CASE REPORT The Korean Journal of
Endocrine Surgery
ISSN 1598-1703 (Print) ISSN 2287-6782 (Online) Korean J Endocr Surg 2016;16:51-55 http://dx.doi.org/10.16956/kaes.2016.16.2.51
The Primary Thyroid Lymphoma Treated by Surgery without Chemotherapy: Two Cases Reports Eun Hwa Park, Ji Hoon Kim, Jae Young Kwak, Cheon Soo Park, Jin Ho Kwak Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
Primary thyroid lymphoma (PTL) is a relatively rare disease, accounting for less than 0.5∼ 5% of all thyroid malignancies. We encountered two cases of a primary thyroid lymphoma with Hashimoto`s thyroiditis; one in a 63-year-old man and the other in a 79-year-old woman. The first case was a mucosa-associated lymphoid tissue lymphoma, and the other was a diffuse large B-cell lymphoma. Both patients underwent surgery and radiotherapy after being diagnosed using fine-needle aspiration cytology (FNAC). Both patients recovered well with no recurrence throughout the study period. The role of the surgeon in the treatment and diagnosis of thyroid lymphoma has been reduced due to the development of FNAC and combination therapy with chemotherapy and radiotherapy. On the other hand, surgery can be an effective treatment option for PTL confined to the thyroid, for achieving a definitive diagnosis, and in the treatment of patients with an airway obstruction. Key Words: Thyroid gland, Lymphoma, Large B-Cell, Thyroidectomy
INTRODUCTION
Received March 31, 2016, Revised May 30, 2016, Accepted June 3, 2016 Correspondence: Jin Ho Kwak Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, 38, Bangdong-gil, Sacheon-myeon, Gangneung 25440, Korea Tel: ＋82-33-610-3224 Fax: ＋82-33-641-8120 E-mail:
[email protected]
a rapidly growing thyroid mass and may experience hoarseness, stridor, or, less commonly, dysphagia. The rate
Primary thyroid lymphoma (PTL) is a rare malignancy,
of thyroid enlargement tends to be more rapid in patients
accounting for 0.5% to 5% of all thyroid malignancy cases
with PTL than in those with other thyroid malignancies,
and 2.5% to 7% of all extranodal lymphoma cases.(1,2) In
with the exception of anaplastic thyroid carcinoma.(2) The
South Korea, with the increasing detection rate of papillary
treatment of thyroid lymphoma remains controversial.
thyroid microcarcinoma, its prevalence has decreased to
Initially, surgery was used extensively for the treatment of
0.1% of all thyroid malignancy cases.(1) It usually occurs
PTL. But surgery-alone was recently found to show limited
among middle-aged to elderly women, with a peak
effects. More recently, the combination therapy with
incidence in women in their late sixties. The most common
radiotherapy and chemotherapy has been more frequently
histological type of PTL is diffuse large B cell lymphoma
recommended. From the surgeon’s perspective, we report
(DLBCL), followed by mucosa-associated lymphoid tissue
two cases of PTL treated with surgery.
(MALT) lymphoma.(3) Hashimoto’s thyroiditis is associated with development of PTL. The relative risk of developing thyroid lymphoma in patients with Hashimoto`s thyroiditis has been reported to be 40 to 80 times greater than that in
CASE REPORTS 1. Case 1
the general population.(4,5) Patients typically present with
A 63-year-old man visited our department because of a
Copyright © 2016 Korean Association of Thyroid and Endocrine Surgeons; KATES. All Rights Reserved. cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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bilateral thyroid nodule that was incidentally discovered
thyroidectomy. The surgical finding was a 2.5×2.0×2.0
during his routine health examinations. No abnormalities
cm ill-defined mass in the right lobe, adhesion to the
were found in the patient’s medical and familial history. He
sternothyroid muscle, but no lymphadenopathy was
complained of a recent aggravation of hoarseness and a
observed around the thyroid gland. In the histopatho-
palpable neck mass. On physical examination, he had a
logical examination, the tumor was 2.5×2.1×2.0 cm in
firm 2 cm mass was palpable on the right side of the thyroid
size, and the cut surface was solid and grayish white, with
gland. Thyroid function test was euthyroid status, thyro-
focal hemorrhage. A diagnosis of malignant lymphoma,
globulin antibody and anti-microsomal Ab were both
MALT type with Hashimoto’s thyroiditis, was histopatholo-
measured higher than normal range. Other laboratory
gically confirmed (Fig. 1C). Immunohistochemical staining
results were within the normal limits. Thyroid ultrasono-
indicated that the proliferating atypical lymphoid cells
graphy revealed two hypoechoic nodules; a right thyroid
were positive for CD20 and bcl2 (Fig. 1D, E), but negative
hypoechoic nodule about 1.8×1.9×2.3 cm in size and a left
for CD3 and CD5. The Ki67 labeling index was 30%. Ann
thyroid hypoechoic nodule 1.6×2.0×2.2 cm in size (Fig. 1A).
Arbor stage was IE, and the International Prognostic Index
No lymphadenopathy was observed around the thyroid
score was 1 (age). The patient underwent only external
gland. According to the result of a fine needle aspiration
beam radiotherapy but did not receive chemotherapy. The
biopsy, the left thyroid nodule was diagnosed chronic
total irradiation dose was 3,000 cGy during 20 times. He was
lymphocytic thyroiditis and the right thyroid nodule was
followed up annually neck computer tomography and
diagnosed with suspicion of low-grade B-cell lymphoma
positron emission tomography every few years. He has
(Fig. 1B). The result of two months follow-up cytology for
developed no local recurrence or systemic metastasis for
right thyroid nodule was a possibility of lymphoma cannot
114 months.
be completely excluded. We determined the surgery for accurate histologic diagnosis. The patient underwent total
Fig. 1. A 63-year-old man who was diagnosed with mucosa-associated lymphoid tissue (MALT) lymphoma. (A) Thyroid ultrasonography shows about 1.8×1.9×2.3 cm sized hypoehoic mass with ill-defined margin in right thyroid gland. (B) Thyroid fine needle aspiration cytology smear (Pap stain ×400) shows diffuse polymorphous lymphoid cells of medium sized cleaved, large round, and small round nuclei. (C) histopathology of thyroid (H&E, ×200). Lymphoid cells invade and expand the thyroid follicles, forming the lymphoepithelial lesion. The lymphoid cell have cleaved centrocyte-like nuclei or small round nuclei. (D) Immumohistochemical stain show CD20＋ and (E) bcl2＋.
Eun Hwa Park, et al: Primary Thyroid Lymphoma Treated by Surgery Without Chemotherapy
2. Case 2
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53
Unfortunately, her dyspnea rapidly worsened and respiratory failure was imminent. We determined total thyroi-
A 79-year-old woman who had been previously healthy
dectomy for the treatment of respiratory distress, and
was referred to our institution with a palpable neck mass
conventional surgical incision was performed. Both lobes
and respiratory discomfort. She complained of recent
of the thyroid were enlarged, and a soft, white tumor had
aggravation of dyspnea, odynophagia, and a palpable neck
replaced the normal thyroid tissue. Grossly, we observed
mass. She denied B symptoms (fever, night sweat and
extracapsular, recurrent laryngeal nerve, and tracheal
weight loss). On physical examination, a firm anterior neck
invasion. Histopathological examination results confirmed
mass about 10 cm in size was palpable and a wheezing
DLBCL (Fig. 2D). Immunohistochemical staining results
sound was audible. The result of an initial thyroid function
were positive for CD20, BCL-2, and BCL-6 but negative for
test indicated a euthyroid status, and the results of other
CD 3, CD5, and CD 10. The Ki67 labeling index was 99%.
laboratory examinations were non-specific, except a
We performed a staging work up after the surgery.
slightly elevated serum lactate dehydrogenase (LDH) level
Thereby, we determined the Ann Arbor stage as 1E and the
(230 U/L). The O2 saturation level in room air was 97%.
International Prognostic Index score as 2 (age and LDH
Computer tomography (CT) and ultrasonography revealed
level). Positron emission tomography revealed only a focal
a 10×7 cm heterogeneous mass, which narrowed the
hyper-metabolic lesion in the right thyroid surgical bed
tracheal diameter and even extended to the thoracic inlet
(Fig. 2C). Treatment of choice was combined radiation and
(Fig. 2A, B). At first, we suspected anaplastic thyroid cancer
chemotherapy, but the patient and her family refused
and performed fine needle aspiration biopsy accordingly.
chemotherapy because of her old age and general condition
However, the result showed lymphocytic thyroiditis.
weakness. Sequential radiotherapy was recommended
Fig. 2. A 79-year-old woman who was diagnosed with diffuse large B-cell lymphoma. (A) Preoperative CT scan shows a diffusedly enlarged thyroid gland with (B) narrowed tracheal diameter and extended to the thoracic inlet. (C) Postoperative positron emission tomography shows only a focal hyper-metabolic lesion in the right thyroid surgical bed. (D) Microscopically, there is a diffuse infiltration of large monomorphic lymphoid cells in the thyroid (H&E, ×200).
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after multidisciplinary discussions. A total irradiation dose
It has been postulated that the chronic antigenic stimu-
of 5,040 cGy was administered in 28 equal fractions
lation and proliferation of lymphoid tissue in Hashimoto’s
without any complications. She achieved complete
thyroiditis created cells that are susceptible to neoplastic
remission at the 1 month and 13 month follow-up physical
transformation, which lead to PTL.(1,2) The incidence of
examination, and neck and chest CT scans every three
Hashimoto’s thyroiditis in patients with PTL has been
months revealed no evidence of recurrence.
reported in previous studies to be 27% to 100%. Hwang et al. reported that 57% of patients with PTL have clinical or
DISCUSSION
histological evidence of Hashimoto’s thyroiditis.(1) Although MALT lymphoma were more frequently associated with
Primary thyroid lymphoma (PTL) is a rare malignancy.
Hashimoto’s thyroiditis, the incidence of Hashimoto’s
However, the distinction of thyroid lymphoma from other
thyroiditis did not significantly differ between DLBCL and
thyroid malignancies, especially anaplastic thyroid carci-
MALT lymphoma. In terms of cellular immunophenotype,
noma, is crucial in relation to management strategies. PTL is
thyroid DLBCLs are CD20 positive, and most are B-cell
more common in women (3:1 predominance) between the
lymphoma (Bcl)-6 positive. Approximately half are Bcl-2
age of 50 and 80 years, with a peak incidence in their late
positive, and most are negative for CD5, CD10, and
60s.(3) Patients typically present with a rapidly growing
CD23.(8) MALT lymphomas have an immunoglobulin light
thyroid mass and may experience hoarseness, stridor, or less
chain, and are CD20 and Bcl-2 positive, but are negative for
commonly, dysphagia. The rate of thyroid enlargement tends
CD5, CD10, and CD23.(2) In addition, the Ki-67 labeling
to be more rapid in patients with PTL than in those with other
index of the cell proliferation maker was measured to be
thyroid malignancies, with the exception of anaplastic
30% in MALT lymphoma and 99% in DLBCL, in our patients.
thyroid carcinoma.(2) Class B symptoms of fever, night sweat
Fine needle aspiration cytology (FNAC) is an excellent
and weight loss are less common. Most patients are euthyroid.
diagnostic tool for thyroid disorders, as it is minimally
Our cases had no B symptoms and euthyroid status.
invasive and can be performed in the clinic. Unfortunately,
PTL can be classified according to histological subtype.
the FNAC test has a low reported accuracy for the diagnosis
The most common PTL subtypes are diffuse large B-cell
of PTL because of the pathological similarities between
lymphoma (DLBCL), marginal zone B-cell lymphoma of the
thyroid lymphoma and Hashimoto’s thyroiditis. In one
mucosa-associated lymphoid tissue (MALT) lymphoma,
report,(1) PTL was accurately diagnosed by using the FNAC
and follicular lymphoma.(6) Hodgkin’s lymphoma, small
test in only 59% of patients, who were later proven to have
lymphocytic lymphoma and T-cell lymphoma are
the malignancy. For both of our patients, the FNAC test
relatively rare subtypes.(6) DLBCL is the most common
result indicated lymphocytic thyroiditis. The lack of marked
subtype (70%) and most aggressive, with almost 60% of
nuclear atypia in PTL makes the cytological differentiation
cases diagnosed with dissemination, whereas MALT
between the lymphoid infiltrate of Hashimoto’s thyroiditis
lymphomas (6∼27%) have a relatively indolent course.(7)
and lymphoma difficult.(1,9) Takano et al.(9) proposed a
In some patients, DLBCL may arise from a preexisting
new diagnostic method to detect B-cell monoclonality that
MALT lymphoma, and a component of MALT lymphoma
combines digestion with restriction enzymes and vecto-
can be seen in one-third of thyroid DLBCL cases.(2)
rette polymerase chain reaction for aspiration biopsy-
PTL typically develops in patients with a background of
nucleic acid diagnosis of thyroid malignant lymphoma.
Hashimoto’s thyroiditis. Because the normal thyroid gland
Despite advances in FNAC testing and adjunctive techni-
has no native lymphoid tissue, thyroid lymphoma is
ques, differentiation of PTL from Hashimoto’s thyroiditis
thought to develop from lymphocytic tissue acquired
by using the FNAC test may be difficult, especially when
during the course of chronic inflammation or an auto-
the thyroid lymphoma is of a low-glade histology such as
immune process such as that in Hashimoto’s thyroiditis.(1)
MALT lymphoma. Therefore, confirmatory procedures such
Eun Hwa Park, et al: Primary Thyroid Lymphoma Treated by Surgery Without Chemotherapy
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55
as tissue biopsy or surgery are strongly recommended when
and respiratory distress was improved after surgery. No
PTL is suspected in the FNAC test. Open surgical biopsy is still
postoperative complications such as nerve injury, bleeding,
required in many cases, particularly when treatment
and permanent hypocalcemia, were observed.
strategies differ according to histological subtype (MALT vs.
In summary, FNAC and other current diagnostic tools,
diffuse or mixed large cell) or the diagnosis is still in question.
including flow cytometry and immunostaining, serve as
Ann Arbor stage classification is most widely used for
first-line diagnostic tools for thyroid lymphoma. Since the
PTL, with up to 90% of patients presenting with early stage
development of FNAC and the use of radiotherapy and
disease.(3) Five year after diagnosis, disease-specific
chemotherapy, the need for surgery has decreased. How-
survival was 86% for stage IE (confined to the thyroid gland),
ever, there remains an important role for surgery in the
81% for stage IIE (confined to the thyroid gland and
management of thyroid lymphoma, especially for achiev-
regional lymph node), and 64% for stage IIIE (involved the
ing a definitive diagnosis when the FNAC test result is
lymph nodes on both sides of the diaphragm)/IVE
unclear, and in the treatment of patients with a rapidly
(systemic dissemination).(3) Fortunately, our patients had
growing mass and airway obstruction.
stage IE disease, In case 1 (MALT lymphoma) and Case 2 (DLBCLs), no recurrence was observed during 10 years and 13 months follow-up, respectively. Appropriate treatment for patients with PTL depends on histological subtype, as the tumor grade and the efficacy of each treatment modality vary by subtype. The current treatment modalities for thyroid lymphoma include radiotherapy, chemotherapy, surgery, and combined chemoradiotherapy.(2) The role of surgery in PTL is still controversial and its use for diagnosis and treatment has decreased over time. Graff-Baker et al.(3) reported that the use of surgery for PTL has declined from 81% of patients in 1973 to 1987 to 61% in 1997 to 2005 in the United States. More recently, surgical removal has been shown to have a limited benefit. Meanwhile, non-surgical treatment, including chemotherapy and/or radiotherapy, depending on histological subtype, has become the mainstay of treatment in recent years.(6) However, surgery is generally used for palliation or diagnosis of thyroid lymphoma. When the mass rapidly grows, compressive symptoms such as dysphagia, dyspnea, and pain can be managed with a prompt debulking surgery. A study by Sippel et al.(10) that included 27 patients with thyroid lymphoma and significant airway obstruction who underwent palliative surgery showed good long term result (overall 5-year survival, 77%) and low operative morbidity. Furthermore, surgery and/or radiotherapy improved the survival of patients with stage I and II MALT, DLBCL, and small lymphocytic histology.(3) In our cases, surgery was successful
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