Primary Thyroid Lymphoma (PTL) is an uncommon disease, although its incidence is of 5%. Ultrasound and Fine Needle Aspiration Cytology (FNAC) usually do not provide the diagnosis. Surgery is one of the treatment options because it enables histological diagnosis and can also relieve compression symptoms in patients with rapid growth cervical mass. We present 7 cases of PTL diagnosed in the last 10 years in our unit. Five were female (71.4%) and 2 were male (28.6%). The mean age was 64.2 (range: 40 - 81); 4 patients (57.1%) had associated Hashimoto’s Thyroiditis (HT). One patient (14.2%) had concomitant Graves disease. 5 cases presented with compressive symptoms and cervical mass. Ultrasound was not diagnostic in any case. FNAC was diagnostic only in one patient (14.3%). Five patients underwent total thyroidectomy (71.4%). All the cases were diagnosed with lymphoma postoperatively. Two interventions consisted of left hemithyroidectomies (28.6%). No complications appeared. 5 patients (71.4%) were classified as M ucosa-Associated Lymphoid Tissue (MALT) lymphoma. We also observed 1 Follicular grade I lymphoma and 1 Burkitt case. When the extension study was done, 1 patient was at stage IIIE (14%), 2 at IIE (28.5%) and 4 at IE (57.14%). Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) and Iphosphamide, ethoposide and h igh dose Cytarabine (IVAC) were the treatment scheme when chemotherapy was used (in three cases) . Two cases were treated only with t otal t hyroidectomy, and 2 with total thyroidectomy and r ituximab, and the latter w as MALT. Complete Remission (CR) was achieved in all patients in the first year. All are still alive and in CR. In our experience, PTL diagnose can be challenging before surgery. Although surgery is not the gold standard for treatment, when it is done , it should be curative in MALT lymphomas confined to the thyroid.
Primary Thyroid Lymphoma (PTL) is defined as a lymphoma arising in the thyroid gland. It accounts for only 5% of all thyroid malignancies [
The most common clinical presentation is a rapidly enlarging painless thyroid mass. Sometimes it may be associated with compressive symptoms such as dysphagia, dyspnea and hoarseness. B-symptoms are referred in 20% of cases [
Tumors are usually cerebroid and well vascularized. Ultrasonography is the imaging modality of choice and typically shows one of the three patterns: nodular, diffuse or mixed. When appearing as a solitary mass, the tumor may resemble an anaplastic thyroid carcinoma, but the lack of calcification, necrosis and cystic degeneration favors diagnosis as lymphoma.
T-cell PTL is extremely rare, accounting for only 2% [
Staging is based on Modified Ann Arbor criteria [
Although in the last few years ultrasound guided FNAC and core-biopsy have increased their sensitivity [
Treatment strategy depends on histological subtype and stage. Due to the low incidence, there is no evidence-based treatment. DLBCL requires multimodal therapy, including immunochemotherapy and radiotherapy for bulky disease. Early stage IE MALT PTL has an indolent course and may call for single-modality treatment including surgery, radiotherapy or a combination of both.
Prognosis is generally excellent although dependent on histological subtype.
The PTL cases detected in the unit of Endocrine Surgery of the University Clinic Hospital of Valencia, Spain, in the last 10 years were reviewed and analyzed. It is a retrospective and descriptive study. Cases were obtained from Oncology, Pathology and Surgery database.
1267 patients underwent thyroid surgery in our unit during the period from 2005 to 2015. From that, 7 cases were diagnosed with PTL (0.55%). Five were female (71.4%) and 2 were male (28.6%). The mean age was 64.2 (range: 40 - 81); 4 patients (57.1%) had associated HT. One patient (14.2%) had concomitant Graves disease.
Five patients debuted as a cervical mass with compressive symptoms. Three of them developed as a rapidly growing cervical mass, one of which grew from 2 to 8 cm diameter (
In all cases a cervical ultrasound was performed as an initial study. In no case did the ultrasound show evidence of thyroid lymphoma.
FNAC was diagnostic only in one patient (14.3%).
Five patients underwent total thyroidectomy (71.4%). All were diagnosed with lymphoma postoperatively. Two interventions consisted of left hemithyroidectomies (28.6%). One was indicated preoperatively in order to relieve compressive symptoms and the other was called because the intraoperative biopsy informed of a lymphoma, which made the complete thyroidectomy unnecessary.
No postoperative complications appeared in any case.
Histological report was of MALT lymphoma in 5 patients (71.4%). We also observed a Follicular grade I lymphoma and a Burkitt case (Figures 3-5).
The extension was evaluated in all patients with cervical and thoracic CT scan, Bone Marrow Biopsy (BMB), beta-2 microglobuline and serum lactate dehydrogenase (LDH) levels. BMB showed normal cellularity. Beta-2 microglobuline did not rise in any patient and LDH levels only increased in 1 of the 7 cases. One case (the Burkitt case) was staged as IIIE (14%), 2 as IIE (28.5%) and 4 as IE (57.14%).
Three patients completed treatment with R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone). The Burkitt lymphoma was treated with Dexamethasone, methotrexate and IVAC (iphosphamide ethoposide and cytarabine). Two cases were treated only with Total Thyroidectomy, and 2 with total thyroidectomy and Rituximab, the latter were MALT.
Complete remission (CR) was achieved in all patients in the first year. All are still alive and in CR (see results in
PTL has a very low incidence, with 1 - 2 cases per million. Due to this low frequency it is especially interesting to report case-series. Most published studies are retrospective with a limited number of patients. Series with a larger number of patients were presented by Matsuzuka (n = 119) and Onal (n = 87) [
The main clinical presentation included a mass in the thyroid or a diffuse enlargement that caused symptoms related to compression such as hoarseness, dysphagia and dyspnea. Rarely, stridor or superior vena cava obstruction may occur. There was a report of one case presenting a thyroid abscess which was in fact affected by Hodgkin’s lymphoma [
show thyroid enlargement and surgical treatment indication was based on unmanageable hyperthyroidism with medical treatment. Classic B-symptoms such have been reported in up to 20% of patients. None of our patients referred B-symptoms.
The pathogenesis of PTL lymphoma is closely related to chronic antigen stimulation, and the major risk factor for MALT lymphomas is the presence of Hashimoto’s thyroiditis (HT). The risk of PTL in an HT patient is increased 40 - 80 times compared to the general population [
CASE (Year) | 1 2005 | 2 2006 | 3 2007 | 4 2008 | 5 2010 | 6 2013 | 7 2014 |
---|---|---|---|---|---|---|---|
AGE | 61 | 40 | 76 | 81 | 72 | 69 | 51 |
SEX | F | F | M | F | F | F | M |
THYROIDITIS | − | Graves | Hashimoto | Hashimoto | Hashimoto | − | Hashimoto |
ASSOCIATED SYMPTOMS | Fast grow nodule (3 cm) | − | Compressive symptoms | Compressive symptoms | Fast grow nodule (2 cm) | Fast grow mass (8 cm) and compressive symptoms | − |
FNAC DIAGNOSTIC | − | − | − | − | − | + | − |
HISTOLOGY | MALT | MALT | MALT | =MALT | Folilcular grade I | Burkitt | MALT |
CT STAGE (RYE) | IIE | IE | IE | IIE | IE | IIIE | IE |
BMB | − | − | − | − | − | − | − |
β-2 MICROGLOBULINE/LDH | − | − | LDH 498 (range 240 - 480) | − | − | − | − |
TREATMENT | TT + CT (R-CHOP) | TT | TT | TT + RITU XIMAB | Lobectomy + CT (R-CHOP) | Lobectomy + RITUXIMAB + CORTICOID + METOTREXATE + IVAC | TT + RITU XIMAB |
SURVIVAL (YEARS) | 11 | 10 | 9 | 8 | 6 | 3 | 2 |
M = Male, BMB = bone marrow biopsy, TT = total thyroidectomy. R = Rituximab, CT = chemotherapy, CHOP = cyclophosphamide, doxorubicin, vincristine and prednisone, IVAC (iphosphamide ethoposide and high dose cytarabine).
and PTL [
MALT lymphoma of the thyroid usually has an indolent course and a better prognosis but transformation into higher grade subtypes has been previously documented. Although the most frequent site of involvement is the gastrointestinal tract, it may also arise in other extranodal locations such as skin, breast, lung or thyroid. MALT PTL accounts for 5% of all extranodal lymphomas [
In our experience MALT lymphoma was more frequent than the other subtypes, with 5 out of 7 patients, and only one DLBCL was present. We registered a Burkitt lymphoma, very rare. Gac et al. published another case in their series in 2009 [
Dawson proposed a specific classification for cases with only extranodal disease: Stage I for those affecting only the thyroid gland and Stage II when there is regional node involvement [
Half of our patients can be considered in stage IE and half had regional lymph nodes affected.
Ultrasound can show a diffuse gland enlargement. It looks like a heterogeneous hypoechoic parenchyma with the presence of structures resembling septae [
Despite advances in ultrasonography, as well as in guided core biopsy, accurate diagnosis with an open surgical biopsy is usually needed, especially in MALT subtypes, where no diagnosis can be achieved with FNAC [
In our series, although all the patients had a previous FNAC, only one patient could be diagnosed by FNAC; the other patients required an open surgical approach. A core-needle biopsy (CNB) yields more tissue than FNAC and it may be guided by ultrasonography to avoid the risk of trauma to adjacent structures. It can facilitate the differential diagnosis with anaplastic carcinoma, which is not always possible with FNAC. Recent studies have shown that a core-biopsy can provide enough tissue for diagnosis in up to 95% of lymphomas [
No CNB was performed in our series due to the lack of experience.
Staging procedures for PTL are essentially the same as other subtypes and includes blood cell analysis, biochemistry including LDH and beta2-microglobulin both important prognostic factors for lymphoma, a bone marrow biopsy and a whole-body CT. An updated diagnosis and response criteria favours the PET/CT use for staging and response evaluation, especially in the aggressive variety, although MALT cases may result in false negative [
The optimal treatment of PTL is controversial and usually based on histologic subtype. In general, they are sensitive to both chemotherapy and radiotherapy. Due to its more aggressive clinical course, the gold standard for DLBCL is multimodal therapy based on the combination of the monoclonal antibody Rituximab, targeting CD20 antigen with the classical chemotherapy schedule CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), as well as radiotherapy. In the very aggressive subtypes, like Burkitt’s lymphoma, a chemotherapy schedule based on Methotrexate, Cyclophosphamide and Cytarabine is the treatment of choice. A systematic review performed by Doria et al, showed relapse rates of 7.7% following chemo-radiotherapy modality, 37.1% following radiotherapy alone and 43% following chemotherapy alone [
However, the introduction of Rituximab, a chimeric monoclonal antibody against CD20 represents the most significant advance in the treatment of lymphoma since the introduction of chemotherapy. Adding Rituximab to the therapy has shown to improve overall and disease-free survival in virtually all subtype of B-cell lymphomas and can also reduce CHOP volume in elderly patients that do not tolerate chemotherapy [
Treatment may range from surgery alone, radiotherapy alone, single-agent rituximab or a combination of them. MALT lymphomas may be treated with single-modality treatment because of the indolent course of the disease. Laing et al. reported a series of 31 patients with MALT lymphoma stage I-IIE, who received only surgery followed by single agent rituximab, with a 5-year survival rate of 90% [
3 out of our 7 patients in our series were treated with chemoinmunotherapy (2 R- CHOP and 1 Methotrexate-based schedules) two with surgery and rituximab and the other two with only surgery. None of them received radiotherapy probably due to the favourable outcome following chemoinmunotherapy.
The role of surgery in the treatment of PTL remains controversial. It allows an accurate histologic diagnosis and avoids the compressive symptoms due to enlarged masses. However, the potential morbidity of the procedure should be kept in mind as well as the fact that surgery does not appear to improve overall survival when compared to other treatment strategies [
Radiotherapy should be considered only for localized stage IE MALT lymphomas. In most cases RT is not necessary due to the good results achieved with chemotherapy. It has been used in patients that cannot undergo surgery or chemotherapy, improving local control [
Prognosis of PTL is mainly related to histological subtype. The surveillance Epidemiology and End Results database estimates a 5-year disease-free survival of 96% for MALT lymphoma, 75% for DLBCL, 87% for follicular PTL and 86% for small lymphocytic lymphoma. The 5-year overall survival was 66%. The outcome is also based on other prognostic factors included in the International Index [
100% of our patients are still alive at a mean follow-up of seven years.
PTL is very infrequent, so it is difficult to protocolize its diagnosis and treatment. Multimodal treatment gives good results, when histology and stage are taken into account to decide the best combination. Due to the low number of cases, there is no evidence of which is the best treatment option, but experience suggests restricting surgery to cases where previous diagnosis fails. In aggressive histological variants or larger tumors, surgery can be risky and will not improve survival, but for MALT lymphoma confined to the thyroid gland, given their benign presentation and course, if surgery is done, this could work as a single and resolutive treatment.
Authors state that no conflict of interest exists.
Alfonso-Ballester, R., Terol Castera, M.J., García Rodríguez, O., Martínez Ciarpaglini, C., Boscá-Watts, M.M., Cassinello Fernández, N. and Ortega Serrano, J. (2016) The Role of Surgery in Primary Thyroid Lymphoma: Experience in the Last 10 Years of a Specialized Unit. Journal of Can- cer Therapy, 7, 1059-1070. http://dx.doi.org/10.4236/jct.2016.713102