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Endocrine Care |
Service d’Hématologie (C.T., C.D., G.S., B.C.), Service d’Endocrinologie (A.M., X.D., C.M., J.O.), Service d’Anatomie Pathologique et de Cytologie Hématologique (P.F., F.B.), Service de Radioanalyse et Radiopharmacie (Y.B.), and Service de Cytogénétique (E.C.-B.), Centre Hospitalier Lyon-Sud, 69495 Pierre-Bénite, France
Address all correspondence and requests for reprints to: Dr. Catherine Thieblemont, Service d’Hématologie, Center Hospitalier Lyon Sud, Hospices Civils de Lyon-Université Claude Bernard, 69495 Pierre Bénite, France. E-mail: catherine.thieblemont{at}chu-lyon.fr
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Abstract |
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Introduction |
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The thyroid gland contains no native lymphoid tissue. Intrathyroid lymphoid tissue is accrued in various pathological conditions, but more evidently in the course of autoimmune thyroid disease, notably autoimmune thyroiditis (Hashimoto’s thyroiditis) (3, 4). Histologically, this acquired lymphoid tissue bears a close resemblance to mucosa-associated lymphoid tissue (MALT) and can evolve to lymphoma, the so-called MALT lymphoma of generally good prognosis (5, 6). The evolution from Hashimoto’s thyroiditis to MALT lymphoma occurs in 0.5% of the cases and can be difficult to characterize from both the morphological and the clinical point of view. Indeed, MALT lymphoma usually develops after a long period of Hashimoto’s thyroiditis evolution, sometimes as long as 30 yr (7), and the evolution is often characterized by an indolent course that cannot be easily differentiated from the evolution of Hashimoto’s thyroiditis, but transformation from MALT lymphoma to aggressive lymphoma can occur (5, 7, 8, 9) and is thus associated with a poor prognosis.
We retrospectively analyzed a series of 26 patients who presented between 1987–2000 at our department with lymphoma involvement of thyroid gland to characterize the various clinical and functional biological presentations of both thyroid and lymphoma according to the different histological subtypes. We also searched for parameters that may help to diagnose Hashimoto’s thyroiditis evolution to MALT lymphoma. Finally, we analyzed the therapeutic approaches, survival, and the prognostic factors in these patients.
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Materials and Methods |
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Between October 1987 and December 2000, 26 patients with thyroid lymphoma were referred to our department, representing approximately 0.01% of all lymphoma patients seen during this period. Only patients with lymphoma involvement of the thyroid gland at the first presentation were included in this study. Patients with thyroid lymphoma occurring as the result of the relapse or progression of a previous lymphoma were excluded. The term primary designated patients with lymphomateous involvement of the thyroid at diagnosis, the disease being localized or disseminated to nodal or extranodal sites. All of the cases were retrospectively studied to collect complete clinical information and health history of the patients.
Staging procedure
Initial staging procedures included complete physical examination; thyroid ultrasonography; computed tomography of the thorax, abdomen, and pelvis; and bone marrow biopsy. Serum lactic dehydrogenase (LDH), ß2-microglobulin, blood count, and serum protein electrophoresis were systematically tested. Performance status (PS) was evaluated according to the Eastern Cooperative Oncology Group scale (10). Symptoms related to lymphoma, including fever, weight loss of 10% or more, and noctural sweating (B symptoms), were specifically collected. Patients were staged according to the Ann Arbor classification modified by Mussoff (11): stage IE disease corresponds to disease confined to the thyroid, stage IIE corresponds to disease confined to the thyroid gland and the regional lymph nodes on the same side of the diaphragm, stage IIIE corresponds to disease confined to the thyroid and lymph nodes on both sides of the diaphragm and/or spleen; and stage IV corresponds to disease confined corresponds to a disseminated nodal and/or additional extranodal involvement. Localized disease was defined as IE and IIE disease, and disseminated disease as stage IIIE and stage IV.
TSH and antithyroid antibodies levels. Levels of TSH and antithyroid (anti-Tg and antithyroperoxidase) antibodies (Ab) were retrospectively determined in 17 (66%) and 5 (20%) patients, respectively, using RIAs of patient sera collected and frozen at the time of the diagnosis.
Histology, cytology, and cytogenetic analysis
Tissue biopsies were submitted to routine histopathological evaluation, immunohistochemistry, and cytochemistry using a panel of monoclonal Ab (anti-CD3, anti-CD5, anti-CD10, anti-CD19, anti-CD20, anti-CD23, anti-CD30, anti-CD43, anti-CD45, anti-CD79a, surface Ig characterization, and MIB-1) and flow cytometry. The diagnosis of lymphoma was based on the more recent lymphoma classification (REAL) (12). After 1993, tissue cytogenetic studies were systematically performed.
Treatment modalities
Patients were treated according to the stage and histological subtype of the disease. Patients with localized and indolent subtypes of lymphoma (subtypes of MALT lymphoma or small lymphocytic lymphoma) were treated with surgery alone. Patients with disseminated lymphoma were treated with chemotherapy, using either single agent (chlorambucil) for indolent subtypes of lymphoma or multidrug regimens [cyclophosphamide, doxorubicin, vincristin, and prednisone (CHOP) or adriamycin, cyclophosphamide, vincristin, and bleomycin] (13) if adverse prognostic factors such as PS of 2 or more, high LDH level, more than two extranodal locations, and histological aggressivity were present. One patient with aggressive lymphoma newly diagnosed in 2000 received combined treatment with conventional chemotherapy (CHOP) and immunotherapy with monoclonal anti-CD20 antibody (rituximab). Patients with Hodgkin’s disease were treated with classical chemotherapy based on the vincristine, procarbazine, prednisone, doxorubicin, bleomycine, vinblastine regimen (14).
Statistical analysis
Overall survival was defined as the time from diagnosis (first biopsy) to death or last follow-up. Freedom from progression (FFP) survival was defined from the onset of treatment to the date of the first progression or last follow-up. Complete remission was defined as the disappearance of all clinical evidence of lymphoma. Progression was defined as a relapse for patients in complete remission or as the appearance of a new lesion or an increase in the volume of preexisting lesions for patients in partial remission. Actuarial survival curves were calculated using the Kaplan-Meier method, and differences between these parameters were tested for significance with the log-rank test (15, 16). 
2 test was used in univariate analysis to determine significant differences between percentages. P < 0.05 was considered to indicate significant statistical differences. All statistical analyses were performed using Statistica software (version 5, 1997 edition, Statsoft, Torlsa, OK).
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Results |
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The clinical characteristics of the patients are shown in Table 1
. The median follow-up for patients was 4.6 yr (range, 2 months to 6 yr). Twenty-three (86%) patients were female. The median age at diagnosis was 59 yr (range, 30–87 yr). Eighty-seven percent of the patients presented with a rapidly growing nodular goiter (median size, 7.5 cm; range, 2–15 cm), with clinical consequences such as pressure symptoms in the neck or pain and, rarely, dysphagia and/or dyspnea. Two thirds of the patients were hypothyroid with a high level of TSH (median, 27; range, 4.9–124 mIU/liter). At diagnosis, 81% of the patients had a performance status less than 2 and did not have any clinical symptoms related to lymphoma. Half of the patients had localized disease. Levels of LDH and ß2-microglobulin were elevated in only four (15%) and five (19%) patients, respectively. A monoclonal component was detected in two patients, one with an IgG 
(22 g/liter) and the other with an IgG 
(<10 g/liter).
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Histology of the 26 patients determined 6 different subtypes of lymphoma (Fig. 1): diffuse large B cell lymphoma (DLCL), MALT lymphoma, follicular lymphoma, Burkitt’s lymphoma, small lymphocytic lymphoma (SLL), and Hodgkin’s disease.
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DLCL was the most frequent histological subtype and occurred in 13 (50%) patients, mostly females, with a median age of 66 yr. Fifty percent of them were hypothyroid (median TSH, 23 mIU/liter; range, 9–121), and 1 was hyperthyroid at diagnosis (TSH, <0.01). All of these patients presented with a rapidly growing compressive enlargement of the neck, associated in half of them with symptoms related to lymphoma, poor performance status, and high levels of LDH and/or ß2-microglobulin. Disseminated disease occurred in 57% of these patients, invading generally several organs (Table 2). Four of the six DLCL patients with localized disease had cervical lymph nodes associated with the thyroid tumor. In 5 of the 13 (38%) patients with DLCL, histological evidence of mixed components of MALT lymphoma and DLCL lesions was indicative of the transformation of a MALT lymphoma into an aggressive DLCL. Three of these 5 patients had a previous history of goiter with hypothyroidism, suggestive of Hashimoto’s disease 6 months, 4 yr, and 30 yr before the diagnosis of lymphoma. The 2 other patients did not have any previous thyroid history, but histological examination of the biopsy showed Hashimoto’s thyroiditis lesions associated with the transformed and nontransformed MALT lesions. Antithyroid Ab were present at low level in 2 and were absent in 1 of these 5 patients (Table 3). None of the 8 other patients with DLCL had a previous history of thyroid disease or any histological evidence of lymphocytic thyroiditis. Antithyroid Ab assay was not available for these patients. Clinical presentation of the 2 groups of DLCL patients with or without MALT lymphoma lesions is similar, but patients with mixed DLCL and MALT lesions had a prior history of Hashimoto’s disease. No statistical analysis was performed because of the low number of patients. Cytogenetic analysis performed in 1 DLCL without MALT lymphoma lesions showed complex abnormalities, particularly in chromosome 6 with add (6) (p24-p25).
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Six (23%) patients had MALT lymphoma. All were female with a median age of 62 yr. Before lymphoma diagnosis, all were followed for Hashimoto’s thyroiditis and had presented, after a variable period of time (median, 3 yr; range, 2–13 yr), a rapidly growing nodular thyroid mass leading to thyroid surgery. At lymphoma diagnosis, all were hypothyroid (median TSH level, 27 mIU/liter; range, 4.7–124), and the only patient for whom serum was available had an elevated antithyroid Ab level. No patient had B symptoms. All but one had a localized disease without any cervical adenopathy. The only patient with stage IV disease presented bone marrow involvement without any other visceral involvement. Biologically, none of them had elevated LDH or ß2-microglobulin. One had a monoclonal component (IgG ), with a stable level (22 g/liter) detected at the diagnosis of Hashimoto’s thyroiditis made 8 yr previously.
Follicular lymphoma occurred in three patients, SLL in one patient, and Hodgkin’s disease in two patients. Clinical presentations were similar for the three subtypes, occurring in women (median ages for the three subtypes: 42, 48, and 37 yr, respectively), without any previous thyroid history, with a good PS, no B symptoms, and no adverse biological factors. Thyroid function status was variable. The only patient so tested did not have any antithyroid Ab. Cytogenetic analysis available for one patient with follicular lymphoma showed a characteristic translocation t(14;18).
Burkitt’s lymphoma was diagnosed in one patient, and at the same time as with a typical Hashimoto’s thyroiditis with hypothyroidism. Lymphoma disease involved the thyroid and the stomach. No MALT lymphoma was detected in the thyroid as well as in the stomach. No Helicobacter Pylori infection was seen in the gastric biopsies. Clinically, patient had good PS and no adverse biological parameters. Cytogenetic analysis showed a characteristic translocation t(8;14).
Treatment
All patients with either localized or disseminated DLCL received multidrug regimens, CHOP or CHOP-like. None of them had radical thyroid surgery. The patients with MALT lymphoma or SLL were treated with total thyroidectomy. The MALT patient with a stage IV disease received an adjuvant chemotherapy with chlorambucil for 1 yr. Patients with Hodgkin’s disease were treated with chemotherapy only, without radiation therapy. The three patients with follicular lymphoma were treated with various protocols according to the time of diagnosis: in 1983, the treatment proposed was a multidrug regimen (CVP, cyclophosphamide (750 mg/m2·j, J1), vepeside (100 mg/m2·j, J1), and prednisone (60 mg/m2·j, J1–J5), six cycles); in the 1990s, one patient received chlorambucil for 1 yr, and the other was treated with total thyroidectomy, followed by an adjuvant treatment including fludarabine (six cycles) and interferon-
(5 million units, three times a week for 1 yr).
Response to treatment and progression of the disease
Complete remission in response to treatment was achieved in 19 of the 25 (76%) available patients. Three of them, 1 with a follicular lymphoma, 1 with a DLCL, and 1 with Hodgkin’s disease, relapsed at 10 yr, 6 months, and 22 yr, respectively. None of the patients with MALT lymphoma treated with surgery alone relapsed after complete remission. Partial remission was obtained in 6 patients, 5 with DLCL and 1 with follicular lymphoma. Progression of the disease occurred in all of these patients in a median time of 5 months (range, 1–20.5 months).
Survivals
The 5- and 10-yr probability of overall survival (OS) was, for all patients, 77% and 54%, respectively (Fig. 2). The median survival was 10.9 yr. OS was significantly influenced by age (by log rank test, P = 0.03) and performance status (P = 0.01), and a complete response was achieved with the treatment (P = 0.003). The 5- and 10-yr probability rates of FFP were 66% and 53%, respectively (Fig. 2). FFP survival was significantly influenced by performance status (P = 0.006), number of extranodal sites (P = 0.01), and a complete response achieved with the treatment (P < 0.0001).
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. The 5-yr probability rate of OS was 44% for the DLCL patients and 100% for the other lymphoma subtypes. The 5-yr probability rates of FFP survival were 40% for DLCL, 60% for follicular lymphoma, and 100% for the other lymphoma subtypes. Because of the small number of patients, we did not perform any statistical comparison among the DLCL with marginal zone lymphoma lesions in the biopsy (five patients) and the others DLCL without marginal zone lesions (eight patients).
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Discussion |
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Aside from this common presentation largely reported in literature (7, 9, 20, 22, 27, 28, 29), clinical differences between patients may be observed, reflecting the considerable histological diversity of this disease. Among the 6 histologic subtypes reported in our series of 26 patients, including MALT lymphoma, DLCL, follicular lymphoma, SLL, Burkitt’s lymphoma, and Hodgkin’s disease, 2 clinical presentations emerge. The first clinical presentation corresponds to the patients with aggressive DLCL, representing the most frequent histology in thyroid lymphoma in our series as well as in other reports (7, 30, 31). Patients present with thyroid tumor associated with clinical symptoms of aggressive lymphoma: severe PS of 2 or more, fever, night sweating, loss of weight, disseminated disease with adenopathy and/or visceral involvement, and elevated biological parameters related to lymphoma, such as serum LDH and/or ß2-microglobulin. Thyroid status is heterogeneous. Prognosis is poor despite polychemotherapy. Two subtypes can be histologically distinguished in DLCL: 1)MALT lymphoma secondarily transformed in an aggressive DLCL at the time of diagnosis, in which tumors correspond to mixed lesions of DLCL and marginal zone lymphoma cells (31); and 2) DLCL without associated marginal zone lymphoma lesions. Patients with DLCL and MALT lymphoma lesions generally have a previous history of thyroid disease. Antithyroid Abs in these patients were undetectable or present at lower levels than in MALT lymphoma patients, possibly reflecting the fact that at this stage of the evolution, lymphoma might grow without B cell stimulation. Patients with DLCL with no associated marginal zone lymphoma lesions do not describe any previous thyroid history. In half (5 of 9) of them, lymphoma was disseminated, raising the question of the involvement of the thyroid being primary or secondary from the other involved site(s). Except for these differences in history and biological features, clinical courses of DLCL evolving from MALT and DLCL without associated marginal zone lymphoma lesions seem to be similar, as reported by Derringer et al. (31). Our series was too small to statistically analyze survival differences between these 2 DLCL subtypes.
Secondly, patients with MALT lymphoma, representing one fourth of our patients and between 6–27% of the patients with thyroid lymphoma reported in the literature (7, 30, 31), are usually around 60 yr, female, and have a history of Hashimoto disease, as we confirmed in our analysis. The presenting symptoms of these patients with lymphoma are related to the thyroid mass that has rapidly grown within a few months, leading to surgery, which is very uncommon in Hashimoto disease. None of the patients had constitutional B symptoms of lymphoma, and all presented with an indolent clinical course. Biologically, they presented a high level of serum antithyroid Ab, which confirms the hypothesis that antigenic stimulation is essential for MALT development. The other histological subtypes are exceptional. Clinical presentation of follicular lymphoma, reported to represent 1–6% of thyroid lymphoma (30, 31) and 12% in our series, is similar to that of the usual follicular lymphoma. In our series, no MALT or thyroiditis lesions were associated with follicular lymphoma cells, and none of the patients had previous thyroid disease. SLL has been described in only one report by Kossev et al. (32), in which the patient has been, in fact, documented with chronic lymphocytic leukemia shortly before thyroid localization. Diagnosis of the case reported in our series relied on cytological and immunological data showing characteristic positivity for CD5, CD23, and CD43 and negativity for CD10 and FMC7, lacking definitive features of MALT lymphoma lesions and/or lymphocytic thyroiditis. Unexpectedly, the disease was localized, and no bone marrow involvement was observed. As for the diagnosis of Hodgkin’s disease in our two patients, it might be debated, as Derringer et al. suggested (31), because Reed-Sternberg-like cells are known to occur in a wide variety of lymphoma subtypes, but this was assessed in our patients by cytological and immunological analyses. Finally, concerning the localization of Burkitt’s lymphoma to the thyroid, it has been reported infrequently (33). Our single patient with thyroid Burkitt’s lymphoma had also mediastinal adenopathy and gastric involvement. Surprisingly, histological examination of the thyroid showed lesions of Hashimoto’s thyroiditis. Despite careful examination, no MALT lymphoma lesions were seen in the thyroid or gastric biopsies. Cytogenetic analysis of the thyroid biopsy showed a characteristic t(8–14) chromosomal translocation. Lymphomas of the thyroid are almost exclusively of B cell origin, but few thyroid T cell lymphomas have been described as anecdotal cases (34, 35), even one in association with Hashimoto’s thyroiditis (36). We did not find any T cell lymphoma in our series.
The majority of the primary thyroid lymphoma, 60% of the patients in this series, arise in a background of Hashimoto’s thyroiditis. Clinically, Hashimoto’s thyroiditis patients present most commonly with goiter and hypothyroidism, but patients with euthyroidism or even hyperthyroidism with normal gland size have been reported (for review, see Refs.37). Pressure symptoms due to an enlarging mass may occasionally occur in these patients. Antibodies to one or more thyroid antigens, including thyroperoxidase, Tg, and TSH receptor are usually present. Even if endocrinologists are aware of the increased risk of lymphoma in these pathologies, diagnosis of TL remains difficult because the clinical history, the physical examination, the thyroid function tests, and the ultrasound examination are not specific to detect the occurrence of lymphoproliferative disorders. Biologically, the presence of serum monoclonal Ig has been detected in two patients in our series. In one patient, diagnosis of the presence of this monoclonal protein was made at the same time of Hashimoto’s thyroiditis diagnosis, and the level did not progress during the evolution to MALT lymphoma. Monoclonal Ig does not seem to be a good parameter, if present, to detect an evolution to MALT lymphoma. High LDH or ß2-microglobulin levels are usually associated with aggressive lymphomas, and at this stage of the disease, histological diagnosis is usually not difficult. Fine needle aspirations guided by the ultrasound, thyroid biopsy, or thyroidectomy are the three diagnostic tools that can be chosen. As reported by Kossev et al. (32), fine needle aspiration is a potential tool allowing diagnosis of thyroid diseases with experienced cytological examination, but tissue biopsies are essential to assess histologically the diagnosis and should be considered the gold standard for histological diagnosis in thyroid. Moreover, it can provide material for complete flow cytometric analysis and molecular assays, such as Ig heavy chain gene rearrangement with PCR, that could be useful to distinguish diagnosis between thyroid lymphoma and Hashimoto’s thyroiditis (38, 39). The third tool, total thyroidectomy, can be dangerous, particularly in massive tumor (40), and moreover, it has no proven benefit in diagnostic advantages over biopsy (41).
The choice of treatment in thyroid lymphoma depends on the histological subtype and the stage of the disease. For aggressive diffuse large B cell lymphoma, the most frequent subtype in thyroid lymphoma, the standard treatment is based on chemotherapy with anthracyclin-containing multidrug regimen [CHOP (42) or CHOP-like (13)]. Surgery in this case is rarely complete and, as reported by Ansel et al. (40), should not be performed, as the disease generally is disseminated and responds quickly to therapy with no surgical risks. The combination of chemotherapy and radiotherapy is the standard treatment of localized aggressive lymphoma (43), but in some patients, under 60 yr and without any adverse prognostic factors, chemotherapy alone may be proposed (44). For localized MALT lymphomas, we proposed total thyroidectomy, with a good response rate (predicted OS and FFP survival, 100% at 5 yr). Involved-field radiation therapy can be also proposed to these patients with an OS at 5 yr reported at 90% (8). For disseminated MALT lymphoma, total thyroidectomy can be proposed in association with single agent chemotherapy such as chlorambucil. The other subtypes of histology are very rare, and no guidelines of therapy can be easily proposed.
In conclusion, we confirmed in this series the considerable heterogeneity of thyroid lymphomas, and the very close relation between Hashimoto’s thyroiditis with antigenic stimulations and the occurrence of the MALT lymphoma subtype. Unfortunately, there is actually no really simple test, such as a blood test, to easily diagnose the evolution from chronic lymphocytic thyroiditis to lymphoma without resort to biopsy. Diffuse large cell lymphoma, which can evolve from MALT lymphoma, is the most frequent subtype. Its pronostic is similar to that of other diffuse large cell lymphoma from other localizations and could benefit from new treatment based on a combination of chemotherapy and immunotherapy.
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Acknowledgments |
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Footnotes |
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Received June 13, 2001.
Accepted October 1, 2001.
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T-cell lymphoma of the thyroid gland. N Engl J Med 336:1391–1392This article has been cited by other articles:
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