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1.  Problems of primary T-cell lymphoma of the thyroid gland -A case report 
In the following report we discuss a very rare case of malignant T-cell lymphoma of the thyroid gland that developed in a 70-year-old woman with a past history of hypothyroidism due to chronic thyroiditis. The chief complaint was a rapidly growing neck mass. CT and ultrasonographic examination revealed a diffuse large thyroid gland without a nodule extending up to 13 cm. Although presence of abnormal lymphoid cells in the peripheral blood was not found, the sIL-2 Receptor antibody and thyroglobulin measured as high as 970 U/ml and 600 ng/mL respectively. Fine needle aspiration cytology diagnosed chronic thyroiditis. A preoperative diagnosis of suspicious malignant lymphoma of the thyroid gland accompanied by Hashimoto’s thyroiditis was made, and a right hemithyroidectomy was performed to definite diagnosis. Histological examination revealed diffuse small lymphocytic infiltration in the thyroid gland associated with Hashimoto’s thyroiditis. Immunohistochemical examination showed that the small lymphocytes were positive for T-cell markers with CD3 and CD45RO. The pathological diagnosis was chronic thyroiditis with atypical lymphocytes infiltration. However, Southern blot analysis of tumor specimens revealed only a monoclonal T-cell receptor gene rearrangement. Finally, peripheral T cell lymphoma was diagnosed. Therefore, the left hemithyroidectomy was also performed one month later. No adjuvant therapy was performed due to the tumor stage and its subtype. The patient is well with no recurrence or metastasis 22 months after the surgical removal of the thyroid. As malignant T-cell lymphoma of the thyroid gland with Hashimoto’s thyroiditis was difficult to diagnose, gene rearrangement examination needed to be performed concurrently.
PMCID: PMC3414802  PMID: 22515161
Peripheral T-cell lymphoma; Thyroid; Hashimoto’s thyroiditis; Molecular diagnosis; Gene rearrangement
2.  Immunohistochemical detection of p53 and Bcl-2 proteins in Hashimoto's thyroiditis and primary thyroid lymphomas. 
Journal of Clinical Pathology  1995;48(3):239-241.
AIMS--To investigate whether immunohistochemical staining using p53 and/or bcl-2 distinguishes between florid Hashimoto's thyroiditis and low grade mucosa associated lymphoid tissue (MALT) lymphoma of the thyroid. METHODS--Ten cases of Hashimoto's thyroiditis and eight of primary thyroid lymphoma were stained with monoclonal antibodies directed against p53 and bcl-2. RESULTS--In Hashimoto's thyroiditis most small lymphoid cells in mantle zones, within the thyroid parenchyma and in lymphoepithelial lesions expressed bcl-2 protein. Very occasional centroblasts in reactive germinal centres were positive for p53, but all other lymphoid cells from cases of Hashimoto's disease were negative for p53. In diffuse, low grade lymphomas bcl-2 protein was uniformly expressed by most tumour cells. However, low grade lymphomas with a follicular pattern did not express bcl-2. The diffuse, low grade lymphomas were negative for p53, while occasional larger cells in the follicular subtype were positive. Both high grade lymphomas were bcl-2 negative but strongly p53 positive. CONCLUSIONS--This study indicates that there is an inverse correlation between p53 and bcl-2 immunostaining in thyroid lymphomas (low grade lymphomas: bcl-2 positive, p53 negative; high grade lymphomas: bcl-2 negative, p53 positive). Furthermore, immunohistochemical staining for bcl-2 and p53 proteins does not distinguish florid Hashimoto's thyroiditis from diffuse, low grade thyroid lymphoma.
PMCID: PMC502457  PMID: 7730485
3.  A minute focus of extranodal marginal zone B-cell lymphoma arising in Hashimoto thyroiditis diagnosed with PCR after laser capture microdissection: a case report 
Thyroid Research  2009;2:9.
Primary thyroid gland lymphomas are uncommon tumours that occur in the setting of lymphocytic thyroiditis or Hashimoto's disease in almost all cases. In this condition a distinction between an inflammatory lymphoid infiltrate and a low grade lymphoma may be extremely difficult and precise criteria are necessary for a correct diagnosis.
Patient and methods
We report a case of a minute focus of primary extranodal marginal zone B-cell lymphoma (EMZBCL), incidentally discovered in a 63-year-old man with Hashimoto thyroiditis (HT) and diagnosed by means of polymerase chain reaction (PCR) after laser capture microdissection.
The histological examination of surgical specimen confirmed the diagnosis of HT and showed a minute focus of dense lymphoid infiltrate (less than 4 mm in diameter), composed by centrocyte-like cells forming MALT balls. Immunoistochemistry was not useful. A microscopic focus of EMZBCL was suspected on the basis of morphological features. PCR assays revealed the rearrangement of the heavy chain of immunoglobulins only in the microdissected suspicious area, confirming the diagnosis of EMZBCL.
Our finding suggests that in cases of autoimmune thyroiditis a careful examination of the thyroid specimen is warranted, in order to disclose areas or small foci of lymphomatous transformation. Furthermore, in difficult cases with doubtful immunohistological findings, ancillary techniques, such as molecular studies, are necessary for a conclusive diagnosis.
PMCID: PMC2745362  PMID: 19735541
4.  Extranodal marginal zone B cell lymphoma of MALT type with extensive plasma cell differentiation in a man with Hashimoto’s thyroiditis 
BMJ Case Reports  2011;2011:bcr0520114277.
Primary thyroid gland lymphomas are uncommon tumours that occur in the setting of lymphocytic thyroiditis or Hashimoto’s disease in almost all cases. Rarely these tumours show extensive plasmacytic differentiation. In these conditions, a distinction between an inflammatory thyroid infiltrate and extramedullary plasmacytoma may be extremely difficult and precise criteria and ancillary techniques are necessary for a correct diagnosis. The authors report a case of mucosa associated lymphoid tissue (MALT) lymphoma of the thyroid gland in a 69-year-old Iranian man with Hashimoto’s thyroiditis which was diagnosed by means of immunohistochemical stains. This case demonstrates that histology may not distinguish between extramedullary plasmacytoma and MALT lymphoma of the thyroid gland and the use of immunohistochemical staining stains were essential to prove definite diagnosis.
PMCID: PMC3207737  PMID: 22673712
5.  Co-Occurrence of Papillary Thyroid Carcinoma and Mucosa-Associated Lymphoid Tissue Lymphoma in a Patient with Long-Standing Hashimoto Thyroiditis 
Endocrinology and Metabolism  2013;28(4):341-345.
Papillary thyroid carcinoma (PTC) is a common affliction of the thyroid gland, accounting for 70% to 80% of all thyroid cancers, whereas mucosa-associated lymphoid tissue (MALT) lymphoma of the thyroid gland is uncommon. The simultaneous occurrence of both malignancies is extremely rare. We report the case of a patient with both PTC and MALT lymphoma in the setting of Hashimoto thyroiditis. An 81-year-old female patient was first admitted with goiter and hoarseness, which was attributed to an ultrasonographic thyroid nodule. Subsequent fine-needle aspirate, interpreted as suspicious of papillary thyroid cancer, prompted total thyroidectomy. MALT lymphoma was an incidental postsurgical finding, coexisting with PTC in the setting of Hashimoto thyroiditis. Although the development of MALT lymphoma is very rare, patients with longstanding Hashimoto thyroiditis should undergo careful surveillance for both malignancies.
PMCID: PMC3871033  PMID: 24396701
Thyroid cancer, papillary; Lymphoma, B-cell, marginal zone; Hashimoto disease
6.  Incidental MALT Type Lymphoma Exhibiting Prominent Plasma Cell Differentiation Associated with Hashimoto’s Thyroiditis. A Two Case Report 
Head and Neck Pathology  2008;3(1):27-30.
We present here two cases of incidental extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) showing prominent plasma cell differentiation associated with Hashimoto’s thyroiditis (HT). Histological examination demonstrated that both lesions exhibited HT including lymphoplasmacytic infiltration with the formation of germinal centers, destruction of the normal thyroid follicular architecture, Hürthle cell changes, and squamous metaplasia. The dominant tumor nodules of both cases contained large, well-circumscribed but unencapsulated aggregation of mature plasma cells and scattered centrocyte-like cells (CCL-cells). Both lesions contained a few lymphoepithelial lesions. Moreover, immunohistochemical study demonstrated that plasma cells and CCL-cells of these two lesions contained monotypic intracytoplasmic kappa light chain. Other small B-cell lymphomas, plasmacytoma and plasmablastic lymphoma were excluded using stains for CD5, CD10, CD23, CD43, CD56. Cyclin D1, human herpes virus type-8.
PMCID: PMC2807536  PMID: 20596985
Thyroid gland; MALT type lymphoma; Hashimoto’s thyroiditis; Plasma cell granuloma; Immunohistochemistry
7.  Follicular Lymphoma of the Thyroid Gland 
The majority of lymphomas arising in the thyroid gland are MALT lymphomas and diffuse large B cell lymphomas, which arise from a background of chronic lymphocytic thyroiditis. Follicular lymphoma may also present in the thyroid gland, but its clinicopathological features at this site are not well characterised, leading to difficulties in diagnosis and clinical management. We have addressed this problem by studying the clinical, morphological, immunophenotypic and genetic features of 22 such cases. All cases showed morphology characteristic of follicular lymphoma, However, in many the interfollicular neoplastic infiltrate was particularly prominent and all lymphomas contained readily identifiable and often striking lymphoepithelial lesions, features heretofore considered indicative of MALT lymphoma at this site. Furthermore, 13 of 18 cases for whom sufficient evidence was available had clinical and/or histological evidence of chronic lymphocytic thyroiditis. Analysis of genetic and immunohistochemical features identified two distinct groups. In one group, similar to typical adult follicular lymphoma, cases carried a t(14;18)/IGH-BCL2 and/or expressed Bcl2, and were mostly CD10-positive and of WHO grade 1-2. Follicular lymphomas in the other group lacked IGH-BCL2 and Bcl-2 expression, were often of WHO grade 3 and were often CD10-negative, similar to the minority of follicular lymphomas previously described that are Bcl-2-negative and are often encountered at other extranodal sites. The two groups differed in clinical stage at presentation, 11 patients in the former group but none in the latter group having disease beyond the thyroid gland. Appreciation of the spectrum of morphological, immunophenotypic and genetic characteristics of follicular lymphoma presenting in the thyroid gland should aid both diagnosis and clinical management.
PMCID: PMC2673478  PMID: 18830125
Thyroid gland; follicular lymphoma; extranodal lymphoma
8.  Malignant lymphoma of the urinary bladder: a clinicopathological study of 11 cases 
Journal of Clinical Pathology  2000;53(6):458-461.
Aim—To report the clinical and histological features and outcome of primary and secondary malignant lymphomas of the urinary bladder.
Methods—Eleven cases of malignant lymphoma of the urinary bladder were obtained from the registry of cases at St Bartholomews and the Royal London Hospitals. The lymphomas were classified on the basis of their morphology and immunophenotype, and the clinical records were reviewed.
Results—There were six primary lymphomas: three extranodal marginal zone lymphomas of mucosa associated lymphoid tissue (MALT) type and three diffuse large B cell lymphomas. Of the five secondary cases, four were diffuse large B cell lymphomas, one secondary to a systemic follicular follicle centre lymphoma, and one nodular sclerosis Hodgkins disease. Four patients with secondary lymphoma for whom follow up was available had died of disease within 13 months of diagnosis. Primary lymphomas followed a more indolent course. In one case, there was evidence of transformation from low grade MALT-type to diffuse large B cell lymphoma. The most common presenting symptom was haematuria. Cystoscopic appearances were of solid, sometimes necrotic tumours resembling transitional cell carcinoma, and in one case the tumours were multiple. These cases represented 0.2% of all bladder neoplasms.
Conclusions—Diffuse large B cell lymphoma and MALT-type lymphoma are the most common primary malignant lymphomas of the bladder. Lymphoepithelial lesions in MALT-type lymphoma involve transitional epithelium, and their presence in high grade lymphoma suggests a primary origin owing to transformation of low grade MALT-type lymphoma. Primary and secondary diffuse large B cell lymphomas of the bladder are histologically similar, but the prognosis of the former is favourable.
Key Words: bladder • lymphoma • mucosa associated lymphoid tissue lymphoma
PMCID: PMC1731210  PMID: 10911804
9.  Maltoma of Thyroid: A Rare Thyroid Tumour 
Case Reports in Otolaryngology  2013;2013:740241.
Introduction. Primary thyroid lymphomas constitute up to 5% of all thyroid malignancies and can be divided into non-Hodgkin's lymphomas (NHLs) of B- and T-cell types, as well as Hodgkin's lymphomas. Mucosa-associated lymphoid tissue (MALT) lymphomas are a relatively recently recognized subset of B-cell NHLs, and they are listed as extranodal marginal zone lymphomas according to the revised European-American lymphoma classification. Case Report. We report an uncommon case of a 44-year-old man, who noted a painless, growing mass on right side of his neck of the three-month duration. Thyroid profile was within normal limits. FNAC showed lymphocytic thyroiditis. The patient underwent a right hemithyroidectomy. The histologic examination and the immunohistochemistry showed an extra nodal marginal B-cell type maltoma (malt lymphoma). CHOP chemotherapy with rituximab was given. The clinical course has been favourable in the first year of followup, with no evidence of local or systemic recurrence of the disease. Discussion. Marginal zone lymphoma encompasses a heterogeneous group of B-cell tumours that variously arise within the lymph nodes, spleen, or extranodal tissues. A case of maltoma of thyroid is presented for its rarity and diagnostic dilemmas. Conclusion. Maltomas are slow-growing lymphomas. The optimal treatment and followup of patients with thyroid maltomas remain controversial at present.
PMCID: PMC3582082  PMID: 23476858
10.  Primary thyroid mucosa-associated lymphoid tissue lymphoma; a clinicopathological study of seven cases 
Primary thyroid mucosa-associated lymphoid tissue (MALT) lymphoma is a very rare subgroup of thyroid lymphoma, accounting for about 6 to 28% of all primary thyroid lymphomas. The purpose of this study was to evaluate its clinicopathological features and treatment outcomes.
We identified seven patients with thyroid MALT lymphoma who were treated between January 1997 and December 2007, and reviewed their clinicopathological features and follow-up outcomes.
There were five female and two male patients, and their mean age was 73 years. All patients presented with palpable neck mass. Two patients had hoarseness and dyspnea. All patients had a history of Hashimoto's thyroiditis with a mean of 175 months. Malignant lymphoma was suspected in only three patients using core needle biopsy. Four patients underwent thyroidectomy in the absence of preoperative pathologic confirmation, and histologic diagnosis was obtained after surgery. As initial treatment, complete surgical resection was performed in five patients, radiotherapy in one, and a combination of chemotherapy and radiotherapy in one. Six patients were alive for the mean follow-up period of 66 months and one patient died of unrelated causes. There were neither recurrences nor disease-specific mortalities.
When primary thyroid MALT lymphoma occurs in the thyroid or is confined to the neck, it responds well to local treatment such as surgical resection and external beam radiation therapy.
PMCID: PMC3243853  PMID: 22200037
Primary thyroid MALT lymphoma; Hashimoto's thyroiditis; Diffuse large B-cell lymphoma
11.  Somatostatin-receptor scintigraphy for staging and follow-up of patients with extraintestinal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT)-type 
British Journal of Cancer  2001;85(10):1462-1466.
The majority of lymphomas of the mucosa-associated lymphoid tissue (MALT)-type arise in the stomach, but extragastric locations are also frequently encountered. Due to previous results indicating that somatostatin receptor (SSTR)-expression distinguishes between gastric and extragastric MALT-type lymphoma, we have initiated a study to evaluate the role of SSTR-scintigraphy for staging and follow-up of patients with extragastric manifestations of MALT-type lymphoma. A total of 30 consecutive patients, including 24 with primary extragastric MALT-type lymphoma, 5 patients with dissemination to extragastric sites (including colon, lung, parotid, ocular adnexa and breast) following an initial gastric MALT-lymphoma and one patient with spread to stomach, lung and lymph nodes following parotid lymphoma were prospectively studied. All patients had histologically verified MALT-type lymphoma: 2 patients had lymphoma presenting in the lung, 9 in the ocular adnexa, 7 had lymphomas in the parotid, 2 patients had disease located in the breast, 3 patients had lymph-node relapse following MALT-type lymphoma of the parotid, the lacrimal gland and the thyroid, and 1 had primary MALT-lymphoma of the liver. All patients underwent SSTR-scintigraphy using 111In-DTPA-D-Phe1-Octreotide (111In-OCT) before initiation of therapy, while 13 also had a second scan after treatment. The results of gamma camera imaging were compared to conventional staging. No positive scans could be obtained in patients with dissemination following gastric lymphoma, while all patients with primary extragastric lymphoma had positive scans at the site of histologically documented involvement before initiation of therapy. In addition, also the patient with secondary spread to stomach, lung and lymph nodes was positive in all documented lymphoma sites. In one patient, focal tracer uptake in projection to the maxillary sinus was documented, which was bioptically verified as inflammation. In the scans performed after therapy, focal tracer accumulation in the left orbit indicated persistance of disease following irradiation in one patient with otherwise negative work-up, which was verified by MRI and biopsy 6 months later. In another patient, a positive scan indicated disease relapse in the lacrimal gland 9 months before clinical verification by means of ultrasound. In one patient, a focus not present in the pretherapeutic scan was found in the ethmoidal sinus, corresponding to a hyperplastic polyp. Both SST-scan as well as CT indicated disease persistance in one case, while negative scans corresponding to complete remission as judged by conventional staging were obtained following therapy in the remaining patients, and absence of relapse has been confirmed for a median follow-up of 2 years. These results indicate that 111In-OCT is an excellent tool for staging and non-invasive therapy-monitoring in extragastric MALT-type lymphomas. These data further confirm our initial finding that gastric MALT-type lymphomas do not express relevant amounts of respective SSTR, and that SSTR-scanning is able to distinguish between gastric vs extragastric origin of MALT-type lymphoma irrespective of the site of presentation.© 2001 Cancer Research Campaign
PMCID: PMC2363931  PMID: 11720429
somatostatin; extraintestinal MALT-lymphoma; scintigraphy
12.  Primary mucosa-associated lymphoid tissue thyroid lymphoma: a rare thyroid neoplasm of extrathyroid origin 
Rare Tumors  2012;4(1):e2.
Primary thyroid lymphoma is a rare malignancy, representing 2–8% of all thyroid malignancies and 1–2% of all extranodal lymphomas. The majority of cases concern non-Hodgkin's lymphoma of B cell origin, following by Hodgkin's disease, T cell lymphomas and rarely marginal zone B-cell mucosa-associated lymphoid tissue (MALT) lymphomas. MALT lymphomas have been associated with long-standing autoimmune Hashimoto's thyroiditis. We present the case of a 44-years-old woman with thyroid MALT lymphoma in the background of multinodular goiter of autoimmune origin.
PMCID: PMC3325747  PMID: 22532918
thyroid MALT lymphoma; thyroiditis Hashimoto.
13.  Clonal B cell populations in a minority of patients with Hashimoto’s thyroiditis 
Journal of Clinical Pathology  2004;57(12):1258-1263.
Background: Hashimoto’s thyroiditis (HT) is a risk factor for thyroid lymphoma, and clonal B cell populations in HT support this link. The literature on B cell clonality in HT is controversial.
Aims: To identify clonal B cell populations in HT and to assess their usefulness in differentiating HT from mucosa associated lymphoid tissue (MALT) lymphoma and predicting future development of lymphoma.
Methods: DNA from formalin fixed, paraffin wax embedded blocks of thyroid specimens from 10 patients with HT and two thyroid MALT lymphomas was analysed for B cell clonality by seminested polymerase chain reaction (PCR) using FRIII/LJH and FRIII/VLJH primers to amplify the IgH gene VDJ region. In one case, PCR products were sequenced. Immunohistochemistry was performed by labelled streptavidin–biotin technique using antibodies to: CD45, CD45RO, CD3, CD20, and cytokeratin.
Results: The histopathological and clinical findings were characteristic of HT. Clonal bands were seen in three and a polyclonal smear pattern was seen in seven cases. The clonal bands in HT were associated with a background smear, and could not be reproduced from other blocks from the same case or from deeper sections of the same block. The clonal bands in thyroid lymphomas were not associated with a background smear and were reproducible. None of the patients with clonal B cells has developed malignant lymphoma during a follow up of 10–13 years.
Conclusions: B cell clonal bands in HT have different features from those in lymphoma (non-pure and non-reproducible) and do not predict future development of lymphoma.
PMCID: PMC1770528  PMID: 15563664
Hashimoto’s thyroiditis; clonality; immunoglobulin gene rearrangements; polymerase chain reaction; thyroid lymphoma
14.  Importance of extensive staging in patients with mucosa-associated lymphoid tissue (MALT)-type lymphoma 
British Journal of Cancer  2000;83(4):454-457.
Lymphoma of the mucosa-associated lymphoid tissue (MALT) type usually arises in MALT acquired through chronic antigenic stimulation triggered by persistent infection and/or autoimmune processes. Due to specific ligand–receptor interactions between lymphoid cells and high-endothelial venules of MALT, both normal and neoplastic lymphoid cells display a pronounced homing tendency to MALT throughout the body. In the case of neoplastic disease these homing properties may be responsible for lymphoma dissemination among various MALT-sites. According to this concept, we have standardized staging procedures in all patients diagnosed with MALT-type lymphoma. All patients with MALT-type lymphoma underwent standardized staging procedures before treatment. Staging included ophthalmologic examination, otolaryngologic investigation, gastroscopy with multiple biopsies, endosonography of the upper gastrointestinal tract, enteroclysis, colonoscopy, computed tomography of thorax and abdomen and bone marrow biopsy. Biopsy was performed in all lesions suggestive for lymphomatous involvement, and evaluation of all biopsy specimens was performed by a reference pathologist. 35 consecutive patients with histologically verified MALT-type lymphoma were admitted to our department. Twenty-four patients (68%) had primary involvement of the stomach, five (15%) had lymphoma of the ocular adnexa, three (8.5%) had lymphoma of the parotid, and three (8,5%) of the lung. Lymph-node involvement corresponding to stage EII disease was found in 13 patients (37%), only one patient with primary gastric lymphoma had local and supradiaphragmatic lymph-node involvement (stage EIII). Bone marrow biopsies were negative in all patients. Overall, eight of 35 patients (23%) had simultaneous biopsy-proven involvement of two MALT-sites: one patient each had lymphoma of parotid and lacrimal gland, conjunctiva and hypopharynx, conjunctiva and skin, lacrimal gland and lung, stomach and colon, and stomach and lung. The remaining two patients had bilateral parotideal lymphoma. Staging work-up was negative for lymph-node involvement in all of these eight patients. The importance of extensive staging in MALT-type lymphoma is emphasized by the demonstration of multiorgan involvement in almost a quarter of patients. In addition, our data suggest that extra-gastrointestinal MALT-type lymphoma more frequently occurs simultaneously at different anatomic sites than MALT-type lymphoma involving the GI-tract. © 2000 Cancer Research Campaign
PMCID: PMC2374656  PMID: 10945490
MALT-type lymphoma; multifocal involvement; staging
15.  Early cytological diagnosis of extranodal stage I, primary thyroid Non-Hodgkin lymphoma in elderly patients. Report of two cases and review of the literature 
BMC Surgery  2013;13(Suppl 2):S49.
Primary thyroid lymphomas (PTLs) account for 5% of thyroid malignant tumors and often develop in patients with Hashimoto Thyroiditis (HT). Fine-needle cytology (FNC) is widely used in the diagnosis of thyroid nodules, including those arising in HT. Two PTL cases in HT elderly patients are here described and discussed.
FNC was performed in rapidly enlarged thyroid nodules of 2 elderly patients under ultrasound (US) control. FNC was used to prepare conventional cytologic smears, immunocytochemistry (ICC) and flow cytometry (FC) assessment of cell populations.
The above cases were diagnosed as well differentiated, small B-cell and diffuse large B-cell thyroid lymphomas, respectively, by means of FNC. The histological diagnoses were mucosa-associated non Hodgkin lymphoma (MALT) and diffuse large B-cell lymphoma (DLBCL), confirming FNC diagnoses, and patients were treated accordingly.
FNC diagnosis of PTL is reliable and accurate; it may be conveniently used in the clinical practice since it provides indications for appropriate therapeutic procedures or diagnostic surgery, and avoids to treat benign nodules.
PMCID: PMC3851195  PMID: 24267471
16.  Primary gastric T cell lymphoma mimicking marginal zone B cell lymphoma of mucosa-associated lymphoid tissue 
Journal of Hematopathology  2008;1(1):29-35.
Primary gastric T cell lymphoma is rare and mostly of large cell type. In this paper, we present a case of gastric T cell lymphoma morphologically similar to the gastric marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT). Morphologically, the cells are small with abundant clear cytoplasm. Lymphoepithelial lesions are readily identified with diffuse destruction of gastric glands. Immunohistochemically, the neoplastic cells are CD3+/CD4+/CD8−/Granzyme B−. Molecular studies revealed monoclonal T cell receptor γ gene rearrangement. Clinically, the patient responded initially to four cycles of R-CHOP, but then progressed. Because peripheral T cell lymphoma is usually associated with a poor prognosis, whereas marginal zone B cell lymphoma is an indolent lymphoproliferative disorder, this morphologic mimicry should be recognized and completely investigated when atypical small lymphoid infiltrates with lymphoepithelial lesions are encountered in the stomach.
PMCID: PMC2712325  PMID: 19669202
Primary gastric T cell lymphoma; MALT; H. pylori; HTLV-1
17.  Thyroid Lymphoma: Recent Advances in Diagnosis and Optimal Management Strategies 
The Oncologist  2013;18(9):994-1003.
Primary thyroid lymphoma is rare, and there are limited numbers of randomized or prospective trials to guide management, thus controversy remains over optimal treatment. The aim of this paper is to discuss the changes in diagnostic modalities and to focus on the recent alterations in the management of this rare disease, including targeted therapies as well as the more limited role of the endocrine surgeon.
Learning Objectives
Explain the diagnostic modalities used to diagnose primary thyroid lymphoma.Describe the role of the endocrine surgeon in the diagnosis and treatment of thyroid lymphoma.Cite the recent advances in the treatment of primary thyroid lymphoma.
Primary thyroid lymphoma is rare, composing approximately 5% of all thyroid malignancies and less than 3% of all extranodal lymphomas. It typically presents as a rapidly enlarging goiter with associated compressive symptoms. Thyroid ultrasound and fine needle aspiration cytology, using flow cytometry and immunohistochemistry, remain the main modalities used to confirm the presence of lymphoma. The increasing use of an ultrasound-guided core biopsy to achieve an accurate diagnosis has further limited the role of surgery. An open surgical biopsy may still be required not only for definitive diagnosis but also to confirm the subtype of lymphoma. There are limited numbers of randomized or prospective trials to guide management, and controversy remains over optimal treatment. Treatment and prognosis of this disease can be dichotomized into two separate groups: pure mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL) or mixed subtypes. Early stage (stage IE) intrathyroidal MALT lymphomas typically have an indolent course and may be treated with single-modality surgery, radiotherapy, or a combination of both. DLBCLs are more aggressive, and survival outcomes are highest with multimodal therapy incorporating monoclonal antibodies, chemotherapy, and radiotherapy. The prognosis is generally excellent but can be varied because of the heterogeneous nature of thyroid lymphomas. The aim of this paper is to discuss the changes in diagnostic modalities and to focus on the recent alterations in the management of this rare disease, including targeted therapies as well as the more limited role of the endocrine surgeon.
PMCID: PMC3780647  PMID: 23881987
Primary thyroid lymphoma; Thyroid; Lymphoma; Thyroid surgery; Thyroid malignancy
18.  Endocytoscopic findings of lymphomas of the stomach 
BMC Gastroenterology  2013;13:174.
The gastric lesions of various lymphomas were observed at the cellular level using endocytoscopy.
Endocytoscopy and magnifying endoscopy with narrow band imaging (NBI) were performed in 17 patients with lymphomas of the stomach. The lesions consisted of 7 with low-grade mucosa-associated lymphoid tissue (MALT), 5 with gastric involvement by adult T-cell leukemia/lymphoma (ATLL), 4 with diffuse large B-cell lymphoma (DLBCL), and 1 with peripheral T-cell lymphoma.
On conventional endoscopy, 9 were classified as having superficial spreading type, 7 were mass-forming type, and 1 was diffuse infiltrating type. Anti-H. pylori treatment was given in the 7 MALT lymphoma cases. NBI magnification endoscopy invariably showed dilatation or ballooning and destruction of gastric pits and elongation and distortion in microvessels. Endocytoscopy showed mucosal aggregation of interstitial cellular elements in almost all gastric lymphoma cases. The nuclear diversity in size and configuration was exclusively seen in gastric lymphomas other than MALT lymphoma, whereas the nuclei of MALT lymphoma cells were regular and small to moderate in size. Inter-glandular infiltration by lymphomatous cell elements was frequently observed in MALT lymphoma and DLBCL, but it was uncommon in peripheral gastric T-cell malignancies. Endocytoscopy could identify the disease-specific histology, the lymphoepithelial origin, as inter-glandular infiltration of cellular components in MALT lymphoma and the possibly related DLBCL cases. Complete regression (CR) was observed in 2 of the 7 MALT lymphoma patients. In the 2 patients with CR who underwent repeat endocytoscopy, the ultra-high magnification abnormalities returned to normal, while they were unchanged in those without tumor regression.
On endocytoscopy, intra-glandular aggregation of cellular components was invariably identified in lymphomas of the stomach. Nuclear regularity in size and configuration may indicate the cytological grade, differentiating the indolent low-grade from aggressive lymphoproliferative diseases. The inter-glandular infiltration seen on endocytoscopy can indicate the lymphoepithelial lesions seen in MALT lymphoma and related DLBCL. Endocytoscopy would be applicable for virtual histopathological diagnosis of different lymphoproliferative disorders and their clinical assessment during ongoing endoscopy.
PMCID: PMC3877966  PMID: 24369830
ATLL; DLBCL; Endocytoscopy; Gastric low-grade MALT lymphoma; H. pylori; Narrow band imaging
19.  Monocytoid B cell lymphoma: clinical and prognostic features of 21 patients. 
Journal of Clinical Pathology  1990;43(8):619-625.
Twenty one patients between 34 and 83 years of age with monocytoid B cell lymphoma (MBCL) of the lymph node were studied. The histological picture characteristically showed broad strands of medium sized cells with irregularly shaped nuclei and a fairly broad rim of slightly basophilic cytoplasm. One case developed into a centroblastic polymorphic lymphoma. Bone marrow infiltration was documented in three cases and leukaemic conversion in one case of MBCL. Seven patients had enlarged spleens. Eight patients were in stage I, five in stage II/IIE, two in stage IIIs and six in stage IV at the time of diagnosis. Of 18 patients subsequently followed up, eight were in complete remission, two in partial remission, and three were undergoing treatment at completion of the study; five patients had died. Relapse occurred in nine patients and was a common feature of MBCL. The prognosis of MBCL was comparable with that of other low grade malignant lymphomas. Fourteen patients presented with primary nodal lymphoma. In seven patients with nodal MBCL, however, a concomitant low grade B cell lymphoma of the mucosa-associated lymphoid tissue (MALT) was also found in the stomach (n = 4), nasopharynx (n = 1), salivary glands (n = 1) and thyroid gland (n = 1). Two of these cases developed into high grade lymphoma. These extra-nodal manifestations were found simultaneously with MBCL in five patients. In another two patients, however, these symptoms occurred in a later phase of the disease. It is emphasised that adequate staging procedures must be carried out in any case of nodal MBCL to exclude underlying low grade B cell lymphoma of the MALT.
PMCID: PMC502639  PMID: 2401728
20.  Rheumatoid nodules in the thyroid bed following total thyroidectomy: a case report 
Rheumatoid nodules occur in 30 percent of patients with active rheumatoid arthritis. Common sites include the buttocks or the extensor surface of the forearm, with one group documenting their presence in the thyrohyoid membrane. To the best of our knowledge, rheumatoid nodules have not been described in the thyroid bed.
Case presentation
We present the case of a 46-year-old Caucasian woman with active rheumatoid arthritis and Hashimoto's thyroiditis who presented with compressive neck symptoms. An ultrasound scan revealed that both lobes of her thyroid were enlarged. The right lobe measured 7.9×3.4×3.3cm and the left 8.3×3.3×3.1cm. A solitary 1.0×0.6×0.8cm nodule was seen in the right lower lobe. Her thyroid-stimulating hormone level was 4.22uU/mL (0.34 to 5.60). A total thyroidectomy was performed due to her symptoms and the possible growth of a nodule when on levothyroxine. A postoperative ultrasound scan showed no remaining thyroid tissue. The pathology revealed several small neoplasms ranging from a well-encapsulated adenoma to highly atypical follicular and papillary Hurthle cell lesions in the setting of Hashimoto’s thyroiditis. Low-dose radioactive iodine (33.4mCi) was given. Four months later, our patient complained of a feeling of fullness in her neck. A solid nodule of mixed echogenicity (5.6×3.3×2.3cm) was seen in the right level VI of the neck, and solid tissue of mixed echogenicity (2.9×2.3×1.7cm) on the left. Following repeat surgery, the pathology from the right specimen showed Hashimoto’s thyroiditis. The left specimen had areas of granuloma formation with fibrinoid necrosis and palisading histiocytes, consistent with the histology of rheumatoid nodules. No evidence of malignancy was seen. The patient continues to do well and remains disease-free.
Rheumatoid nodules have not been reported in the thyroid bed. Their pathogenesis is not clear. Postoperative release of tumor necrosis factor alpha and local vascular damage may have triggered the nodule formation in this case. Rheumatoid nodules must be kept in the differential diagnosis of an enlarging thyroid in the setting of active rheumatoid arthritis. A fine-needle aspiration biopsy may show granuloma formation and be the most cost-effective initial diagnostic step, especially if there is a concern for malignancy. Early identification of these nodules will help decrease morbidity from unnecessary interventions and result in treatment that is both timely and appropriate.
PMCID: PMC3843512  PMID: 24168730
Rheumatoid nodule; Thyroid bed; Rheumatoid arthritis
21.  Cytological diagnosis of thyroid nodules in Hashimoto thyroiditis in elderly patients 
BMC Surgery  2013;13(Suppl 2):S41.
Long standing Hashimoto Thyroiditis (HT) causes shrinking and atrophy of the thyroid, but may also lead to diffuse enlargement of the gland and/or formation of nodules. These nodules should be differentiated from papillary thyroid carcinoma (PTC) and primary thyroidal non-Hodgkin lymphoma (PTL), which are possible complications of HT, and require pre-surgical diagnoses and different treatments.
This study focuses on the role of fine-needle cytology (FNC) in the clinical surveillance and pre-surgical diagnosis of HT with diffuse and nodular enlargement of the gland in elderly patients.
Thirty-four elderly patients (≥ 65 yrs) with HT and diffuse or nodular enlargement of the thyroid underwent ultrasound (US)-guided FNC. Smears were routinely stained and evaluated; additional passes were used for flow cytometry (FC) assessment of lymphoid infiltrate in 6 cases.
The cytological diagnosis was HT in 12 cases with prevalence of Hurtle cells in 2 cases, PTC in 1 case and PTL in 2 cases. FC assessed the reactive, non-lymphomatous nature of the lymphoid infiltrate in 5 cases and demonstrated light chain restriction, hence the lymphomatous nature of the lymphoid infiltrate in 2 cases of PTL.
FNC plays a key role in the clinical surveillance and pre-surgical diagnosis of diffuse enlargement and nodular presentation of HT in elderly patients. FNC can correctly diagnose HT, PTC and PTL indicating the need for surgery and its extension in suspicious or neoplastic cases, leaving other cases to the medical treatment and clinical surveillance.
PMCID: PMC3851014  PMID: 24266923
22.  Primary Spinal Marginal Zone Lymphoma Relapse at a Different Spinal Level after Remission of the Primary Lesion 
Global Spine Journal  2013;3(4):261-264.
Study Design Case report.
Objective Most spinal lymphomas occur in the context of systematic lymphomas. Marginal zone lymphoma (MZL) is a type of B-cell lymphoma originating from the marginal zone of B-cell follicles. Mucosa-associated lymphoid tissue (MALT) lymphoma is a type of extranodal MZL and rarely occurs in the central nervous system. To date, there has been only one case report of primary spinal MALT lymphoma and there are no case reports of relapsed MALT lymphoma at a different location of the spine.
Results A 58-year-old man complained of gait disturbance and urinary dysfunction. Magnetic resonance images showed an abnormal lesion in the epidural space at T11–L1 compressing the conus medullaris. The patient underwent laminectomy and partial resection of the tumor. Histopathologic and immunohistochemical findings were consistent with MALT lymphoma. Following postoperative radiotherapy, the epidural mass disappeared completely. Three years later, epidural MALT lymphoma at a different location in the thoracic spine (T8–T10) occurred and caused myelopathy again. Histologic diagnosis of the relapsed tumor was the same as had been seen 3 years previously.
Conclusions This is the first case report of relapsed spinal MALT lymphoma at a different location of the thoracic spine. Though the prognosis of MALT lymphoma is fairly good, careful follow-up is needed to screen any relapse or transformation to a high-grade lymphoma.
PMCID: PMC3854575  PMID: 24436880
spinal tumors; epidural tumor; spinal marginal cell lymphoma; MALT lymphoma; thoracic spine
Molecular testing for mutations activating the mitogen-associated protein kinase signaling pathway is being used to help diagnose thyroid carcinomas. However, the prevalence of these mutations in thyroid lymphomas has not been reported. Therefore, we studied the prevalence of BRAF, NRAS, HRAS, and KRAS mutations in 33 thyroid lymphomas and correlated the mutational status with the clinical, pathologic, cytogenetic, and immunophenotypic findings. Eleven cases were also tested for PAX8/PPARγ translocations. The lymphomas included 25 diffuse large B-cell lymphomas, 6 extranodal marginal zone lymphomas of mucosa associated lymphoid tissue type, and 2 follicular lymphomas. Seventeen diffuse large B-cell lymphomas were germinal center type, 6 non-germinal center type and 2 unclassifiable (Hans algorithm). None of the cases had an associated thyroid carcinoma. Mutations of the BRAF gene were identified in 6 (24%) diffuse large B-cell lymphomas (three D594G in germinal center diffuse large B cell lymphomas, two K601N in germinal center diffuse large B cell lymphomas, and one V600E in non-germinal center diffuse large B cell lymphomas) and of the NRAS gene in two (8%) non-germinal center diffuse large B-cell lymphomas (Q61K and Q61H). BRAF and NRAS mutations were not found in any extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type or follicular lymphoma. HRAS and KRAS mutations were not identified in any of the cases, nor were PAX8/PPARγ translocations found. Thus, interpretation of finding a BRAF or NRAS mutation in the thyroid, particularly in preoperative thyroid aspirates, must take into account the differential diagnosis of a lymphoma. In addition to the diagnostic importance, our data also demonstrate that alteration in the mitogen-associated protein kinase pathway may play a role in the pathogenesis of some large B-cell lymphomas of the thyroid with potential therapeutic implications.
PMCID: PMC3434253  PMID: 22575864
thyroid; lymphoma; BRAF; RAS; mutations
24.  Case report: rare case of infiltration of small lymphocytic B-cell lymphoma in the thyroid gland of female patient with B-cell chronic lymphocytic leukemia (CLL-B/SLL-B) 
Thyroid Research  2013;6:1.
The article presents a case of 57-year-old woman with the infiltration of rare small lymphocytic B cell lymphoma in the thyroid gland. Initially, the patient was followed-up due to chronic lymphocytic B-cell leukemia diagnosed on the basis of histopathological examination of cervical lymph node. Eight months later, general symptoms occurred along with lymphocytosis and exacerbation of lesions in lymph nodes, and therefore, chemotherapy was started according to COP regimen. After four chemotherapy cycles, further progression of the disease was observed during chemotherapy. Computed tomography (CT) performed at that time showed generalized lymphadenopathy and the presence of an irregular area in left thyroid lobe. On palpation, the thyroid was asymmetrical, with enlarged left lobe and palpable lymph node packages on the left side of the neck. The levels of thyroid hormones and anti-thyroid antibodies were normal. Ultrasound examination of the thyroid gland showed non-homogeneous hypoechogenic structure of the left lobe and complete focal remodeling. Cytological examination of left-lobe lesion obtained during fine needle aspiration biopsy showed multiple small lymphoid cells, suggestive of small lymphocytic lymphoma. To confirm this diagnosis, flow cytometry of the biopsy material sampled from the left lobe was performed showing B cellimmunophenotype: CD19+/CD20+/CD22 dim/FMC-7, CD23+/CD5+, sCD79b-+, CD38-, CD10-, kappa and lambda-/weak reaction. The results of flow cytometry of the thyroid bioptate and blood were nearly identical, confirming leukemic nature of the infiltration in left thyroid lobe. Cytogenetic findings included the presence of 17p deletion (TP53 gene). The patient received immunochemotherapy with alemtuzumab. The progression of the disease occurred in the sixth week of therapy. The treatment was discontinued after 8 weeks due to worsening of patient’s general status. The patient died 15 months after the diagnosis.
PMCID: PMC3626553  PMID: 23282005
Chronic lymphocytic leukemia; CLL; Cytometry; Lymphoma; Thyroid
25.  Primary MALT Type Skin Lymphoma—Is ‘Wait and See’ a Possible Strategy? 
Clinical Medicine. Oncology  2008;2:153-158.
Primary cutaneous lymphomas are the second most common site of extranodal non-Hodgkin lymphoma. A specifically type named extranodal marginal zone B-cell lymphomas are indolent low-grade neoplasma.
We report a case of a 42-year-old white man with multiple subcutaneous tumors located on the trunk and neck. The histopathological exam showed a non-epidermotropic, dense lymphocytic infiltrate. Histologic, immunohistochemical and cytologenetic analysis diagnosed primary cutaneous B-cell lymphoma MALT type. Investigation for other extranodal MALT lymphoma gastrointestinal tract, lung, salivary and thyroid glands was negative. The patient refused radiotherapy, but he accepted every 6 months close follow-up. Over a seven years period, we noticed a progressively disappearance of the skin lesions.
The necessity of aggressive treatment of this disease with excellent prognosis is discussed.
The treatment necessity of primary cutaneous B-cell lymphoma MALT type is discussed.
PMCID: PMC3161667  PMID: 21892278
primary cutaneous B-cell lymphoma; MALT type; therapy

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