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Chronic autoimmune thyroiditis (Hashimoto's thyroiditis) in patients with MALT lymphoma

      Abstract

      Background

      Autoimmune diseases have been implicated in the genesis of MALT lymphoma of various localizations. The development of thyroidal MALT lymphoma has been described as an adverse event in patients suffering from long-standing chronic autoimmune thyroiditis (CAT, Hashimoto's thyroiditis). The percentage and possible association between CAT and extrathyroidal MALT lymphoma, however, have not been assessed so far.

      Patients and methods

      A retrospective analysis of 80 patients with MALT lymphoma diagnosed and treated at our institution identified a total of 13 patients (16%) with MALT lymphoma suffering from an underlying CAT. Patient characteristics including site of disease, stage, genetic changes and clinical course were assessed and evaluated.

      Results

      In total, 10 patients were female and 3 male, with the median age being 57 years (range: 31–80). Four patients suffered from thyroidal lymphoma and nine patients had extrathyroidal lymphoma (four gastric, two orbital, one small intestinal and two salivary gland lymphomas). Three patients had a long-standing history of CAT at diagnosis of MALT lymphoma, while CAT was discovered during staging and clinical work-up of MALT lymphoma in the remaining 10 patients. All 13 patients had localized disease, i.e. stage I or II. Only one of the four patients with gastric MALT lymphoma responded to antibiotic treatment against Helicobacter pylori infection. Genetic aberrations were detected in four patients, two of whom had a t(11;18)(q21;q21) translocation, one patient had trisomies 3 and 18 and one had trisomy 18.

      Conclusion

      Our findings suggest that CAT is found in patients with not only thyroidal but also nonthyroidal MALT lymphoma. While the nature of our data does not allow for delineation of a direct association between CAT and development of extrathyroidal MALT lymphoma, further prospective studies on this issue are warranted.

      Keywords

      introduction

      Extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) as first described by Isaacson and Wright in 1983 [
      • Isaacson P.
      • Wright D.H.
      Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive type of B-cell lymphoma.
      ] is among the more common types of lymphoma, accounting for 7% of newly diagnosed non-Hodgkin's lymphomas [
      • Pileri S.A.
      • Milani M.
      • Fraternali-Orcioni G.
      • Sabattini E.
      From the R.E.A.L. Classification to the upcoming WHO scheme: a step toward universal categorization of lymphoma entities?.
      ]. Although MALT lymphomas arise in the stomach in a high percentage, they can be found throughout the whole body including organs such as the intestine, salivary gland, orbit, thyroid gland, lung and liver [
      • Raderer M.
      • Woehrer S.
      • Streubel B.
      • et al.
      Assessment of disease dissemination in gastric compared with extragastric mucosa-associated lymphoid tissue lymphoma using extensive staging: A single-center experience.
      ].
      The association between MALT lymphoma and chronic inflammation/infection has become a focus of attention in recent years, as was impressively shown by discovering the link between gastric MALT lymphoma and Helicobacter pylori (HP) infection. This close association has provided the basis for successful treatment of early-stage gastric MALT lymphomas using HP eradication, which can be considered standard therapy for such patients [
      • Wotherspoon A.C.
      • Doglioni C.
      • Diss T.C.
      • et al.
      Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori.
      ,
      • Fischbach W.
      • Goebeler-Kolve M.
      • Dragosics B.
      • et al.
      Long-term outcome of patients with gastric marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT) following exclusive Helicobacter pylori eradication therapy: Experience from a large prospective series.
      ]. In patients with HP-associated gastric MALT lymphoma, risk factors predictive of lymphoma regression following antibiotic treatment have been published in recent years. For example, restriction of the disease to mucosa and submucosa is thought to be a positive predictive factor [
      • Sackmann M.
      • Morgner A.
      • Rudolph B.
      • et al.
      Regression of gastric MALT-lymphoma after eradication of Helicobacter pylori is predicted by endosonographic staging. MALT Lymphoma Study Group.
      ], while the presence of t(11;18)(q21;21) or an underlying Sjogren's syndrome seems to identify nonresponders [
      • Raderer M.
      • Österreicher C.
      • Machold K.
      • et al.
      Impaired response of gastric MALT lymphoma to Helicobacter pylori eradication in patients with autoimmune disease.
      ,
      • Liu H.
      • Ye H.
      • Ruskone-Fourmestraux A.
      • et al.
      T(11;18) is a marker for all stage gastric MALT lymphomas that will not respond to H. pylori eradication.
      ,
      • Liu H.
      • Ye H.
      • Ruskone Fourmestraux A.
      • et al.
      Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy.
      ].
      According to the literature, 30%–40% of MALT lymphomas occur at an extragastric site [
      • Zinzani P.L.
      • Magagnoli M.
      • Galieni P.
      • et al.
      Nongastrointestinal low-grade mucosa-associated lymphoid tissue lymphoma: analysis of 75 patients.
      ], where autoimmune diseases are thought to play an important role in the development of MALT lymphoma [
      • Isaacson P.G.
      Extranodal lymphomas: The MALT concept.
      ,
      • Wohrer S.
      • Troch M.
      • Streubel B.
      • et al.
      MALT lymphoma in patients with autoimmune diseases: A comparative analysis of characteristics and clinical course.
      ]. Especially the correlation between Sjogren's syndrome and MALT lymphoma of the salivary gland and chronic autoimmune thyroiditis (CAT, Hashimoto's thyroiditis) with thyroidal lymphoma has been published before [
      • Harris N.L.
      • Jaffe E.S.
      • Diebold J.
      • et al.
      The World Health Organization classification of hematological malignancies report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997.
      ]. In these cases, however, the lymphoma develops in the organs primarily affected and damaged by the autoimmune disease. As opposed to this, we have also reported a potential influence of Sjogren's syndrome on the clinical course and probably development of MALT lymphoma restricted to the stomach, which is further indicated by the fact that such patients do not show regression of the lymphoma following HP eradication. As assessment of CAT is part of the routine clinical work-up in all patients with MALT lymphoma diagnosed at our institution since 2002, and the fact that virtually nothing is known about CAT in patients with nonthyroidal MALT lymphoma, we have analyzed the frequency of CAT in patients with MALT lymphoma.

      patients and methods

      All patients with MALT lymphoma diagnosed and managed at our institution underwent assessment for autoimmune diseases as a part of routine clinical work-up starting in 1997. Routine evaluation of CAT, however, has only been implemented as of 2002. From our data, we have thus retrospectively assessed the frequency and clinical course of patients with CAT and MALT lymphoma. CAT was defined as outlined by Colin et al. [
      • Weissel M.
      • Mayr N.
      • Zeitlhofer J.
      • et al.
      Clinical significance of autoimmune thyroid disease in myasthenia gravis.
      ], i.e. the presence of markedly elevated levels of thyroglobulin antibodies or thyroperoxidase antibodies and a pathologic, i.e. hypoechogeneic appearance of the thyroid on ultrasound examination or—ultimately—histologic assessment of fine-needle biopsies or surgical specimens. Thus, patients with high levels of thyroglobulin or thyroperoxidase antibodies underwent an additional ultrasound or a fine-needle biopsy to assess an autoimmune process in the thyroid gland.
      Diagnosis of MALT lymphoma was carried out on biopsy samples evaluated by two reference hematopathologists (AC, LM) according to the criteria established by Isaacson and adopted in the recent World Health Organization classification for MALT lymphoma. Analysis of MALT lymphoma-associated genetic aberrations was done in all patients. t(11;18)(q21;q21) involving API2 and MALT1 was assessed by reverse transcription–PCR; t(14;18)(q32;q21) involving IGH and MALT1, t(1;14)(p22;q32) involving BCL10 and IGH and trisomies 3 and 18 were investigated by fluorescence in situ hybridization as previously described. Immunologic phenotyping on paraffin sections was done for demonstration of light chain restriction and the phenotype CD20+CD5-CD10-cyclinD1-CD23-, which is consistent with MALT lymphoma.
      All patients underwent extensive staging according to our standardized procedure, consisting of ophtalmologic and otorhinolaryngologic examination with sonography/magnetic resonance imaging of lacrimal and salivary glands, gastroscopy with multiple biopsies, endosonography of the upper gastrointestinal tract, enteroclysis, colonoscopy and computed tomography scan of thorax and abdomen.

      results

      Out of 80 consecutive patients with MALT lymphoma, in whom assessment of CAT had been carried out, 13 were found to have evidence of CAT (16%). In these 13 patients (10 female and 3 male), the median age was 57 years [inter-quartile range (IQR): 31–80 years] and the median follow-up time was 41 months (IQR: 3–90 months). Four patients had thyroidal lymphoma (one patient with infiltration of cervical lymph nodes and one with concurrent involvement of the paroid gland), four patients suffered from gastric lymphoma, one patient from lymphoma of the small intestine, while two patients each had lymphoma of the orbit and the salivary glands, respectively. For detailed characteristics see Table 1.
      Table 1Characteristics of patients with CAT and MALT-lymphoma
      No.GenderOrgan involvementAge at diagnosis of lymphomaPrevious history of CATLevothyroxine substitutionGenetic abberationsStageTreatmentResponse to treatmentRelapseFollow-up (months)Alive
      1MaleSubmandibular + cervical lymph nodes47NoYesTrisomy 18IIChemotherapyCRNo37Yes
      2FemaleStomach + abdominal lymph nodes63NoYest(11;18)IIHP eradication, chemotherapy, radiatioCRYes
      Following treatment with chemotherapy resulting in CR, patient relapsed after 18 months and achieved a second CR with radiotherapy.
      90Yes
      3FemaleStomach43NoNoNoneIHP eradicationCRNo22Yes
      4MaleParoid31NoNot(11;18)IRadiation + chemotherapyCRNo83Yes
      5FemaleOrbit61YesYesNoneIDoxycyclineCRNo54Yes
      6MaleThyroid49YesYesNoneISurgeryCRNo38Yes
      7FemaleThyroid + cervical lymph nodes80YesYesNoneIIRituximabCRNo43Yes
      8FemaleOrbit58NoNoNoneINone3Yes
      9FemaleStomach73NoNoNoneIHP eradication, chemotherapyCRNo11Yes
      10FemaleSmall intestine66NoNoTrisomies 3, 18ISurgeryCRNo20Yes
      11FemaleStomach63NoYesNoneIHP eradication, chemotherapyPRNo46Yes
      12FemaleThyroid44NoYesNoneISurgery, radiatioCRNo45Yes
      13FemaleThyroid65NoYesNoneISurgeryCRNo36Yes
      CAT, chronic autoimmune thyroiditis; CR, complete remission; PR, partial response.
      a Following treatment with chemotherapy resulting in CR, patient relapsed after 18 months and achieved a second CR with radiotherapy.
      A long-standing history of CAT was known in three patients, two of whom developed thyroidal and one patient orbital MALT lymphoma. In the remaining 10 patients, CAT was discovered during staging after a diagnosis of MALT lymphoma had been established. In the three patients with already demonstrated CAT, clinical symptoms of hypothyroidism had led to the diagnosis, and a total of eight patients were given substitution with levothyroxine in the course of the disease (see Table 1, for detailed thyroid parameters see Table 2).
      Table 2Thyroid parameters in patients with CAT and MALT lymphoma at diagnosis
      Patient no.TSH (μU/ml)T4 (ng/ml)fT 4 (ng/dl)TPO antibody (IU/ml)TG antibody (IU/ml)Location of lymphoma
      15.5550n.d.n.e.228Submandibular + cervical lymph nodes
      28.980n.d.n.e.3000Stomach + abdominal lymph nodes
      33.55n.d.1.222702310Stomach
      42.01101n.d.n.e.474Paroid
      53.2677n.d.565n.e.Orbit
      62.9260n.d.n.dn.dThyroid
      710.4n.d.1.1725333000Thyroid + cervical lymph nodes
      81.1591n.d.495350Orbit
      96.966n.d.1183n.e.Stomach
      100.8287n.d.n.e.106Small intestine
      1112.9263n.d.2507135Stomach
      12
      Diagnosis of CAT was established histologically following thyroidectomy.
      48.177n.d.n.d.n.d.Thyroid
      132.59n.d.0.772449793Thyroid
      Normal ranges: TSH, 0.44–3.77 μU/l; T4, 58–124 ng/ml; fT4, 0.76–1.66 ng/dl; TPO antibodies, <60 IU/ml; TG antibodies, <280 IU/ml.
      CAT, chronic autoimmune thyroiditis; TSF, thyroid-stimulating hormone; TPO, thyroperoxidase; TG, thyroglobulin; n.d., not done; n.e., not elevated.
      a Diagnosis of CAT was established histologically following thyroidectomy.
      HP infection was detected in 7 of 13 patients; three suffered from gastric MALT lymphoma, two from lymphoma of the thyroid, one had a MALT lymphoma of the small intestine and one of the salivary gland. All patients with gastric MALT lymphoma and HP infection were given HP eradication treatment of their early-stage MALT lymphoma. One patient responded with total regression of the lymphoma, while no change was seen in the other two cases after a follow-up time of 14 and 36 months, respectively.
      Plasmacytic differentiation defined as the presence of sheets of light chain-restricted plasma cells was found at a relatively high rate, i.e. in 6 of 13 patients, while a monoclonal gammopathy was found in only 2 of 10 patients available for assessment, and both showed plasmacytic differentiation.
      Genetic aberrations were detected in 4 of 13 patients (30%), two of them showing a t(11;18)(q21;q21) translocation, one had trisomies 3 and 18 and one had trisomy 18.
      After a median follow-up of 53 months (IQR: 3–90), all 13 patients are alive. Various forms of treatment (see Table 1) including HP eradication, surgery, radiation, chemotherapy and antibody treatment with rituximab were applied in 12 patients, while one patient refused further therapy in the absence of symptoms following diagnostic excisional biopsy for orbital MALT lymphoma. Eleven patients achieved a complete remission (CR) of their lymphoma, while one patient had a partial response now ongoing for 41 months without further progression of the lymphoma. Out of 11 patients with CR, one relapsed 18 months after treatment with 2-chlorodeoxyadenosine had resulted in CR and underwent radiotherapy leading to a second CR.

      discussion

      Autoimmune diseases are thought to be risk factors for the development of MALT lymphoma, most notably within the organs affected by chronic inflammation. Consequently, patients suffering from CAT have been reported to have an elevated risk for the development of thyroidal MALT lymphoma, while no data on autoimmune thyroiditis and extrathyroidal MALT lymphomas have been published so far.
      The overall rate of patients with CAT in MALT lymphoma was 13 of 80 (16%). While the overall number of patients is too small to draw significant conclusions; this suggests that the percentage is higher than the incidence of CAT in the general population, that has been shown to between 5% and 6% in our borderline iodine sufficient area [
      • Weissel M.
      • Mayr N.
      • Zeitlhofer J.
      • et al.
      Clinical significance of autoimmune thyroid disease in myasthenia gravis.
      ] with a female predominance as it is also found in the patient cohort presented here.
      According to our data, however, CAT is not only found in patients with thyroidal MALT lymphoma but it could also be demonstrated in MALT lymphomas of various other localizations. In fact, only four of our 13 patients (30%) with CAT had thyroidal lymphoma, and a long-standing history of chronic thyroid dysfunction necessitating substitution with levothyroxine had been known in two of these four patients.
      Out of the remaining nine cases with MALT lymphoma, only one, however, had a history of CAT, while in eight patients it was discovered during assessment following the diagnosis of MALT lymphoma. In view of this, it is difficult to assess a potential causative role of CAT in the development of nonthyroidal MALT lymphoma. In the majority of studies, MALT lymphoma developed after a long period of CAT and the associated chronic inflammatory stimulation within the thyroid, but the time to diagnosis of MALT lymphoma, however, is very variable [
      • Thieblemont C.
      • Mayer A.
      • Dumontet C.
      • et al.
      Primary thyroid lymphoma is a heterogeneous disease.
      ,
      • Pedersen R.
      • Pedersen N.
      Primary non-Hodgkin's lymphoma of the thyroid gland: A population based study.
      ].
      No organ preference could be found in this cohort of patients with nonthyroidal MALT lymphoma (see Table 1), but again the data have to be interpreted with caution due to the small number of patients. Three patients had early-stage gastric MALT lymphoma with evidence of HP infection in all cases. As mentioned in the literature before [
      • Raderer M.
      • Österreicher C.
      • Machold K.
      • et al.
      Impaired response of gastric MALT lymphoma to Helicobacter pylori eradication in patients with autoimmune disease.
      ], patients with an autoimmune disease, i.e. Sjogren's syndrome and early-stage gastric MALT lymphoma, have a low response rate to antibiotic treatment. Out of these three patients with gastric MALT lymphoma and CAT, one responded to antibiotic treatment with regression of the lymphoma, while the remaining two showed no change during a follow-up period of 14 and 36 months after successful eradication of HP. As the number of patients is very small, it would be premature to suggest CAT as an adverse prognostic factor for HP eradication. This is even more so, as one patient had a t(11;18) translocation which has been demonstrated as the most significant adverse marker of nonresponse to HP eradication [
      • Liu H.
      • Ye H.
      • Ruskone-Fourmestraux A.
      • et al.
      T(11;18) is a marker for all stage gastric MALT lymphomas that will not respond to H. pylori eradication.
      ,
      • Liu H.
      • Ye H.
      • Ruskone Fourmestraux A.
      • et al.
      Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy.
      ].
      Interestingly, all patients diagnosed with CAT had early-stage MALT lymphomas. Various forms of therapy resulted in CR of the lymphoma in 11 of 12 patients undergoing therapy, and at the time of this analysis, all 13 patients are alive. After a median follow-up time of 53 months (IQR: 3–90 months), only one patient has relapsed. However, due to the small number and the retrospective nature of our assessment, a potential influence of CAT on the clinical course of MALT lymphoma cannot be ruled out with certainty, although these data suggest that such patients do not have an impaired clinical outcome.
      Taken together, we have found an unexpectedly high rate of CAT in patients with MALT lymphomas of various sites of origin, suggesting that it might be more common in patients with MALT lymphoma than in the general population. Further studies, however, are warranted to assess the exact frequency as well as a potential causative role of this condition in the development of nonthyroidal MALT lymphomas.

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