Received: 5 July 2020 | Accepted: 18 September 2020

DOI: 10.1111/pin.13031

CASE REPORT

The first reported case of primary extranodal counterpart

of follicular T‐cell lymphoma of submandibular gland

Reiji Muto1,2 | Naoki Uemura3 | Norikazu Mitsui4 | Fumiko Arakawa2 | Takanori Negishi5 |
Hiroaki Miyoshi | Koichi Ohshima2 | Toshihiko Murayama1
1
Department of Pathology, National Hospital Organization, Kumamoto Medical Center, Japan
2
Department of Pathology, Kurume University School of Medicine, Japan
3
Department of Otolaryngology, National Hospital Organization, Kumamoto Medical Center, Kumamoto, Japan
4
Department of Hematology, National Hospital Organization, Kumamoto Medical Center, Kumamoto, Japan
5
Department of Radiology, National Hospital Organization, Kumamoto medical center, Kumamoto, Japan

Abbreviations:
FTCL, follicular T‐cell lymphoma; CXCL13,
chemokine (C‐X‐C motif) ligand 13; FDC,
follicular dendritic cell; PCR, polymerase chain
reaction; PTCL–NOS, peripheral T‐cell
lymphoma, not‐otherwise‐specified; HIV,
Human immunodeficiency virus; HTLV‐1,
Human T‐cell leukemia virus type 1; FFPE,
formalin‐fixed paraffin‐embeded; PD‐1,
programmed cell death protein 1; EBER,
Epstein–Barr virus encoded small RNA; AITL,
angioimmunoblastic T‐cell lymphoma; LEL,
lymphoepithelial lesion
This is the first reported case of follicular T‐cell lymphoma (FTCL) that primarily
developed in the extranodal site of the right submandibular gland. An 86‐year‐old
man was detected with a right cervical mass suspected to be malignant lym-
phoma during his physical examination. Imaging studies revealed that the mass
was a submandibular gland tumor. The tumor was excised for diagnosis and
treatment. Pathologically, the tumor was composed of densely aggregated lym-
phocytes with a follicular growth pattern. The immunohistochemical investigation
showed that the lymphoma cells expressed CD3, CD4, programmed cell death
protein 1, BCL6, chemokine (C‐X‐C motif) ligand 13, and BCL2. Staining of the
follicular dendritic cell revealed its meshwork structure limited in the germinal
center. Monoclonal rearrangement of the T‐cell receptor was detected using
polymerase chain reaction. These findings are consistent with the characteristics
of FTCL. Here, we describe the first reported case of extranodal counterpart of
FTCL of the submandibular gland. Accumulation and investigation of such ex-
tranodal cases is essential.

Correspondence
KEYWORDS
Reiji Muto, 1‐5, Kumamotojyo Ninomaru,
Kumamoto, Kumamoto 860‐0008, Japan. extranodal, follicular T‐cell lymphoma, malignant lymphoma, submandibular gland, T‐cell
Email: sugarless610@hotmail.com lymphoma

INTRODUCTION (WHO) classifications of 2008. However, it is described as an

Follicular T‐cell lymphoma (FTCL) is a rare subtype of
malignant lymphoma. Earlier, it was considered as a variant
of the peripheral T‐cell lymphoma, not‐otherwise‐specified
(PTCL–NOS) according to the World Health Organization
independent disease concept in the revised WHO classi-
fications of 2017. FTCL is a subtype derived from follicular
helper T‐cells and is characterized by its follicular growth
pattern.1 While its exact frequency is unknown, FTCL is
estimated to account for less than 1% of all the T‐cell

Pathology International. 2020;1–5. wileyonlinelibrary.com/journal/pin © 2020 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd | 1
2 R. Muto et al.
lymphomas.1 FTCL develops predominantly in lymph nodes;
however, in its advanced stage, involvement of skin, bone
marrow, peripheral blood, and pleural effusion have also
been reported. To date, no cases have been reported of
FTCL primarily arising in extranodal sites. Here, we delineate
the first reported case of extranodal counterpart of FTCL
primarily arising in the submandibular gland.
CLINICAL SUMMARY
An 86‐year‐old man with diabetes and dyslipidemia was
detected with a right cervical mass by his previous doctor
during a physical examination and was referred to our hos-
pital for scrutiny. The patient presented with no subjective
symptoms.
On physical examination, a small mass was palpable in
the right submandibular area; it was elastic hard, painless,
and movable. Ultrasonography revealed that the mass was
submandibular gland tumor rather than lymphadenopathy.
The tumor was rich in blood flow with a low‐echo irregular
inside and posterior echo enhancement, indicating the pos-
sibility of malignancy. Computed tomography showed a
slightly lobulated tumor 25.6 × 18.2 × 25.6 mm in size. No
lymphadenopathy was found. The patient had a total white
cell count of 9100 /μL with 70.8% neutrophils and 23.7%
lymphocytes. No atypical lymphocytes were found in the
peripheral blood. Slight increases in the levels of C‐reactive
Figure 1 (a) Macroscopically, a grayish‐white solid mass was observed in the submandibular gland. (b) Microscopically, the medium‐sized
atypical lymphocytes proliferated with follicular growth pattern. (c) Proliferation of high endothelial venules was not observed.
© 2020 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd
protein (CRP; 0.03 mg/dL), IgG (1872 mg/dL), and sIL‐2R
(555 U/mL) were observed. The levels of other im-
munoglobulin fractions, lactate dehydrogenase, hemoglobin,
platelets, total protein, and albumin were within the normal
ranges. The patient was positive for hepatitis C virus and
negative for human immunodeficiency virus and human
T‐cell leukemia virus type 1. Surgical resection of the tumor
was performed to confirm the diagnosis. There was no sign
of tumor adhesion to the surrounding tissue during the
operation.
The postoperative course was uneventful, and the patient
was discharged three days after the surgery. Two months
after the surgery, there was no relapse or symptoms without
radiation and chemotherapy. The tumor was considered as
stage I because no residual disease was found in the post-
operative positron emission tomography–computed tomog-
raphy.
PATHOLOGICAL FINDINGS
Macroscopically, a grayish‐white solid mass was observed in
the submandibular gland (Fig. 1a). Microscopically, the mass
consisted of a dense aggregation of medium‐sized, atypical
lymphocytes that had replaced the existing salivary gland.
The lymphocytes proliferated with follicular growth pattern on
hematoxylin and eosin (HE) staining (Fig. 1b). There was
neither any proliferation of the high endothelial venules
(Fig. 1c) nor a lymphoepithelial lesion.
 3

The immunohistochemical examination revealed that the
atypical lymphocytes were immunoreactive for CD3 (poly-
clonal, DAKO JAPAN, Kyoto, Japan; Fig. 2a), CD4 (4B12,
Leica Biosystems, Tokyo, Japan), programmed cell death
protein 1 (PD‐1; NAT105, Abcam, London, UK; Fig. 2d),
BCL6 (PG‐B6p, DAKO JAPAN; Fig. 2e), chemokine (C‐X‐C
motif) ligand 13 (CXCL13; 53610, R&D Systems, Minneap-
olis, MN, USA), and BCL2 (124, DAKO JAPAN; Fig. 2f).
Conversely, the lymphocytes were negative for CD20 (L26,
DAKO JAPAN; Fig. 2b), CD8 (CD8/144B, DAKO JAPAN),
and CD10 (56C6, Nichirei Biosciences Inc., Tokyo, Japan;
Fig. 2g). CD23 (1B12, Leica Biosystems) and follicular
dendritic cell (FDC; CNA42, DAKO JAPAN; Fig. 2c) staining
revealed FDC meshwork structure limited in the germinal
center. There were no Epstein–Barr virus encoded small
RNA (EBER) positive cells around the lesion. The procedure
for in situ hybridization for EBER was described in detail
previously.2 Flow cytometry and G‐banding was not
performed because lymphoma was not suspected at the time
of surgery. The monoclonality of T‐cell receptor (TCR)‐
gamma was confirmed (Fig. 3); DNA was extracted from
the formalin‐fixed, paraffin‐embedded tissue, and poly-
merase chain reaction (PCR) was performed in accordance
with the method previously described.3 Although mutations
in the exon 2 of RHOA gene, including the G17V mutation,
were not detected by Sanger sequencing, our findings were
consistent with the characteristics of extranodal counterpart
of FTCL.
DISCUSSION
Follicular T‐cell lymphoma was first described in the 2008
WHO classification as a variant of PTCL–NOS with a
follicular growth pattern. It was later identified as an
independent disease in the 2017 WHO classification, in which

Figure 2 Immunohistochemical study. Lymphoma cells were positive for CD3 (a) and negative for CD20 (b). Follicular dendtiric cell (FDC)
staining revealed FDC meshwork structure limited in the germinal center (c). CD3‐positive cells were positive for PD‐1 (d) and BCL6 (e) and
negative for BCL2 (f) and CD10 (g).

© 2020 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd
4 R. Muto et al.
Figure 3 The monoclonality of TCR‐gamma was confirmed by PCR.
FTCL is a lymph node‐based lymphoma of the follicular
helper T‐cells.1 Histologically, FTCL is characterized by
two features: (i) a predominantly follicular growth pattern
and (ii) a lack of extrafollicular expansion of the follicular
dendritic cells (FDCs) and proliferation of the high endo-
thelial venules characteristic of angioimmunoblastic T‐cell
lymphoma (AITL).1
Pathogenesis of FTCL is still unclear, but t(5;9)(q33;q22)
was observed in approximately 20% of the FTCLs.4,5 A re-
cent study revealed that RHOA mutation was detected in
only 56.3% (9 out of 16 cases) of FTCL, using deep se-
quencing and Sanger sequencing.6 Thus, although no
RHOA mutation was detected in our case, it does not affect
our diagnosis of FTCL. Clinically, FTCL has been recognized
to have features in common with AITL, including multiple
lymphadenopathy (89%), stage III–IV (65%), B symptoms
(26%), and skin rash (26%).4
Follicular T‐cell lymphoma is predominantly a disease of
the lymph nodes, but as the disease progresses, extranodal
sites may be involved, including bone marrow, peripheral
blood, pleural effusion, liver, and spleen.1,4,7 Lymphomas
derived from follicular helper T‐cells include AITL, nodal
PTCL with T follicular helper phenotype, and primary cuta-
neous CD4+ small/medium T‐cell lymphoproliferative dis-
order other than FTCL.
Angioimmunoblastic T‐cell lymphoma is the second most
common type of PTCL accounting for approximately 18.5%
of the T‐cell lymphomas and the most common lymphoma of
the follicular helper T‐cell origin.8 AITL is a clinically ag-
gressive systemic disease. Similar to FTCL, AITL frequently
presents advanced stage disease, systemic lymphadenop-
athy, and skin eruptions.9 Histologically, AITL is
© 2020 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd
characterized by the deformation of existing lymph node
structure, proliferation of high endothelial venules, and ex-
pansion of FDC meshwork. In contrast, FTCL lacks pro-
liferation of high endothelial venules and extrafollicular
dendritic cells.1
Nodal PTCL with T follicular phenotype is a new category
in the WHO classification. It shows similar histological find-
ings to PTCL–NOS; however, the immunohistochemical
study exhibits follicular helper cell markers, including CD4,
PD‐1, CD10, BCL6, CXCL13, and ICOS. Although the exact
frequency of the disease is unknown, Basha et al. reported
that approximately 40% of the cases diagnosed as
PTCL–NOS could be re‐classified as nodal PTCL, using the
these markers.10 Proliferation with mainly follicular growth
pattern is characteristic to FTCL, and this is its point of dif-
ferentiation from PTCL–NOS.1
Primary cutaneous CD4+ small/medium T‐cell lympho-
proliferative disorder is an excellent prognosis lesion, which
often appears as a single skin lesion; its common sites are
the face, neck, and upper trunk.1 Histologically, small to
medium sized lymphocytes proliferate densely in the dermis,
and the T‐cells are positive for CD3 and CD4 and negative
for CD8 and CD30. The PTCL differs from FTCL in that
FTCL proliferates mainly in lymph nodes and grows in a
follicular pattern.
As to the indolent lymphoma of the head and neck region,
primary PTCL–NOS of the thyroid was reported.11 The
postulated normal counterparts were also follicular helper
T‐cells. It developed in the background of autoimmune dis-
ease, including Hashimoto's thyroiditis. Histologically, the
lymphoma displayed a lymphoepithelial lesion (LEL) rather
than follicular growth pattern.11 Clinically, our case is

considered to be an indolent lymphoma, but is different from
the salivary gland counterpart of this tumor.
Here, we presented the first reported case of FTCL that
developed in the salivary gland, and the first reported
case of primary extranodal counterpart of FTCL. Our
histological findings are quite similar to FTCL in the lymph
node, but the clinical features are different: lack of lym-
phadenopathy, stageⅠcase, and no B symptoms and skin
rash. Among the T‐cell lymphomas, it is known that
the prognosis and gene mutation differ between those
with lymph node development and extranodal
development.11,12 Therefore, accumulation and inves-
tigation of such extranodal cases is desired.
ACKNOWLEDGEMENTS
None.
DISCLOSURE STATEMENT
None declared.
AUTHOR CONTRIBUTIONS
RM, TM, HM, and KO designed this study. NU, NM, and
TN acquired the data. RM, TM, HM, and KO evaluated the
pathological and immunohistochemical findings. FA an-
alyzed and interpreted the molecular findings. RM and
HM wrote the main part of the manuscript. NU, NM, FA,
TN, TM, HM, and KO reviewed the draft with critical
comments.
© 2020 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd
5
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