The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 4 1206-1209
Copyright © 1999 by The Endocrine Society
Maltoma of the Thyroid in a Man with Hashimoto’s Thyroiditis
Robert Wozniak,
Lee Beckwith,
Howard Ratech and
Martin I. Surks
Departments of Medicine (R.W., M.I.S.) and Pathology (L.B., H.R.),
Montefiore Medical Center and Albert Einstein College of Medicine,
Bronx, New York 10467
 |
Abstract
|
|---|
We report the case of a 42-yr-old man with primary thyroid lymphoma
arising from mucosa-associated lymphoid tissue (MALT-lymphoma,
maltoma). The patient underwent a hemithyroidectomy for a growing mass
in the right lobe of the thyroid while being treated with l-thyroxine
for Hashimoto’s thyroiditis. The clinical diagnosis of Hashimoto’s
disease was confirmed by aspiration biopsy of the mass during the
course of L-thyroxine treatment. Postoperatively, histology
showed atypical lymphoproliferative infiltrates suspicious of low-grade
non-Hodgkin’s lymphoma of mucosa-associated lymphoid tissue-type,
coexisting with a reactive process typical of chronic lymphocytic
thyroiditis. Immunophenotyping showed a mixed B- and T-lymphocyte
population, which was nondiagnostic. However, Southern blot analysis
revealed a clonal rearrangement of the Ig heavy chain gene. This case
demonstrates that cytology or histology may not distinguish between
reactive or low-grade lymphomatous thyroid processes. The use of
molecular technique was essential to prove clonality and the presence
of lymphoma.
|
Introduction
|
|---|
Primary thyroid lymphomas constitute up to 5% of all thyroid
malignancies and can be divided into non-Hodgkin’s lymphomas (NHL) of
B and T cell type, as well as Hodgkin’s lymphomas. Mucosa-associated
lymphoid tissue (MALT) lymphomas are a relatively recently recognized
subset of B cell NHL, and they are listed as extranodal marginal zone
lymphomas according to the revised European-American lymphoma
classification (1). Clinically, they are characterized by an indolent
course and better prognosis than non-MALT lymphomas. Their most common
location is the mucosa of the gastrointestinal tract. However, they may
also occur in lungs, salivary glands, skin, and other sites, including
the thyroid (2, 3, 4). MALT-lymphomas are thought to develop from acquired
lymphocytic tissue during the course of a chronic inflammatory or an
autoimmune process. In the thyroid, a gland normally devoid of
lymphocytic tissue, chronic autoimmune thyroiditis (Hashimoto’s
disease) has been associated with an increased risk of lymphoma,
including MALT-type (5). The coexistence of reactive and neoplastic
processes in the thyroid may cause significant difficulty in diagnosing
maltoma using cytology or histology. This has led to the use of
immunohistochemistry, flow cytometry, and molecular techniques
(Southern blotting, PCR) to confirm or exclude the diagnosis. Although
clinical information about thyroid maltomas and the criteria for their
diagnosis are well known to oncologists and pathologists, they have not
been well described in endocrine literature and are not widely known by
consulting thyroidologists.
|
Case Report
|
|---|
A 39-yr-old man was referred to an endocrinologist (M. I.
Surks) for evaluation of a lump in the neck. 131I thyroid
scintigraphy, ordered by the primary care physician, showed a 24-h
thyroid uptake of 32% and a homogenous (but asymmetric) distribution
of isotope on thyroid scan, the right lobe containing more isotope than
the left. The patient reported a recent 5-kg weight gain and difficulty
sleeping. He denied fatigue, cold intolerance, hoarseness, dysphagia,
or dyspnea. On examination, blood pressure was 110/78 mm Hg, and
resting pulse was 76 beats per minute. His weight was 92 kg, and his
height was 180 cm. Upon neck examination, a firm, nontender thyroid
gland was felt, approximately twice normal size, with the right lobe
slightly larger than the left. Serum T4 was 6.4 µg/dL
(normal, 5–12), and serum TSH was 4.8 mU/L (normal, 0.4–4.6).
Antithyroglobulin antibodies were positive (1:100), and antimicrosomal
antibodies were not detected. A diagnosis of Hashimoto’s thyroiditis
was made, and the patient was started on 0.1 mg of
[scapl-thyroxine per day. On follow-up visit, 5 months after
l-thyroxine was started, the thyroid was not palpable. Serum
T4 was 11.1 µg/dL, and serum TSH was 0.82 mU/L. At the
12-month follow-up visit, the thyroid was palpable, firm, but not
enlarged. Serum T4 was 10.1 µg/dL, and serum TSH was 0.92
mU/L. Two years later, while the patient remained on the same dose of
l-thyroxine, a firm 3.5-cm nodule was detected in the right lobe of the
thyroid. His serum free T4 was 1.4 ng/dL (normal,
0.8–2.0), serum TSH was 1.82 mU/L, serum thyroglobulin was 289 ng/ml
(normal, 2–60), and antimicrosomal antibodies remained undetectable. A
fine needle aspiration of the nodule was performed, and it revealed a
mixed population of lymphoid cells, mainly small round and small
cleaved lymphocytes, with numerous plasma cells and rare clusters of
atypical Hürthle cells, a pattern consistent with Hashimoto’s
thyroiditis. The dose of l-thyroxine was then raised to 0.125 mg per
day. Six months later, the right thyroid mass had increased to about 5
cm in diameter. There was no lymphadenopathy. In view of the rapid
growth of the mass, the patient was referred for surgery, and a right
hemithyroidectomy was performed. The surgical specimen contained a
5 x 4 x 3.5-cm nodule with focal areas of hemorrhage, and
serial sections were taken for histologic evaluation.
|
Methods and Results
|
|---|
Histology
Microscopic examination was performed on paraffin-embedded
sections stained with hematoxylin and eosin. The thyroid parenchyma was
diffusely replaced by a dense, atypical lymphoproliferative infiltrate,
composed of monocytoid lymphocytes with small, slightly irregular or
centrocyte-like nuclear contours, condensed nuclear chromatin,
inconspicuous nucleoli, and abundant pale cytoplasm (Fig. 1
). Sheets of plasma cells were present.
The lymphoepithelial lesions were rare (Fig. 2). Reactive lymphoid follicles, with
well-circumscribed germinal centers and mantle zones, were scattered
within the gland. The marginal zones were greatly expanded by
monocytoid cells. However, small- to medium-size lymphocytes
surrounding normal thyroid epithelium, oxyphilic cell metaplasia, and
reactive follicles without cell invasion, were also evident. These
histologic features raised suspicion of low-grade MALT thyroid
lymphoma, in the presence of a reactive process, probably Hashimoto’s
disease.
View larger version (128K):
[in this window]
[in a new window]
|
Figure 1. Atypical (monocytoid) lymphocytes with
abundant pale cytoplasm and minor population of plasmacytoid
lymphocytes. Hematoxylin and eosin, high power magnification. F,
Atrophic thyroid follicle.
|
|
View larger version (117K):
[in this window]
[in a new window]
|
Figure 2. Few residual atrophic thyroid follicles,
stained positively by anticytokeratin antibody, widely separated by
small atypical lymphocytes. Immunoperoxidase stain, medium power
magnification. L, Lymphoepithelial lesion.
|
|
Immunophenotyping
Flow cytometry revealed a polyclonal B cell population: the
/
chain ratio was 1.3:1. Immunohistochemical studies, performed
on formalin-fixed, paraffin-embedded tissue blocks and frozen sections,
with a panel of monoclonal antibodies directed against different
cluster of differentiation (CD) antigens, were
nondiagnostic.
Southern blot analysis of the Ig heavy-chain gene
Genomic DNA was extracted from a thyroid sample and digested with
either HindIII or XbaI restriction endonucleases.
After hybridization to a 32P-labeled Ig heavy chain joining
region (JH) probe, novel bands were detected after digestion with
HindIII and XbaI (Fig. 3). There were only germline
(unrearranged) bands after hybridization to ß T cell receptor gene
(TCRß) probe (data not shown). We interpreted this as evidence of a
clonal Ig heavy chain rearrangement consistent with B cell NHL.
View larger version (135K):
[in this window]
[in a new window]
|
Figure 3. Southern blot analysis of the Ig heavy chain
gene in DNA extracted from thyroid sample. The DNA was hydrolyzed with
the HindIII and XbaI restriction
endonucleases and hybridized to a 32P-labeled Ig heavy
chain joining region (JH) probe. The HindIII and
XbaI digests show novel (rearranged) bands of 13.5 kb
and 5.3 kb, respectively, as indicated (*). The large, unmarked bands
contain the bulk of the genomic DNA (germline bands). Lane M contains a
standard DNA size marker.
|
|
Clinical course
At the time of this report (9 months after surgery), the patient
continues to have an uneventful clinical course. Serum protein
electrophoresis was negative for monoclonal proteins. Computerized
tomography of the neck, chest, abdomen, and pelvis did not show
lymphadenopathy. A bone marrow biopsy was normal. Radiotherapy or
chemotherapy was not used. The patient will be followed at 6-month
intervals.
|
Discussion
|
|---|
The most striking clinical feature in this patient’s presentation
was rapid, nontender enlargement of the thyroid. This is a
characteristic feature of thyroid lymphomas (6). Compressive symptoms,
like hoarseness, dysphagia, or dyspnea, seen in up to 30% of patients,
were absent in our patient. Of note is this patient’s age and sex,
because most thyroid lymphomas, including maltomas, are seen in the
elderly, with a peak incidence in the seventh decade, and the
female/male ratio varies from 4:1 to 8:1 (3, 6). Also, the finding of
low titer of antithyroglobulin antibodies and undetectable antithyroid
microsomal antibodies is unusual in patients with Hashimoto’s disease.
Methods of determination of antithyroid peroxidase antibodies were not
available when the patient was evaluated. The presence of
antithyroglobulin antibodies may have resulted in underestimation of
serum thyroglobulin.
Since introduction of the concept of MALT-type lymphomas by Isaacson
and Wright in 1983 (7), various extranodal locations (including
thyroid) have been described. Histologically, thyroid maltomas are
characterized by the presence of atypical lymphoid cells, which
originate within the marginal zone of the lymphoid follicles and can
extend into the interfollicular space and/or into the germinal centers
(follicular colonization) (8). As seen in our patient, other cell types
(including monocytoid and plasma cells), as well as histologic features
typical of Hashimoto’s thyroiditis (such as small lymphocytes,
Hürthle cell metaplasia, and intact reactive follicles) may also
be present. The abundance of reactive components in the presence of a
low-grade neoplastic process may obscure the diagnosis of malignant
lymphoma, when evaluation is limited to conventional cytologic and
histologic techniques. Furthermore, lymphoepithelial lesions (the
characteristic, but not pathognomonic finding for maltoma), which arise
from invasion of marginal zone cells into the thyroid follicular
epithelium, were rare in our patient.
To confirm the suspicion of malignancy after examination of the thyroid
histology, we performed immunophenotypic studies. Flow cytometry did
not reveal the presence of clonality, probably because the monoclonal
lymphoma cells were trapped in the thyroid stroma, whereas the reactive
lymphoid follicles were more easily disaggregated. However,
immunohistochemistry was helpful in excluding follicular lymphoma,
which generally exhibits a cluster of differentiation 10 marker.
Molecular studies of Ig gene rearrangement were required. The Southern
blot technique has emerged as a reliable and specific method for
identification of lymphocytic clone(s) and diagnosis of lymphoma in
thyroid specimens (9, 10). Neoplastic B cell clones can be detected by
the presence of a rearranged sequence of DNA within the JH segment of
the Ig heavy chain gene, which changes the size of a DNA fragment(s)
cut by the restriction enzyme, and ultimately yields a novel band, with
respect to the germline configuration. In contrast, the reactive
process of Hashimoto’s thyroiditis is characterized by a polyclonal
proliferation of lymphocytes, with each individual clone contributing
less than 1% of cells to the sample, which is the sensitivity limit
for a detection of a positive band by Southern blot analysis. However,
the finding of monoclonal antithyroglobulin antibodies (11) and T cell
receptor gene rearrangement in patients with Hashimoto’s disease (12)
indicates that a clonal restriction may be occasionally present in the
reactive process. In recent years, PCR-based assays have offered some
advantages over the Southern blot technique, including higher
sensitivity and requirement for a smaller amount of tissue (allowing,
for example, the detection of gene rearrangements in thyroid aspirates)
(13). The specificity of PCR-based assays, however, is relatively low
(65–80%).
The optimal treatment and follow-up of patients with thyroid maltomas
remain controversial at present. Retrospective reports suggest an
indolent behavior and excellent clinical prognosis for this subset of
thyroid lymphomas. However, recently published observations, in
patients with other extranodal MALT-lymphomas, have documented the
dissemination of disease in about one-third of cases at the time of
diagnosis (14). A potential for relapse after local treatment is also
known (14, 15). In general, the choice of treatment modality depends on
the stage of disease: surgery and/or radiotherapy is used in localized
disease, supplemented with chemotherapy in disseminated cases. There
are no published guidelines for follow-up of patients with MALT-type
lymphomas, e.g. a need for bone marrow biopsy or periodical
gastroscopy after the treatment of local disease.
In conclusion, this case illustrates that: 1) low-grade NHL of
MALT-type arises in the setting of chronic autoimmune thyroiditis; 2)
cytology and histology may be insufficient to diagnose MALT-lymphoma of
the thyroid; 3) molecular techniques may be necessary to distinguish
between MALT-lymphoma and reactive process; and 4) the nature of
follow-up care and long-term results of treatment of patients with
thyroid maltoma are not fully established.
|
References
|
|---|
-
Harris NL, Jaffe ES, Stein H, et al. 1994 A Revised European-American classification of lymphoid neoplasms:
a proposal from the International Lymphoma Study Group. Blood. 84:1361–1392.[Free Full Text]
-
Thieblemont C, Berger F, Coiffier B. 1995 Mucosa-associated lymphoid tissue lymphomas. Curr Opin Oncol. 7:415–420.[Medline]
-
Pedersen RK, Pedersen NT. 1996 Primary
non-Hodgkin’s lymphoma of the thyroid gland: a population based study. Histopathology. 28:25–32.[CrossRef][Medline]
-
Sasai K, Yamabe H, Tsutsui K, et al. 1996 Non-Hodgkin’s lymphoma of the thyroid. A clinical study of twenty-two
cases. Acta Oncol. 35:457–462.[Medline]
-
Hyjek E, Isaacson DM. 1988 Primary B cell lymphoma
of the thyroid and its relationship to Hashimoto’s thyroiditis. Hum
Pathol. 19:1315–1326.[Medline]
-
Anscombe AM, Wright DH. 1985 Primary malignant
lymphoma of the thyroid-a tumour of mucosa-associated lymphoid tissue:
review of seventy-six cases. Histopathology. 9:81–97.[Medline]
-
Isaacson PG, Wright DH. 1983 Malignant lymphoma of
mucosa-associated lymphoid tissue. A distinctive type of B cell
lymphoma. Cancer. 52:1410–1416.[CrossRef][Medline]
-
Isaacson PG, Andoulakis-Papachristou A, Diss TC, Pan L,
Wright DH. 1992 Follicular colonization in thyroid lymphoma. Am J Pathol. 41:43–52.
-
Cleary ML, Chao J, Wornke R, Sklar J. 1984 Immunoglobulin gene rearrangement as a diagnostic criterion of B cell
lymphoma. Proc Natl Acad Sci USA. 81:593–597.[Abstract/Free Full Text]
-
Matsuzuka F, Fukata S, Kuma K, Miayauchi A, Kakudo K,
Sugawara M. 1998 Gene rearrangement of immunoglobulin as a marker
of thyroid lymphoma. World J Surg. 22:558–561.[CrossRef][Medline]
-
Nye L, De Carvalho LP, Roitt IM. 1981 An
investigation of the clonality of human autoimmune thyroglobulin
antibodies and their light chains. Clin Exp Immunol. 46:161–170.[Medline]
-
Katzin WE, Fishleder AJ, Tubbs RR. 1989 Investigation of the clonality of lymphocytes in Hashimoto’s
thyroiditis using immunoglobulin and T cell receptor gene probes. Clin
Immunol Immunopathol. 51:264–274.[CrossRef][Medline]
-
Lovchik J, Lane MA, Clark DP. 1997 Polymerase chain
reaction-based detection of B cell clonality in the fine needle
aspiration biopsy of a thyroid mucosa-associated lymphoid tissue (MALT)
lymphoma. Hum Pathol. 28:989–992.[CrossRef][Medline]
-
Thieblemont C, Bastion Y, Berger F, et al. 1997 Mucosa-associated lymphoid tissue gastrointestinal and
nongastrointestinal lymphoma behavior: analysis of 108 patients. J
Clin Oncol. 15:1624–1630.[Abstract]
-
Pyke CM, Grant CS, Habermann TM, et al. 1992 Non-Hodgkin’s lymphoma of the thyroid: is more than biopsy necessary? World J Surg. 16:604–610.[CrossRef][Medline]
Top
Abstract
Introduction
