Case Report
Preoperative Diagnosis of Primary Malt Lymphoma in Graves’ Disease
Di Cesare T1*, Morano C1, Cilurso F1, Neri T1, Scarinci A1, Misischi I2, Taccogna S3, Guglielmi R2, Papini E2 and Liverani A1
1Department of General Surgery, Ospedale Regina Apostolorum, Italy
2Department of Endocrinology and Metabolism, Ospedale Regina Apostolorum, Italy
3Department of Pathology, Ospedale Regina Apostolorum, Italy
*Corresponding author: Tatiana Di Cesare, Department of General Surgery, Ospedale Regina Apostolorum, Via S. Francesco 50, 00041 Albano Laziale RM, Italy
Published: 09 Oct, 2018
Cite this article as: Di Cesare T, Morano C, Cilurso F,
Neri T, Scarinci A, Misischi I, et al.
Preoperative Diagnosis of Primary Malt
Lymphoma in Graves’ Disease. Clin
Surg. 2018; 3: 2146.
Abstract
Rare case of MALT lymphoma in Graves’ disease with preoperative diagnosis through the use of
ultrasound (US), Fine-Needle Aspiration Citology (FNAC) and Core-Needle Biopsy (CNB). US
showed solid hypoechoic nodule in hyperfunctioning goiter. FNAC diagnosed autoimmune chronic
thyroiditis (Bethesda II), and then US-guided CNB resulted in a diagnosis of Lymphoproliferative
Parenchymal Disorder (LPD). Immunohistochemistry was the clue for diagnosis of MALT
lymphoma. CNB should be used as method of choice for differential diagnosis of thyroid LPDs.
Keywords: Core-needle biopsy; Lymphoma; MALT, Graves’ disease; Thyroid surgery
Abbreviations
MALT: Mucosa-Associated Lymphoid Tissue; US: Ultrasound Examination; FNA: Fine Needle Aspiration; FNAC: Fine Needle Aspiration Cytology; CNB: Core-needle Biopsy; AID: Autoimmune Disorders; PTL: Primary Thyroid Lymphoma; TSH: Thyroid Stimulating Hormone; FT3: Free Triiodothyronine; FT4: Free Thyroxine; TPOAb: Anti-thyroperoxidase Antibodies; ATA GL: ATA Thyroid US Classification; FLUS: Lesion of Undetermined Significance; N.V.: Normal Value
Introduction
Non-gastric MALT lymphoma may arise from various anatomical sites, most commonly from
the parotid and salivary glands (18% to 26%), eyes (7% to 14%), head and neck (11%), lung (8%),
and breast (2% to 3%) [1]. The occurrence of Primary Thyroid Lymphoma (PTL) is also reported as
increased in patients with Autoimmune Disorders (AID), usually in a background of Hashimoto's
thyroiditis. So, even if an uncommon disease, PTL should be considered in the differential diagnosis
of thyroid lesions because its preoperative identification may result in a complete cure with surgical
treatment [2].
Aim of our clinical report is to describe an unusual case of PTL in Graves’ disease and the
efficacy of its preoperative diagnosis with the use of thyroid Ultrasound examination (US), USguided
Fine Needle Aspiration biopsy (FNA) and Core-Needle Biopsy (CNB).
Case Presentation
A 43-year-old Italian woman was diagnosed as affected with Graves’ disease in December 2015.
Increased uptake at radioisotope thyroid scan, elevated serum thyroid hormones and suppressed
Thyroid Stimulating Hormone (TSH) confirmed the clinical diagnosis. Medical treatment was well
tolerated and provided a fairly good control of hyperthyroidism for several months.
In June 2017 the patient was referred to the thyroid outpatient clinic of our hospital for a clinical
control. She was assuming methimazole (20 mg/day) and did not complain of local pressure or
general symptoms. Her serum thyroid profile was as follows: TSH 0.01 (n. v. 0.20-4.0 μIU/mL), Free
Triiodothyronine (FT3) 2.91 (n.v. 1.71-3.71 pg/mL), free thyroxine (FT4) 5.79 pg/mL (n.v. 0.70-
1.48), anti-thyroperoxidase antibodies (TPOAb) 81U/mL (n.v. <35 U/mL). Serum determinations
were performed with chemiluminescent assays (IMMULITE® 2000 immunoassay system, Siemens
S.p.A. - Milano). Physical examination demonstrated a diffuse and slightly irregular enlargement of
the gland without palpable nodules or regional lymph nodes. Ultrasonography (US) demonstrated
a diffuse enlargement of the thyroid gland with a slightly hypoechoic appearance and increased
vascular signals. A solid, deeply hypoechoic, nodule (21 mm × 1 mm
× 16 mm in size) with fairly regular margins and no intranodular
hyperechoic spot was present in the right lobe (Figure 1A). No
pathologic lymph node was observed.
On the basis of current Thyroid Guidelines recommendations [3],
was performed an US-guided FNA that provided a cytological sample
characterized by scanty colloid, rare thyrocytes, numerous small and
medium-size lymphocytes, and a few plasmocytoid lymphocytes
(Figure 1B). As the sample was consistent with, but not conclusively
diagnostic for, autoimmune chronic thyroiditis (Bethesda II
cytological classification), after one month was performed an USguided
CNB that resulted in a micro histological sample diagnostic
for a lymphoproliferative parenchymal process (Figure 1C).
Immunohistochemical assessment revealed positivity for CD43,
CD3, CD5, and CD4 with rare CD8 elements. B immunophenotyped
(CD20+) elements were present, as well (Figure 1D).
In October 2017 the patient underwent total thyroidectomy.
Preoperative US staging and intraoperatory evaluation of the neck
excluded the presence of regional lymphadenopathy. Pathologic
examination of the gland confirmed the presence of a 2 cm tumor
consisting of polymorphic lymphoid population CD20+ CD3- (CD3+
in T component) CD5-. These findings, the destruction of normal
thyroid gland architecture induced by lymphoid cell, and the results
of flow-cytometry (kappa light-chain restriction) confirmed the
diagnosis of Malt Lymphoma. No infiltration of the thyroid capsule
was observed and the remaining glandular parenchyma showed a
diffuse nodular hyperplasia (Table I). PET/TC scan and endoscopic
examination of the digestive tract excluded further localizations of
the disease. So, according to the Ann Arbor staging system [1], the
conclusive diagnosis was stage I Malt Lymphoma (disease localized to
the thyroid gland). After surgical therapy the patient was started on
levothyroxine 100 mcg/day with no need of additional treatments. No
evidence of relapse was present at the six-month follow-up.
Figure 1
Figure 1
A solid, hypoechoic, nodule (21 mm × 14 mm × 16 mm in size)
with fairly regular margins and no intranodular hyperechoic spot was present
in the right lobe.
Figure 1B: Aspiration smear showing monomorphic population of atypical
lymphoid cells infiltrating and growing into the thyroid follicle (MGG × 200).
Figure 1C: Core needle biopsy showed heavy lymphoid infiltrate with
intraepithelial lymphocytosis and involvement of the thyroid epithelium by the
neoplastic lymphocytes. Shown is a focus of intraluminal lymphoma cells,
representing a so-called ‘MALT ball’.
Figure 1D: Immunohistochemical findings disclose diffuse positive staining
for CD20 (immunohistochemistry, × 200).
Table 1
Discussion
Thyroid MALT lymphoma is a rare thyroid neoplasia that is
reported to represent about 0.6% of all thyroid tumors and less than
2% of the extranodal lymphomas [1]. Primary thyroid extranodal
marginal zone lymphomas is usually diagnosed in the 5th to 7th
decades of life and almost always arise in the background of chronic
lymphocytic thyroiditis (Hashimoto's thyroiditis). The natural
history of the disease, indeed, is supposed to involve the chronic
stimulation of the gland often associated with autoimmune diseases
and lymphocyte infiltration [4]. Malt lymphoma traditionally
develops after an at least 10-year history of Hashimoto’s thyroiditis
[5]. Large cell lymphoma probably develops from low-grade MALT
malignant lymphoma, advancing a morphological conversion from
chronic lymphocytic thyroiditis to low-grade MALT lymphoma, and
subsequently, to high-grade large-cell lymphoma [6].
The preoperative diagnosis of thyroid lymphoma is generally
difficult in the absence of clinical signs or symptoms and the present
case is of interest because it showed a few unusual features:
• The association of MALT lymphoma with Graves’ disease
is exceedingly rare and nearly all the reported cases concern Japanese
patients [7]. Our patient is the second case, after a former French
patient [8], diagnosed in Europe. So in patients with Graves’ disease
thyroid lymphoma is rarely considered in the differential diagnosis of
thyroid nodules.
• Thyroid lymphoma is frequently difficult to differentiate
from chronic thyroiditis at US examination. Nodular lymphoma has
a profound hypoechoic pattern and the border between lymphoma
and non-lymphomatous tissue is usually lobulated or irregular [9].
In our case, conversely, lymphoma had a distinct and regular border
between the tumour and the non-lymphomatous thyroid gland and
its internal echoes were of uniform low intensity without evidence
of necrosis or calcifications. These findings were consistent with an
intermediate risk thyroid nodule at the ATA Thyroid US Classification
and were not predictive of a lymphomatous lesion [3].
• FNA has an established role in the management of thyroid
nodules and goiters but it is often inconclusive in the differential
diagnosis between thyroiditis and lymphoma [3,10]. In this case
cytological findings were not diagnostic and the nature of the nodule
was reliably established only with the micro-histological sample
obtained with US-guided core-needle biopsy. Cutting-needle biopsy
is rarely employed as the initial diagnostic procedure, because of the
risk of bleeding and cervical pain. However, a repeat biopsy that offers
a microhistologic sample may provide a more reliable information
about thyroid architecture in lesions that are read as follicular lesion
of undetermined significance (Bethesda Class III and IV), and in case
of suspected lymphoma [11].
The importance of a timely preoperative diagnosis is relevant
in the management of thyroid lymphoma. About 80% of patients
with primary thyroid lymphoma have an I or II stage of the disease
[12]. Prospective randomized trials have shown an advantage in
combining chemotherapy with radiotherapy for patients with stage I
and II intermediate- and high-grade NHL, while Mucosa-Associated
Lymphoid Tissue (MALT) lymphomas demonstrate a more indolent
behavior. The stage IE of this subgroup responds well to total
thyroidectomy or radiation with a complete response rate of more
than 90% [13]. Surgery is recommended as the primary therapy in the
management of localized MALT lymphomas and in stage IE cure is
attained with a complete thyroid resection with minimal morbidity
and low risk of recurrence [14].
Conclusion
This is the second European case of primary thyroid MALT lymphoma in patients with Graves’ disease. Clinical and US examination and US-guided FNA did not provide a conclusive diagnosis of the nodular lesion within the hyperfunctioning thyroid gland. Immunohistochemical staining and flow-cytometry on a micro histological sample obtained with US-guided core-needle biopsy were the clue for the differential diagnosis. This procedure allowed an appropriate surgical indication and an effective treatment for the patient preventing the risk of diagnostic delay and the probability of a second definitive surgery.
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