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

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

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