Lymphoma



Lymphoma


Lester D. R. Thompson, MD





Key Facts


Terminology



  • Primary thyroid lymphoma comprising heterogeneous group of tumors



    • Nearly all arise within chronic lymphocytic thyroiditis (80x increased risk)


Clinical Issues



  • ˜ 2-5% of all thyroid gland neoplasms


  • Mean age: 65 years


  • Female > > Male (3-7:1)


  • Patients usually present with stage IE or IIE


  • Adjuvant chemotherapy and radiation


  • Mortality is grade and stage dependent (overall, 60% 5-year survival)


Microscopic Pathology



  • Soft to firm, lobular, bulging cut surface, “fish flesh”


  • Thyroid gland effaced by atypical lymphoid cells


  • Lymphoepithelial lesions (LELs) are diagnostic


  • EMZBCL: Vague nodularity to diffuse effacement



    • Colonization or follicle lysis by neoplastic B-cells


    • Atypical small lymphocytes, marginal zone cells, monocytoid B-cells, immunoblasts and centroblast-like cells, plasma cells


  • DLBCL: Diffuse, large, atypical cells with increased mitotic figures


Ancillary Tests



  • Usually B-cell immunophenotype (CD20, CD79a)


  • Keratin highlights lymphoepithelial lesions


Top Differential Diagnoses



  • Chronic lymphocytic thyroiditis, undifferentiated carcinoma







This EMZBCL shows a vague nodularity or “follicular” effacement of the thyroid parenchyma. The multifocal zones begin to show aggregation. There is a background of chronic lymphocytic thyroiditis image.






Lymphoepithelial lesions (LELs) are one of the best diagnostic features of thyroid lymphomas. They are comprised of atypical lymphoid cells infiltrating and destroying the thyroid follicular epithelium image.


TERMINOLOGY


Abbreviations



  • Diffuse large B-cell lymphoma (DLBCL)


  • Extranodal marginal zone B-cell lymphoma (EMZBCL)


Synonyms



  • WHO terminology is used



    • Past lymphoma classifications systems are not to be used


Definitions



  • Primary lymphoma arising within thyroid gland, usually associated with lymphocytic thyroiditis, comprising a heterogeneous group of tumors



    • Mucosa-associated lymphoid tissue (MALT) is setting for development of extranodal marginal zone B-cell lymphoma, which may transform into diffuse large B-cell lymphoma


    • Lack systemic involvement



      • Regional lymph nodes may occasionally be affected


    • Rare: Follicular lymphoma (FL), extraosseous (extramedullary) plasmacytoma, Hodgkin lymphoma


ETIOLOGY/PATHOGENESIS


Pathogenesis



  • Carcinogenesis is multistep, multifactorial process with progressive accumulation of genetic changes


  • Nearly all lymphomas arise in setting of chronic lymphocytic thyroiditis (Hashimoto disease)


  • Acquired MALT from autoimmune, immune deficiency or inflammatory process



    • Nodular or diffuse infiltrate of lymphoid cells, frequently with follicles and germinal centers, and oncocytic metaplasia of thyroid epithelium


    • Fibrosis and epithelial atrophy supports chronicity


  • MALT lymphoma shows increased ratio of CD8(+) cells (suppressor/cytotoxic cell) to CD4(+) cells (helper/inducer cell) as compared to lymphocytic thyroiditis


  • MALT lymphoma cell of origin is from post germinal center, marginal zone B-cells


CLINICAL ISSUES


Epidemiology



  • Incidence



    • Uncommon



      • ˜ 2-5% of all thyroid gland neoplasms


      • ˜ 5% of all extranodal lymphomas


      • EMZBCL: < 2% of all extranodal lymphomas; DLBCL: ˜ 15%


    • Relative risk of developing a lymphoma is 80x greater in patients with chronic lymphocytic thyroiditis (compared to age- and sex-matched controls)


  • Age



    • Mean: 65 years



      • Wide age range (14-90 years)


  • Gender



    • Female > > Male (3-7:1)


Site



  • Must exclude secondary involvement of thyroid gland



    • Neck or mediastinal lymph nodes affected by lymphoma directly extending into thyroid gland


    • Relates to different staging and management


Presentation



  • Mass or goiter, often with recent rapid enlargement



    • Causes obstructive symptoms related to compression


  • Pain


  • Dysphagia, dyspnea, and hoarseness



    • ˜ 30% of patients


  • Hypothyroidism (associated with Hashimoto thyroiditis)



    • Rarely, hyperthyroidism due to follicle destruction



  • Associated cervical adenopathy in some cases


  • Choking, coughing, and hemoptysis are uncommon


  • Symptoms are usually present for short duration



    • EMZBCL: Mean: 6-12 months


    • DLBCL: Mean: 4 months


  • Patients usually present with stage IE or IIE


  • Patients usually lack B symptoms



    • Fever, profound night sweats, weight loss, anorexia


Laboratory Tests



  • Antithyroid serum antibodies usually present


  • Most patients are euthyroid


Treatment



  • Options, risks, complications



    • Surgery for debulking and tissue diagnosis


    • Radiation may result in mucositis, hypothyroidism, and radiation pneumonitis


  • Surgical approaches



    • Obtain tissue for diagnosis: Core needle or partial lobectomy


    • Previously, surgery included lobectomy or thyroidectomy with lymph node dissection


    • Surgery is used to debulk or decompress


  • Adjuvant therapy



    • Adjuvant chemotherapy and radiation after appropriate classification through needle biopsy


    • DLBCL: Combined modality therapy


  • Drugs



    • Chemotherapy regimens based on histologic type, grade, and stage



      • EMZBCL: Oral chlorambucil or intravenous chemotherapy


      • DLBCL: Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy


  • Radiation



    • Based on histologic type, grade, and stage



      • EMZBCL: Single modality radiation therapy (usually up to 40 Gy)


      • “Involved field only” or “extended field radiotherapy”; latter associated with lower rates of local recurrence or relapse


      • DLBCL: Hyperfractionated radiation


  • New modalities



    • Anti-CD20 therapy and new forms of immunotherapy are experimental but hold promise


Prognosis



  • Mortality is grade and stage dependent


  • Overall, approximately 60% 5-year disease-specific survival (DSS), although grade and stage dependent



    • Stage IE or IIE, low-grade histology: > 95% 5-year DSS


    • Stage IE or IIE, DLBCL: 50-70% 5-yr DSS


    • Stage IVE: ˜ 30% 5-yr DSS


  • Poor prognostic features include



    • Age > 65 years


    • Male


    • High stage (IIIE, IVE)


    • Dysphagia (vocal cord paralysis)


    • Extrathyroidal extension


    • Tumor histology (DLBCL > FL > EMZBCL)


    • Diffuse architecture


    • Vascular invasion


    • High mitotic rate


  • Combined conservative treatment: Lower relapse rate, reduced distant recurrence, least side effects


  • Most patients present at stage IE or IIE (extranodal)



    • DLBCL: More likely to have stage IIIE or IVE


  • If disseminated, most frequently involved sites are



    • Regional (cervical), mediastinal, and abdominal lymph nodes


    • Less common: Bone marrow, gastrointestinal tract, lung, bladder, and liver


IMAGE FINDINGS


Radiographic Findings



  • Ultrasound



    • Marked hypoechoic, asymmetrical pseudocystic mass compared with residual thyroid tissue



  • Computed tomography



    • Heterogeneous mass, sometimes with cystic change


  • Radioisotopic scan



    • 131I scan: Lymphoma usually “cold”


    • Tc-99m pertechnetate scintigraphy: Possible “warm” nodule


MACROSCOPIC FEATURES


General Features



  • May affect one or both lobes


  • Soft to firm, lobular and multinodular appearance


  • Effacement of normal thyroid


  • Solid and cystic areas


  • Cut surface: Bulging, smooth, pale-tan, “fish flesh”


  • Usually homogeneous or mottled


  • Extension into perithyroidal soft tissues


Size



  • Wide variation


  • Range up to 20 cm


MICROSCOPIC PATHOLOGY


Histologic Features



  • Nearly constant background of chronic lymphocytic thyroiditis


  • Effacement of normal thyroid gland parenchyma



    • Ranges from vague nodularity to diffuse effacement


  • Extension beyond thyroid gland into fat and skeletal muscle in about 50% of cases


  • Lymphoepithelial lesions (LELs) are diagnostic



    • Atypical lymphoid cells infiltrating and destroying thyroid follicular epithelium


    • 2 types



      • MALT balls: Rounded balls or masses, filling and distending lumen of thyroid follicles


      • Lymphoepithelial lesion: Single or aggregated lymphocytes within or between follicular epithelial cells


  • Lymph-vascular invasion common in high-grade tumors


  • Atrophy of residual thyroid parenchyma and fibrosis


  • Uninvolved thyroid parenchyma: May have adenomatoid nodules, adenomas, or foci of carcinoma (papillary > > > follicular > medullary)


  • Vast majority are B-cell lymphomas: EMZBCL and DLBCL with transitions between the two



    • Single or multifocal areas of large cell transformation adjacent to low-grade component


Extranodal Marginal Zone B-Cell Lymphoma



  • Extranodal marginal zone B-cell lymphoma (EMZBCL) of mucosa-associated lymphoid tissue (MALT) ± large cell component



    • Low-grade tumor by definition


    • Composed of heterogeneous population of B-cells


    • Vague nodularity to diffuse effacement



      • Single or multifocal zones of large cell transformation


      • Transition from low- to high-grade morphology is easy to identify in most cases


  • 20-30% of all thyroid gland lymphomas


  • Background of chronic lymphocytic thyroiditis in almost all cases


  • Reactive germinal centers, ± follicle colonization, are invariably present



    • Colonization or follicle lysis by neoplastic B-cells


    • These cells yield darker zone within follicles on low power


    • Follicular architecture may mimic follicle center cell lymphoma


  • Heterogeneous B-cells include



    • Atypical small lymphocytes, marginal zone (centrocyte-like) small cleaved cells, monocytoid B-cells, scattered large immunoblasts and centroblast-like cells, and plasma cells



      • Monocytoid B-cells are monotonous population of atypical lymphoid cells with abundant, pale cytoplasm with lobulated or kidney-shaped nuclei


      • Small collections of monocytoid cells can be seen


  • Dutcher bodies and Russell bodies easily identified



    • Cytoplasmic immunoglobulin (“Mott cells”) and striking plasmacytoid differentiation may simulate plasmacytoma


    • Crystal-storing histiocytes may be seen


  • LELs easily identified



    • Keratin(s) highlights LELs


  • Increased proliferation index usually within germinal center regions


  • Infrequently, concurrent disease of gastrointestinal tract, salivary gland, orbit, lung, skin, or breast


Diffuse Large B-Cell Lymphoma



  • Diffuse, large, atypical cells with increased mitotic figures suggests transformation into diffuse large B-cell lymphoma


  • 60-70% of all thyroid gland lymphomas


  • Perithyroidal extension into fat or skeletal muscle


  • Vascular invasion is often seen


  • Sheets of large, atypical lymphoid cells destroying the thyroid parenchyma



    • Transitions between EMZBCL and DLBCL are common


    • However, may occur in absence of low-grade areas


  • Large cells have spectrum of cytologic features



    • Centroblasts, immunoblasts, monocytoid B-cells, and plasmacytoid cells


    • Focal Reed-Sternberg-like cells can be seen


    • Burkitt-like growth with brisk mitotic activity, apoptosis, “starry sky” pattern


  • Atrophy of residual thyroid parenchyma and fibrosis are often noted

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Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Lymphoma

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