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(A). Preoperative CT scan shows a diffusedly enlarged thyroid gland with (B) narrowed tra- cheal diameter and extended to the thoracic inlet. (C) Pos- toperative ...
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



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



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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