Primary B cell lymphoma of the thyroid and its relationship to Hashimoto's thyroiditis

Twenty-one cases were selected from 236 thyroidectomies with a diagnosis of Hashimoto's disease for detailed clinicopathologic study on the basis of "early" changes in three cases and an unusually heavy lymphoplasmacytic infiltrate in 18 cases. These cases were studied in conjunction with ten cases of high-grade non-Hodgkin's lymphoma of the thyroid. Immunoglobulin light chain restriction was demonstrated in five cases of Hashimoto's thyroiditis and the diagnosis was accordingly changed to low-grade lymphoma. All ten high-grade lymphoma cases were of B phenotype and light chain restriction could be demonstrated in eight of them. The study revealed close homology between the lymphoplasmacytic infiltrate in Hashimoto's thyroiditis and normal mucosa-associated lymphoid tissue (MALT). Like lymphomas of mucosal sites, thyroid lymphoma appears to be derived from the parafollicular ("centrocyte-like") B cells. The high-grade thyroid lymphomas appear to be derived from low-grade tumors. There were close histologic, immunohistologic, and clinical similarities between low- and high-grade non-Hodgkin's lymphomas of the thyroid and those appearing in mucosal sites. This study confirms the close association between Hashimoto's thyroiditis and B cell lymphoma of the thyroid gland and suggests that this tumor belongs to the group of non-Hodgkin's lymphomas derived from MALT.     

Primary non-Hodgkin's lymphoma of the thyroid gland: a population based study

During a 9-year-period, 50 cases of primary non-Hodgkin's lymphoma (NHL) of the thyroid gland were reported to a population-based lymphoma registry covering western Denmark giving an incidence of 2.06×10⁻⁶ cases per year. The male:female ratio was 1:4, and the mean age was 72.8 years for women and 62.8 years for men. On histomorphological reclassification 83% of the cases showed a high grade and 17% a low grade morphology. 98% had a B-phenotype and 2% a T-phenotype. In at least 33 of the cases, primary NHL of the thyroid gland was preceded by Hashimoto's thyroiditis and at least 25 of the patients had a high grade NHL which was transformed from Hashimoto's thyroiditis through a low grade B-cell lymphoma of MALT type. The most frequent presenting symptoms were goitre (100%), hoarseness (57%), stridor/dyspnoea (55%) and dysphagia (45%); thirty-six percent of the patients were hypothyroid at the time of diagnosis. Seventy-six percent of the patients had localized disease (stages 1–2) and 24% had disseminated lymphoma (stages 3–4). Five year survival was 34.5% and 5 year cause-specific survival 46.2%. The following factors were associated with a poor prognosis: stage 3–4 disease, elevated S-urate, presence of hoarseness and age >66 years. Morphological subtype did not correlate significantly with survival.     

Malignant lymphoma of the thyroid. A 30-year clinicopathologic experience and an evaluation of the presence of Epstein-Barr virus.

Lymphoma of thyroid is uncommon, and Epstein-Barr virus (EBV) is found in many lymphomas. We studied the clinicopathologic characteristics in Hong Kong Chinese and analyzed the presence of EBV in thyroid lymphomas by reviewing data collected during 3 decades. We studied EBV gene expression by in situ hybridization and immunohistochemistry. Primary thyroid lymphomas were found in 23 patients (diffuse large B-cell lymphoma, 18; marginal zone B-cell lymphoma, 4; plasmacytoma, 1), and secondary lymphomas were found in 9 patients (diffuse large B-cell lymphoma, 3; Burkitt lymphomas, 2; Burkitt-like lymphoma, 1; hairy cell leukemia, 1; nasal T-cell and natural killer cell lymphoma, 1; and intestinal T-cell lymphoma, 1). Primary thyroid lymphomas were large (mean, 7 cm), found commonly in older women, and often misdiagnosed as undifferentiated carcinomas. Fine-needle aspiration was not helpful for diagnosis. Fifteen patients had Hashimoto thyroiditis. A history of thyrotoxicosis was found in 3 patients, and coexistence of 3 diseases (papillary microcarcinomas, primary thyroid lymphoma, and Hashimoto thyroiditis) was found 4 patients. The 5-year survival rate for primary thyroid lymphoma was 53%. Combined surgery and radiotherapy seemed to be the best treatment. Secondary thyroid lymphomas often were asymptomatic. EBV messenger RNAs were detected in 1 primary and 1 secondary thyroid lymphoma. The EBV gene expression in primary thyroid lymphoma showed a type II latency pattern. Thyroid lymphomas in Chinese had important clinicopathologic features. EBV may have a role in a subset of cases.     

Small cell carcinoma of the thyroid. A reclassification of cases originally diagnosed as small cell carcinomas of the thyroid

99 cases of undifferentiated carcinomas of the thyroid and nine cases of primary malignant Non-Hodgkin lymphomas of the thyroid were examined from 1967 to 1983 in our institute. Among the undifferentiated carcinomas nine cases were classified as small cell subtype. Over the years, the histopathological handling in regard to small cell subtype of undifferentiated carcinoma and primary malignant Non-Hodgkin lymphoma has changed. The frequency of primary malignant Non-Hodgkin lymphoma has increased conspicuously in the last few years, whereas the number of small cell carcinomas decreased. A reclassification, based on immunohistochemical investigation for tumor markers of the nine cases originally diagnosed as small cell carcinomas from 1967 to 1983 revealed that five cases were poorly differentiated carcinomas or undifferentiated carcinomas of the spindle cell type. In three cases the primary diagnosis had to be revised into malignant Non-Hodgkin lymphoma of the diffuse "histiocytic" type. The postmortem examination of the patient with the remaining small cell carcinoma "of the thyroid" revealed a clinically undetected small cell carcinoma of the lung with metastases to the cervical lymph nodes and the thyroid gland. These findings are in agreement with the results of several recently published papers indicating that true small cell carcinoma of the thyroid must be a very rare tumor.     

Malignant T-cell lymphoma of the thyroid gland associated with Hashimoto's thyroiditis

Reported herein is a rare case of malignant T-cell lymphoma of the thyroid gland that developed in a 71-year-old woman with a past history of chronic thyroiditis. The chief complaints were rapidly growing neck mass, weight loss and hoarseness. Presence of abnormal lymphoid cells in the peripheral blood, and an increase in anti-microsome antibodies and anti-thyroglobulin antibodies were found on preoperative laboratory tests. A diagnosis of suspicious malignant lymphoma of the thyroid gland accompanied by Hashimoto's thyroiditis was made, and a total thyroidectomy was performed. 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 CD4 predominance. Southern blot analysis of tumor specimens revealed a monoclonal T-cell receptor gene rearrangement. Peripheral T-cell lymphoma was diagnosed. No adjuvant therapy was performed because of the tumor stage and its subtype. The patient is well with no recurrence or metastasis 25 months after the surgical removal of the thyroid. The present case suggests that Hashimoto's thyroiditis might play an important role in the carcinogenesis of thyroid lymphoma not only of B-cell lineage but also of T-cell lineage.     

Occurrence of non-Hodgkin's lymphoma after therapy for Hodgkin's disease.

We studied the clinical and pathological features of six cases of non-Hodgkin's lymphoma (diffuse undifferentiated in four cases and diffuse histiocytic in two cases) occuring in patients treated for Hodgkin's disease. All six patients had received both radiation and chemotherapy. Abdominal or gastrointestinal involvement was present in five of the six cases. None of the patients had evidence of Hodgkin's disease when the diagnosis of non-Hodgkin's lymphoma was made. Five of the six patients were among a study group of 579 patients with Hodgkin's disease, prospectively followed since diagnosis. At 10 years the actuarial risk of development of non-Hodgkin's lymphoma in this study group is 4.4 per cent (1.2 to 15.0) (per cent probability with 95 per cent confidence limits) and is similar to that of developing acute leukemia: 2.0 per cent (0.3 to 12.9). Non-Hodgkin's lymphoma is a second tumor that may occur late in the course of patients treated for Hodgkin's disease--particularly in patients who have received both radiation therapy and chemotherapy. Like acute leukemia, non-Hodgkin's lymphoma may be another cancer that represents a substantial late risk of combined-modality therapy.     

Nuclear morphometry of primary B cell thyroid lymphoma.

Thyroid lymphoma is usually distinguished from anaplastic thyroid carcinoma and from Hashimoto's thyroiditis by morphological and immunohistochemical assessment of tissue sections. Our objective was to assess the value of nuclear morphometry in the differential diagnosis of these conditions. Nuclear area measurements were performed on 10 cases of thyroid lymphoma using an IBAS 2000 Image Analyser and compared with similar measurements performed on 10 cases of Hashimoto's thyroiditis and 2 of anaplastic thyroid carcinoma. It was found that karyometry demonstrated differences between all three conditions, the cases of thyroiditis being distinguishable from lymphoma on the basis of mean nuclear area alone. Mean nuclear area for lymphomas was greater than for Hashimoto's thyroiditis and lower than for anaplastic carcinomas. The mean nuclear area also reflected the grade of lymphoma, with the exception of one case which had a large reactive T cell population. It is concluded that nuclear morphometry provides valuable information in the diagnosis and assessment of thyroid lymphomas.     

原发性甲状腺非霍奇金淋巴瘤5例报道及文献复习

目的：观察原发性甲状腺非霍奇金淋巴瘤（ＮＨＬ）的病理形态特征,初步探讨其起源问题。方法：通过ＨＥ及免疫组化染色观察５例原发性甲状腺ＮＨＬ,并复习文献,结果：５例原发性甲状腺ＮＨＬ中,中心母细胞型１例,中心细胞－中心母细胞混合型２例,多形性免疫母细胞型１例及青草厢关淋９ＭＡＬＴ）淋巴次１例。免疫组化结果显示瘤细胞均表达ＬＣＡ、Ｌ２６、其中３例Ｋａｐｐａ阳性,２例Ｌａｍｂｄａ阳性。结论：原发性甲状腺Ｎ     

Clinically unsuspected Hodgkin's lymphoma diagnosed primarily from bone marrow trephine biopsy: report of six cases

Bone marrow may be the initial or rarely the only site of involvement in Hodgkin's lymphoma. A high index of suspicion is required to pick up the histopathological changes of Hodgkin's lesions in the bone marrow like necrosis, presence of Reed-Sternberg cell or its variant in a polymorphic background infiltrate, focal fibrosis and myxoid change especially in the absence of classical clinical picture. Bone marrow with immunohistochemistry has a valuable role in the staging and in the diagnosis of primary medullary Hodgkin's lymphoma. B-symptoms may easily masquerade as an infectious process as in all our cases the patients had fever as a presenting feature, in four of them tuberculosis was suspected clinically and two had received antitubercular therapy elsewhere. We report six human immunodeficiency virus-negative patients diagnosed over a period of 5 years in which the initial diagnosis of Hodgkin's lymphoma was suggested from bone marrow histology.     

原发性乳腺恶性淋巴瘤临床病理分析

目的：探讨原发性乳腺恶性淋巴瘤的临床病理、免疫组织化学及预后特征。方法：对8例原发性乳腺恶性淋巴瘤的临床资料、术前诊断、病理形态、免疫组织化学及预后进行分析。结果：8例原发性乳腺恶性淋巴瘤患者均为女性,发病年龄34－65岁,平均年龄46．4岁。左乳4例,右乳3例,双侧乳腺发病1例。7例患者为临床IE期,1例为ⅡE期。5例为弥漫大B细胞淋巴瘤,其中4例为中心母细胞形态,1例为免疫母细胞形态;3例为黏膜相关淋巴组织型边缘区淋巴瘤。8例均为白细胞共同抗原（LCA）、CD20、CD45RA阳性;CD43、CD45RO、CD5、CD10均阴性,3例雌、孕激素受体均阴性。治疗大多采用综合治疗,术后6例随访8－108个月未见复发。结论：原发性乳腺淋巴瘤少见,术前诊断较难。组织学类型主要为弥漫大B细胞淋巴瘤和黏膜相关淋巴组织淋巴瘤,经综合治疗后,原发性乳腺淋巴瘤的预后较好。     

Hashimoto''s thyroiditis manifesting monoclonal lymphocytic infiltration.

Hashimoto's thyroiditis (HT) and lymphoma are sometimes difficult to distinguish between. Moreover, lymphoma sometimes develops in a thyroid gland from pre-existing HT. Open- or large-needle biopsy usually distinguishes between them; the specimen may be examined histologically and subjected to immunohistochemistry. Another possible method of examination is fine-needle aspiration biopsy (FNAB). The cells obtained may be evaluated cytologically, and subjected to flow cytometry, using various antibodies. In this study, anti-kappa and anti-lambda antibodies are especially important, as a gross predominance of kappa or lambda B lymphocytes infiltrating the thyroid is evidence for a B cell monoclone. In this study, 15 patients were selected because of their rapidly growing goitres. They all underwent FNAB. Five had cytology typical of HT, and no evidence of monoclonality on flow cytometry. They were diagnosed as HT without further histopathology. The remaining 10 patients had cytology suspected of lymphoma, or evidence of monoclonality on flow cytometry, or both. These patients underwent open- or large-needle biopsy. Only three of them were diagnosed histopathologically as lymphoma; the other seven were diagnosed histopathologically as HT, making 12 cases of HT in all. Five of these 12 cases, and one of the three cases of lymphoma showed flow cytometrical evidence of monoclonality; thus evidence of monoclonality from FNAB, while interesting, does not necessarily serve to differentiate between HT and lymphoma. Furthermore, the immunohistochemical assessment of monoclonality did not correlate with the flow cytometrical assessment. Follow-up evidence will be required to discover whether those patients with a B cell monoclone in their HT are the ones who develop a lymphoma.     

Monocytoid B cell lymphoma: clinical and prognostic features of 21 patients.

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.     

Fine-needle aspiration cytology of malignant lymphoma of the thyroid

Our experience with fine-needle aspiration cytology in five cases of malignant lymphoma of the thyroid is reported. Only one case was correctly diagnosed as malignant lymphoma from the original cytologic reports. Three cases were misdiagnosed as anaplastic carcinoma of small-cell type and two of these three cases were subsequently revised as malignant lymphoma after a second aspiration. The final case was misdiagnosed as chronic thyroiditis at both the first and second aspirations; following a third aspiration, 8 mo later, it was correctly diagnosed as malignant lymphoma. Cytological findings of malignant lymphoma are as follows: many malignant cells are distributed as isolated cells and show monotonous features. Malignant cells are slightly larger than normal lymphocytes. Sometimes cleaved cells or large nucleoli are visible. The differential diagnosis of cytologic findings of malignant lymphoma and the other thyroid diseases is discussed in detail.     

Postpartum silent thyroiditis simulating a malignant lymphoma of the thyroid

A case of postpartum silent thyroiditis simulating a malignant lymphoma of the thyroid is reported. The patient was a 30-yr-old female who had received irradiation thearapy to the neck for malignant lymphoma of the thyroid 9 yr previously. She was referred to our department because of a struma associated with acute aggravation of chronic thyroiditis after parturition. In this case, the mechanism of the disease was explained by the “immune rebound hypothesis”. It was difficult to differentiate postpartum silent thyroiditis from malignant lymphoma of the thyroid, either clinically or cytologically, when the immune-rebound phenomenon with lymphocytic infiltration and the appearance of lymphoid follicles were prominent. The immunological status of patients with chronic thyroiditis accompanied by morphological changes should be taken into consideration before establishing the diagnosis of malignant lymphoma of the thyroid.     

Primary lymphoma of the thyroid: a clinical, histological and immunohistochemical study of 20 cases

Twenty cases of malignant lymphoma arising in the thyroid gland were studied clinically, histologically and immunohistochemically. Nineteen cases were non-Hodgkin's lymphoma (15 diffuse and four follicular lymphoma) and one was a plasmacytoma. Immunohistochemical analysis of the lymphomas using paraffin-embedded sections disclosed that 17 lymphomas were B-cell type and two were T-cell type. The plasmacytoma was of IgG kappa type. The large majority of the lymphomas were associated with an underlying chronic thyroiditis. The 5-year survival rate of the patients was 70%. An unfavourable diagnosis was more likely when the tumour was diffuse rather than follicular, when it was of diffuse large cell type or of immunoblastic type and when there was cervical lymph node involvement.     

Primary squamous-cell carcinoma of the thyroid gland: new evidence in support of follicular epithelial cell origin

Primary squamous-cell carcinoma (SCC) of the thyroid gland is extremely rare. We had an opportunity to treat two such cases recently. Two elderly females presented with left lobe thyroid swelling that had a history of long-standing goiter. Fine-needle aspiration (FNA) of the thyroid nodule was done in both cases. FNA cytology showed an thyroid abscess in the first, and a Hürthle-cell neoplasm in the second case. Histopathologic diagnosis was a well-differentiated squamous-cell carcinoma with an adjacent area of lymphocytic thyroiditis in the first case, and a moderately differentiated squamous-cell carcinoma in association with a Hürthle-cell adenoma in the second case. Serial sections of the excised gland ruled out any other associated thyroid malignancy. Immunostaining for pan-cytokeratin, thyroglobulin, and calcitonin were performed. The tumor, comprising polygonal and spindle cells, showed positive staining for cytokeratin and thyroglobulin; however, calcitonin did not stain any structures. Exhaustive clinical, endoscopic, and radiological examinations, i.e., X-ray of the chest, contrast-enhanced computer tomography (CECT) of the neck and chest, and ENT checkup in both cases did not reveal any primary site of squamous-cell carcinoma as the likely source of the metastases, or any contiguous spread from neighboring structures. Both patients had ipsilateral nodal metastases, and both succumbed to the disease within 6 mo of histological diagnosis. The interesting observation in both cases was thyroglobulin positivity, indicating a follicular epithelial cell origin of the SCC.     

Primary mucoepidermoid carcinoma and sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid gland: a report of nine cases.

Mucoepidermoid carcinoma is a rare primary thyroid tumor with indolent biologic potential. Two types of tumors have been described under this category: mucoepidermoid carcinoma (MEC) and sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE). The MEC shows both squamous and glandular differentiation in a background of a noninflamed gland, whereas SMECE is characterized by extensive sclerosis, squamous and glandular differentiation, a concomitant inflammatory infiltrate rich in eosinophils, and a background of lymphocytic thyroiditis. We present nine cases of these entities: five MEC and four SMECE. All tumors occurred in women (age 27 to 73 years). Five tumors showed extrathyroidal invasion and multiple lymph node metastases. One case of MEC showed a concomitant tall cell variant of papillary carcinoma with vascular invasion, and two cases showed intimately associated areas of usual papillary carcinoma. One of the latter cases also showed areas of transformation to anaplastic carcinoma. In all cases of SMECE and in only one case of MEC, the uninvolved thyroid tissue showed lymphocytic thyroiditis. Follow-up information was available in four of the nine cases (3 months to 7 years). Two patients with SMECE are alive with no evidence of disease. One patient with MEC and tall cell variant of papillary carcinoma died of disease after 3 months, and the patient with anaplastic carcinoma died after 5 months with lung metastasis. Both MEC and SMECE were positive for cytokeratin and negative for calcitonin. All cases of MEC were positive for thyroglobulin, whereas all cases of SMECE were negative. The immunohistochemical findings suggest that both MEC and SMECE have different histogenesis.     

Investigation of the clonality of lymphocytes in Hashimoto's thyroiditis using immunoglobulin and T-cell receptor gene probes

Southern blotting and DNA hybridization were used for the detection of immunoglobulin and T-cell receptor gene rearrangements in thyroid tissue from six patients with Hashimoto's thyroiditis, three patients with B-cell lymphoma complicating Hashimoto's thyroiditis, and two patients with nonspecific lymphocytic thyroiditis. Immunoglobulin gene rearrangements were detected only in patients with histologic evidence of lymphoma. A single T-cell receptor beta-chain gene rearrangement was detected in one of the patients with uncomplicated Hashimoto's thyroiditis. Based on our knowledge of primary thyroid lymphomas, it is highly unlikely that this case represents an early, histologically occult T-cell lymphoma. The uniform lack of immunoglobulin gene rearrangements in Hashimoto's thyroiditis supports the use of genotypic analysis in differentiating between uncomplicated Hashimoto's thyroiditis and non-Hodgkin's lymphoma. The finding of a T-cell receptor gene rearrangement in a case of Hashimoto's thyroiditis suggests that the immune response in this disease occasionally may be clonally restricted.     

Cytodiagnosis of primary thyroid lymphoma with histologic correlation: A case report

Primary thyroid lymphoma is a very rare disease. Here, we present a case of primary diffuse large B-cell lymphoma (DLBCL) in a 48-year-old female involving thyroid gland. The patient had thyroid swelling for 15 years which rapidly increased during last 5 months. Fine needle aspiration cytology revealed monomorphic large cells arranged discretely. The cells have high nuclear-cytoplasmic ratio with prominent single to multiple nucleoli. Aggregates of thyroid follicular cells were absent in the smears. A cytodiagnosis of DLBCL was made and a differential diagnosis of lymphocytic thyroiditis was also included. Subsequent histologic examination revealed a high-grade non-Hodgkin lymphoma (NHL). Immunohistochemistry showed the tumor cells expressing CD45, CD20, BCl-6, and tumor cells were negative for cytokeratin, epithelial membrane antigen, CD3, CD5, and CD30. Proliferative index (Ki-67) was very high (70%). Thus, a final diagnosis of NHL of DLBCL subtype was established. The patient was treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristin, prednisone) and radiotherapy. The patient is under one-year follow-up which is uneventful.     

Fine-needle aspiration cytology of extranodal lymphoma

The assessment of lymphoproliferative disorders using fine-needle aspriation (FNA) cytology may be problematic particularly when organs other than lymph node are involved. In this report we have reviewed 26 consecutive FNA specimens from superficial extranodal sites which were reported as diagnostic or suggestive of malignant lymphoma. The aspirates were obtained from skin or subcutaneous tissue (ten cases), thyroid (five cases), salivary gland (five cases), breast (four cases), neck, and pharynx (one case each). Ancillary studies including immunocytochemistry, in situ hybridisation to detect immunoglobulin light chain mRNA expression, and polymerase chain reaction for analysis of immunoglobulin heavy chain gene rearrangement were performed in 20, 12, and 7 cases, respectively. Clinicopathologic correlation confirmed the diagnosis of lymphoma in 25/26 aspirates. Nine of the 14 patients whose initial presentation was with an extranodal mass were considered to have primary lymphomas of mucosa-associated lymphoid tissue (MALT) type. In contrast, ten of 11 patients with recurrent extranodal disease had primary nodal type lymphomas. There was one false-positive diagnosis, a neck mass misinterpreted cytologically as B-cell lymphoma which was ultimately shown to be a branchial cyst. FNA cytology supported by appropriate ancillary investigations provides accurate diagnosis in most cases of extranodal lymphoma. Diagn. Cytopathol. 1998;19:260–266. © 1998 Wiley-Liss, Inc.