small residual follicular dendritic cell meshworks.
Immunohistochemical stains for CD68 and CD138 stained admixed
histiocytes and plasma cells, respectively. Flow cytometry showed an
abnormal T-cell population with expression of CD4, CD2, CD5, moderate
CD3, and lack of CD7. Serologic tests showed anti-human T-cell leukemia
virus (HTLV)-1/2 antibodies with subsequent Western blot confirmation of
HTLV-1 infection.~In this context, the histopathologic and
immunophenotypic findings were consistent with adult T-cell
leukemia/lymphoma (ATLL), HTLV-1 associated.

Staging bone marrow evaluation did not demonstrate involvement by
lymphoma. Evaluation of cerebrospinal fluid showed no abnormal cells by
cytology or flow cytometry. The patient began treatment with
brentuximab, cyclophosphamide, adriamycin, vincristine, etoposide and
prednisone (BvCHEP) with intrathecal methotrexate with significant
improvement in adenopathy after one cycle. Treatment is planned for a
total of four cycles followed by allogenic stem cell transplant.

HTLV-1 retrovirus has been present since ancient times {[}1{]}. Its
prevalence is very low (\textless{}0.1\%) in the general population but
exceeds 1\% in certain areas of Caribbean, Pacific and Africa {[}2{]}.
HTLV-1 has a particularly high tropism for CD4 lymphocytes. Via binding
of HTLV-1 envelope surface proteins to CD4 surface receptors and
subsequent fusion with a target cell, viral RNA is delivered into the
cytoplasm, converted by reverse transcriptase into double-stranded DNA
which, in turn, is shuttled into the nucleus and is incorporated into
the T-cell genome as provirus, which can be detected by quantitative PCR
in peripheral blood mononuclear cells {[}3{]}.

The major difference between HIV and HTLV-1 is the fact that the latter
stimulates mitosis of target CD4 T-cells rather than viral replication
{[}2{]}. That is why, in contrast to HIV infection, patients with HTLV-1
infection have normal or high, rather than low, CD4 counts. In addition,
viral transmission between persons occurs through infected cell transfer
and not by cell-free virus. Major mechanisms of infectivity are
breast-feeding, blood transfusion and sexual transmission {[}3{]}. It
has been estimated that in HTLV1-endemic areas, 15-25\% of children of
infected mothers are also infected by the virus {[}4{]}. Major
diagnostic essays of HTLV-1 infection include initial serum
enzyme-linked immunosorbent assay-based screening test, with subsequent
confirmation by Western blot.

All HTLV-1 related disorders are broadly classified into neoplastic,
inflammatory and infectious. Neoplastic HTLV-1 associated disorder is
represented by ATLL, and examples of infectious and inflammatory HTLV-1
related entities include, but are not limited to, tropical spastic
paraparesis (also known as HTLV-1 associated myelopathy), dermatitis,
arthritis, uveitis and myositis.

The 2017 WHO Classification of Tumours of Haematopoietic and Lymphoid
Tissues separates four clinical variants of ATLL: smoldering, chronic,
acute and lymphomatous {[}5,6{]}. Recently, extranodal primary cutaneous
variant of ATLL has been described {[}5{]}. In contrast to most
described cases of ATLL, our patient presented with isolated
lymphadenopathy, without involvement of peripheral blood, bone marrow or
skin. Therefore, it is best classified as the lymphomatous type of ATLL.

Strong and diffuse expression of CD30, as seen in our case, is an
unusual finding in ATLL. However, Takeshita et al described expression
of CD30 in 21 of 91 Japanese patients with ATLL {[}7{]}. Like our case,
patients in their study presented with lymphomatous variant of ATLL,
with only rare cases showing leukemic disease. As a non-specific
activation marker, CD30 may be expressed by a number of non-Hodgkin
lymphoma (NHL) subtypes including ATLL, which should be considered in
the differential diagnosis of CD30-positive lymphoproliferative
disorders. Moreover, the availability of brentuximab vedotin, a targeted
anti-CD30 monoclonal antibody-based therapy, mandates assessment of CD30
expression in T-cell NHL. Also observed in our case was PD-1 expression
by tumor cells, a feature that may provide a rationale for immune
checkpoint inhibitor treatment, which to date has shown variable results
in phase 2 trials of ATLL {[}8,9{]}.

\emph{Key clinical message} : Non-leukemic variant of HTLV-1 associated
adult T-cell leukemia lymphoma (ATLL) is a rare variant, and herein we
describe a case with strong and diffuse positivity of neoplastic cells
for CD30. Even though ATLL is aggressive entity with poor prognosis, in
our case, there was very good clinical response achieved with
Brentuximab-containing regimen. Therefore, HTLV-1 associated ATLL can be
included in the differential diagnostic approach of CD30-positive
lymphoproliferative disorders.

\emph{Author contribution statement:} Both authors (M.P. and A.S.)
equally contributed to manuscript preparation and submission.

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\item
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