Spontaneous Regression of Primary Thyroid Lymphoma: Two Rarities at the Same Time
Francisco ILLÁN-GAMBÍN1, Pablo MANRESA-MANRESA2, Estefanía RODRÍGUEZ-ALEO3, Ignacio ARANDA-LÓPEZ1
1Department of Pathology, University General Hospital of Alicante, ALICANTE, SPAIN
2Department of Hematology, University General Hospital of Alicante, ALICANTE, SPAIN
3Nursing Department, University General Hospital of Alicante, ALICANTE, SPAIN
Keywords: Lymphoma, Thyroid neoplasms, Spontaneous neoplasm regression, PD-L1
Primary thyroid lymphomas are pretty uncommon, and constitute about 5% of the neoplasms of this organ. Spontaneous tumor regression
is defined as the total or partial disappearance of a tumor as proven by microscope without treatment or under inadequate treatment. It is
estimated to happen in one out of 60,000-100,000 cases. We present a case of primary thyroid lymphoma with spontaneous regression after
diagnostic puncture and corroborated with hemithyroidectomy at four months. The patient died after twenty-six months of follow-up because
of endocarditis and there was no relapse at any time.
Primary thyroid lymphomas constitute about 5% of all
primary thyroid neoplasms and around 2% of extranodal
lymphomas. The prototype patient is a woman (up to 4
times more frequent than in men) around the sixth decade
of life. As regards histological subtypes, diffuse large
B-cell lymphoma and marginal zone lymphoma are the
most common (1). Spontaneous tumor regression (STR)
is defined as the total or partial disappearance of a tumor
validated microscopically without treatment or under
inadequate treatment. It is estimated to happen in one
out of 60,000-100,000 cases, although it probably appears
more often. It is difficult to study STR because of its low
prevalence. In addition, regressive changes are usually does
not reported when they are presented in a partial way (2).
Among solid tumors, melanoma seems to have STR most
frequently. Regarding lymphomas, low grade types are
more likely to regress but it is exceptional in those of high
A 63-year-old woman had been followed-up for the last
year because of subclinical hypothyroidism. She had been
surgically treated for tonsils in childhood and for her
gallbladder due to stones, and for aortic-mitral double
replacement 20 years ago secondary to endocarditis.
Because of the last one, she was anticoagulated with
warfarin. Suddenly, she noted a nodule in the front of the neck that became visible, without any other symptoms. The
ultrasound showed a right thyroid lobe replaced by a solid
and heterogeneous tumor of 4.4 x 3.4 cm with ill-defined
contours and abnormal vascularization with Doppler
). The patient underwent an extraclinical fineneedle
aspiration (FNA) which displayed lymphocytes
and large blastic-type cellularity with dispersed epithelial
elements suggestive of thyroiditis but lymphoproliferative
disorder could not be ruled out. Then she was referred to
our hospital for a needle biopsy (16G).
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|Figure 1: Right thyroid ultrasonography.
The tests were performed two months apart.
(upper: first ultrasonography). Note the
The tissue showed a diffuse infiltrate of lymphoid large
cells with lobulated nuclei, marked nucleoli, frequent
mitosis and apoptosis. With broad-spectrum cytokeratins
(CK AE1-AE3), nests of dispersed thyroid epithelium were
identified. After immunohistochemical evaluation, the
lymphoid nature of the neoplasm (CD45 +) was confirmed.
It showed germinal center lymphocyte B-cell differentiation
(CD20 +, CD10 +, BCL-2 +, MUM1 +, BCL-6 - and c-MYC
-) and it had accompanying T lymphocytes (CD3 +). The
proliferation index with Ki67 was greater than 80% (Figure
2A-F) and the immunoglobulin chain rearrangement
analysis showed IgH clonality. Staining for PD-L1 (clone
22C3) showed low expression in atypical lymphoid cells
(1-2%). As there was no adenopathy or alterations on the
imaging tests (including PET/CT), the diagnosis of primary
thyroid diffuse large B-cell lymphoma, germinal center
B-cell subtype (WHO, 2017) was made.
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|Figure 2: Primary thyroid diffuse large B-cell lymphoma. A) Lymphoid large cells with lobulated nuclei, marked nucleoli, frequent mitosis
and apoptosis are present (H&E; x 600). B) Nests of thyroid epithelium are identified (CKAE1/AE3; x100). C) Cells show positivity
for CD20 (IHC; x200). D) Cells show positivity for CD10 (IHC; x200). E) High proliferation (Ki67; x100). F) There is accompanying
T-lymphocytes (CD3; x200).
At the time of staging, two months after the first FNA, a
clinical decrease of tumor dimensions was observed so a
new ultrasound was performed. It showed a nodule with the
same characteristics as the previous one that now measured
2.5 cm (Figure 1B). A new biopsy was taken showing
thyroid follicles, fibrous tracts and non-atypical small
lymphocytes. There was also plasma cells and macrophages
with no apparent neoplastic population. The absence of
tumor cells was confirmed immunohistochemically (CD20
-, CYCLIN D1 -, CD5 - and CD10 -) with Ki67 less than
1% and a marked increase in the T-cell population (Figure
3A-D). Residual lymphocytes showed no morphological
or immunohistochemical characteristics suggestive of any
other type of lymphoma.
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|Figure 3: A) Thyroid with small lymphocytes infiltration (H&E; x100). B) Cells are CD20 negative (IHC; x100).
C) Cells are CD3 positive (IHC; x100). D) Ki67 is less than 1% (IHC; x100).
Finally, a hemithyroidectomy was carried out five months
after the first FNA. The right hemithyroid had regular
weight and dimensions and whitish fibrous bands without
defined solid nodules. After microscopic examination, we
showed thyroid follicles of variable sizes with lymphoid
clusters and germinal centers as well as a fibrotic area with
lymphocytes like scar tissue (Figure 4A-C). No neoplastic
population was demonstrated in any slide and the genetic
rearrangement did not indicate clonality.
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|Figure 4: A-B) Thyroid showing features of thyroiditis with follicles of variable sizes and lymphoid clusters forming
germinal centers (H&E; x20, H&E; x200). C) In some areas, fibrotic bands with lymphocytes are present (H&E; x100).
The patient passed away twenty-six months after the
diagnosis due to endocarditis and there was no clinical
or radiological relapse. In addition, she had undergone a
PET/CT scan prior to her death which only showed the infectious cardiac focus without uptake elsewhere. No new
treatments were added at any time.
The first cause of lymphoid infiltrate in the thyroid is
autoimmune thyroiditis. Currently, it has become the
most frequent autoimmune disease and the first cause
of hypothyroidism (4). Microscopically it displays
lymphocytic infiltration of the stroma with large germinal
centers and thyroid follicles. The last ones can show variable
degrees of activity with regenerative, oncocytic or atrophic
changes (5). Among its complications are lympho- and
myeloproliferative disorders, both systemic and primary
in the gland, whose relative risk will increase 80 times (6)
as well as papillary carcinomas (7). Regarding lymphomas
developing on thyroiditis, the most frequent type is
marginal zone. It shows a heterogeneous infiltrate with
atypical small lymphocytes, centrocytes, immunoblasts
and plasma cells that can colonize germinal centers (1).
Meanwhile, STR is a striking entity described by TC
Everson and WH Cole in the second half of the 20th
century. In their work the definition of STR was proposed
for the first time as well as a review of cases published until
then (8). Most hypotheses trying to explain it have been in
agreement afterwards. Most advocate a massive release of
heteroantigens after aggression on the tumor that would
enhance the immune response against it. In this way, local
or systemic infections, vaccination, contusion, biopsy and even exposure to X-radiation could be triggers. Therefore,
the most accepted theory to explain STR attributes is that
the immune system plays the main role (9, 10). In the
current case, we believe that FNA started the T-lymphocyte
response that we found on needle biopsy and the surgical
specimen and resulted in complete STR.
With reference to non-Hodgkin’s lymphomas, some
studies estimate 10-20% of STR in low-grade types but it
is anecdotal in high-grade lymphomas. Immunoregulation
has been considered important because regression of
the lymphoma appears to a greater or lesser degree if
T-mediated response is promoted on animal or in vitro
models (after virus infection, addition of anti-idiotypic
antibodies, cytokines, etc.) (11). There is also an association
between the immunity status and the presence of some lymphoproliferative disorders as in AIDS patients, posttransplant
lymphoproliferative disorders, and Epstein-Barr
virus-associated lymphomas (11, 12).
Furthermore, it is known that thyroid lymphomas often
show IgH clonality, especially in those from lymphocytic
thyroiditis (1), although its prognostic role is unknown
nowadays. We found only one published case of thyroid
lymphoma regression in which immunoglobulin chain
restriction was studied. This patient had IgH clonality and
recurrence was earlier (13) as opposed to our case.
Finally, regarding PD-L1, its expression in lymphomas
seems to inhibit T-cell activity against the tumor (14). In
the present case, the low expression of PD-L1 could be
a favorable point for the immune response against the
CONFLICT of INTEREST
The authors declare no conflict of interest.
The authors have not received funding from any
1) Chan JKC, Burke JS, Ferry JA, Wotherspoon A. Primary thyroid
lymphoma. In: Lloyd RV, Osamura RY, Klöppel G, Rosai J,
editors. WHO Classification of Tumours of Endocrine Organs.
Lyon: WHO PRESS; 2017. 137-8.
2) Ghatalia P, Morgan CJ, Sonpavde G. Meta-analysis of regression
of advanced solid tumors in patients receiving placebo or no anticancer
therapy in prospective trials. Crit Rev Oncol Hematol.
3) Potts DA, Fromm JR, Gopal AK, Cassaday RD. Spontaneous
remission of an untreated, MYC and BCL-2 coexpressing, highgrade
B-cell lymphoma: A case report and literature review. Case
Rep Hematol. 2017;2017:2676254.
4) Caturegli P, De Remigis A, Chuang K, Dembele M, Iwama A,
Iwama S. Hashimoto’s thyroiditis: Celebrating the centennial
through the lens of the Johns Hopkins Hospital surgical
pathology records. Thyroid. 2013;23: 142-50.
5) Rosai J, Tallini G. Thyroid gland. In: Juan Rosai, editor. Rosai
and Ackerman’s surgical pathology. 10th ed. Edinburgh: Elsevier.
6) Chai YJ, Hong JH, Koo DH, Yu HW, Lee JH, Kwon H, Kim
SJ, Choi JY, Lee KE. Clinicopathological characteristics and
treatment outcomes of 38 cases of primary thyroid lymphoma: A
multicenter study. Ann Surg Treat Res. 2015;89: 295-9.
7) Lai X, Xia Y, Zhang B, Li J, Jiang Y. A meta-analysis of
Hashimoto’s thyroiditis and papillary thyroid carcinoma risk.
Oncotarget. 2017;8: 62414-24.
8) Cole WH, Everson TC. Spontaneous regression of cancer:
Preliminary report. Ann Surg. 1956;144: 366-83.
9) Jessy T. Immunity over inability: The spontaneous regression of
cancer. J Nat Sci Biol Med. 2011;2: 43-9.
10) Sasaki J, Kurihara H, Nakano Y, Kotani K, Tame E, Sasaki A.
Apparent spontaneous regression of malignant neoplasms after
radiography: Report of four cases. Int J Surg Case Rep. 2016;25:
11) Drobyski WR, Qazi R. Spontaneous regression in non-Hodgkin’s
lymphoma: Clinical and pathogenetic considerations. Am J
12) Lim DH, Rhee JY, Park KW. Stage IV advanced diffuse large
B-cell lymphoma in human immunodeficiency virus infection
with achieving cure by using highly active antiretroviral therapy
alone: A case report. Int J STD AIDS. 2017;28: 932-6.
13) Uohashi A, Imoto S, Matsui T, Murayama T, Okimura Y, Chihara
K, Ohbayashi C, Itoh H. Spontaneous regression of diffuse largecell
lymphoma associated with Hashimoto’s thyroiditis. Am J
Hematol. 1996;53: 201-2.
14) Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ,
Timmerman JM. Programmed death ligand 1 is expressed by
non-Hodgkin lymphomas and inhibits the activity of tumorassociated
T cells. Clin Cancer Res. 2011;17: 4232-44.