The pre-treatment evaluation should include a detailed history and physical examination, standard laboratory studies, fine-needle aspiration of the thyroid nodule, unilateral bone marrow biopsy, and imaging in all patients to determine both the extent of the disease and acquire information about the individual's performance status and associated comorbidities, that are likely to affect treatment planning.
The diagnosis of a diffuse large B-cell lymphoma is established by cytologic examination of material obtained by biopsy techniques. The American Thyroid Association recommends fine-needle aspiration biopsyÂ (FNA) as the procedure of choice for evaluating all thyroid nodules [21 Cooper, DS, Doherty, GM, Haugen, BR, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006; 16:109. ]. Other biopsy techniques can be used including fine-needle capillary sampling or fine-needle non-aspiration biopsy (FNC), ultrasound guidance, cutting (core)-needle biopsy (TruCut) to obtain a core of tissue, cutting-needle biopsies, and large-needle aspiration biopsy. Although the diagnosis of lymphoma may be suggested by the FNA, subsequent large-bore needle biopsy or excisional biopsy is required in order to obtain sufficient material for definitive diagnosis by immunohistochemical studies.
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Small cell lymphomas are more difficult to diagnose cytologically because of the coexistence of Hashimoto's thyroiditis in most cases. In these situations immunophenotyping by immunohistochemical staining or flow cytometry may be necessary to establish monoclonality and characterize surface markers.
Immunophenotyping is also important in sub-classification of most forms of non Hodgkin's lymphoma (NHL) by determining the expression of cell surface lymphoid differentiation antigens are used to distinguish between B- and T-cells as well as among their various developmental stages. Genetic studiesÂ including cytogenetic abnormalities, chromosomal translocations, and immunoglobulin or T cell receptor (TCR) gene rearrangements can be important adjunct tests when limited samples are obtained by FNA [75 Zeppa, P, Marino, G, Troncone, G, et al. Fine-needle cytology and flow cytometry immunophenotyping and subclassification of non-Hodgkin lymphoma: a critical review of 307 cases with technical suggestions. Cancer 2004; 102:55.].
Bone marrow examinationÂ -Â a bone marrow (BM) aspiration with an adequate-size biopsy should be performed for all patients to determine the diagnosis, as well as for staging purposes. Material obtained can be used for morphology and immunophenotype, to analysis of cell surface markers by flow cytometry and also for cytogenetic analysis. There can be differences in morphology between the cells in the bone marrow and a lymph node. These differences may point towards the transformation of an indolent NHL into a more aggressive histology.
An endoscopy or lumbar puncture is reserved for patients with symptoms suggesting involvement of these sites.
Radiographic or radionuclide imaging cannot distinguish thyroid lymphomas from carcinomas or Hashimoto's thyroiditis. However thyroid lymphoma can present as stage IV disease in up to 5% of the patients, these imaging studies including computed tomography/ magnetic resonance imaging (CT/MRI) of the neck, thorax, abdomen and pelvis, should be requested as pre treatment workup, as these are useful in defining the extent of disease, planning therapy, and monitoring the response to treatment .
In a suspected case CT or MRI is the initial imaging modality of choice for evaluating local extent. They are superior to ultrasonography because of their greater ability to detect tracheal invasion, substantial extension, and involvement of cervical, mediastinal, or abdominal nodes. Furthermore ultrasound of the thyroid typically demonstrates pseudocystic, hypoechoic areas that can easily be mistaken for cysts. The superiority of MRI over CT is not proven, but it may be more sensitive for defining the extent of extra-thyroidal invasion. . "Donut sign," is a characteristic CT finding, it is seen when the lymphoma completely encircles the trachea.
The role of 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) scan is limited in pre treatment evaluation. Both Hashimoto's thyroiditis and lymphoma can cause diffuse uptake throughout the gland, whereas MALT lymphomas of the thyroid generally produce false negative PET imaging .
Malignant cells lack iodine-concentrating ability thus the Radioiodine scanning has no diagnostic role in patients with thyroid lymphomas, but is still recommended as pre treatment evaluation or initial work up of a thyroid nodule.
The Ann Arbor staging classification is most widely used for primary thyroid lymphoma Table 1 [24,32].
Table 1: Ann Arbor staging classification for Hodgkin and non-Hodgkin lymphomas
The five-year disease-specific survival rate
Always on Time
Marked to Standard
Involvement of a single lymph node region (I)
or of a single extralymphatic organ or site (IE)*
55 % to 80 %
(treated with RT over a 4-5 week)
Involvement of two or more lymph node regions or lymphatic structures on the same side of the diaphragm alone (II)
or with involvement of limited, contiguous extralymphatic organ or tissue (IIE)
20 % to 50 %
(treated with RT over a 4-5 week) [3-6,14,23,37-39].
Involvement of lymph node regions on both sides of the diaphragm (III)
which may include the spleen (IIIS)
or limited, contiguous extralymphatic organ or site (IIIE)
or both (IIIES)
15 to 35 % .
Diffuse or disseminated foci of involvement of one or more extralymphatic organs or tissues **, with or without associated lymphatic involvement
15 to 35 % .
All cases are subclassified to indicate the absence (A) or presence (B) of the systemic ("B") symptoms.
* "E" = extranodal contiguous extension that can be encompassed within an irradiation field.
A single extralymphatic site as the only site of disease should be classified as IE, rather than stage IV.
** bone marrow, gastrointestinal tract, lungs, liver, pancreas, and kidney [3,14,23,33]
Treatment includes both the treatment of the disease and its complications. Patients may present with airway obstruction. Â Severe airway compromise may occur in up to 25% of the patients. Such tumors may shrink within hours after initiation of combination chemotherapy (eg, CHOP: Table 2 ), due to the rapid effect of the steroid component, thus early detection and treatment can avoid the need for tracheotomy. Make sure that histology/ FNA has been obtained if only steroids are given for symptomatic relief, to avoid potential difficulties in histological diagnosis later.
Surgery (thyroidectomy) is not recommended in patients with stage IIE or IIIE thyroid lymphoma [5,6,14,34]. In most centres surgery is utilized for diagnostic biopsy only. Unnecessary radical procedures should be avoided since they do not improve outcome and are more likely to cause complications including the recurrent laryngeal nerves or the upper aerodigestive tract injury and/or hypoparathyroidism.
In patients with early stage disease i.e. clinical stage IE/IIE disease, surgery may be helpful in the distinction between intrathyroid tumor and extra thyroid extension. This is clinically important as patients with intrathyroid tumor may only need local therapy alone i.e. surgery followed by postoperative radiation, while the patients with extrathyroid extension will require systemic chemotherapy .
RADIATION AND CHEMOTHERAPY:Â
Treatment depends upon the type and extent of disease [15,36]. DLBCL, the most common variant, is a potentially curable. Patients with DLBCL of thyroid, should be treated in the same manner as of any other site or extent. The choice of a specific treatment depends mainly upon whether the disease is limited or advanced.
Limited disease is early stage disease that is contained within one irradiation field. Abbreviated chemotherapy plus involved-field radiotherapy is recommended rather than chemotherapy alone, i.e. three cycles of R-CHOP followed by involved-field radiation. In difficult situations eg, involvement of the oronasopharynx or pelvis where high doses of radiation may cause significant morbidity, the dose of chemotherapy can be maximized to allow delivery of a more tolerable radiation dose.
All other disease that can not be contained within one irradiation field is considered as advanced.
For patients with advanced disease, a CHOP-like regimen plusÂ rituximabÂ is recommended, i.e. eight cycles of R-CHOP-21 or six cycles of R-CHOP-14.
Patients with localized extranodal marginal zone lymphoma of the thyroid or other indolent histologies (eg, follicular lymphoma, small cell lymphoma) can be effectively treated with radiation therapy alone. Those with advanced stage indolent histologies are usually treated with chemotherapy alone.
MONITORING AND SPECIAL CONSIDERATIONS
All patients should be given prophylaxis for tumor lysis syndrome and care providers should be alert to the potential hypersensitivity reactions. RituximabÂ therapy carries a risk of reactivation among patients positive for HBsAg or anti-HBc. Dose reduction should be avoided, even in older patients. Older patients should be treated with the same dosing and schedule as younger patients. Adjustments can be made according to tolerance. Restaging scans (PET/CT) should be obtained six to eight weeks after chemotherapy and 12 weeks after the completion of radiation therapy.
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CHOP[(Cyclophosphamide, Doxorubicin (Hydroxydaunomycin), Vincristine (Oncovin), and Prednisone] chemotherapy for non-Hodgkin's lymphoma
CHOP-21: given every 21 days for six to eight cycles.
Dose and Route
Given on day(s)
750 mg/m2 IV
50 mg/m2 IV
1.4 mg/m2 IV
100 mg/day PO
days 1 through 5
CHOP-14: given every 14 days. Filgrastim (G-CSF) is started on day 4 and is continued until day 13.
CNOP: Doxorubicin is replaced by Mitoxantrone (Novantrone, 10 mg/m2 IV, day 1).
CHOPE/CHOEP: given every 21 days, or 14 days along with G-CSF support. Etoposide (100 mg/m2 PO) is also given on days 1 to 3.
CHOP-BLEO (CHOP-B), Bleomycin (10 units/m2 IM) is also given on day 1.
R-CHOP, in which Rituximab (375 mg/m2 IV) is also given.
DOCUMENTATION OF THE DISEASE RESPONSE
Disease response is determined by the International Workshop Criteria (IWC) after the post-treatment evaluation including history, physical examinations, and restaging scan. Following criteria can be used
Complete remission (CR) is defined as no clinical evidence of disease or disease-related symptoms and
For typically FDG-avid lymphomas (Diffuse large B-cell lymphoma, Hodgkin lymphoma, Follicular lymphoma, and Mantle cell lymphoma): a post-treatment residual mass of any size is permitted as long as it is PET negative.
For variably FDG-avid lymphoma/FDG avidity unknown: all lymph nodes normal size by CT.
Spleen and liver non-palpable and without nodules.
If pre-treatment bone marrow biopsy was positive, repeat bone marrow biopsy must be negative; if morphologically indeterminate, immunohistochemistry should be negative.
Partial remission (PR) is defined as regression of measurable disease with at least 50 percent decrease in nodal size as determined by sum of the product of the diameters (SPD) and
For a typically FDG-avid lymphoma, the post-treatment PET should be positive in at least one previously involved site. No increase in the size of other nodes, liver, or spleen.
Regression of splenic or hepatic nodules by at least 50 percent as determined by the SPD.
No new sites of disease
Stable disease (SD) is defined as failure to attain CR/PR or PD and
For typically FDG-avid lymphomas, the post-treatment PET should be positive at prior sites of disease and no new sites should be present on PET or CT.
Following the completion of treatment and documentation of response, the patients are being followed up at periodic intervals to monitor for treatment complications and assess for possible relapse. The frequency and extent of these visits depends upon the comfort of both the patient and physician.
Relapse after CR or Progressive disease (PD) can be defined as appearance of any new lesion more than 1.5 cm in long axis. If long axis is 1.1 to 1.5 cm, it should only be considered abnormal if its short axis is more than 1.0 cm and/or
50 percent increase in the longest diameter of a previously identified node more than 1 cm in short axis or in the SPD of more than one node.
Lesions >1.5 cm should be PET positive in typical FDG-avid lymphoma or if PET positive before therapy.
Increasing FDG uptake in a previously unaffected site should only be considered relapse or PD after confirmation with other modalities.
New or recurrent involvement of the bone marrow.
Prognosis for localized thyroid lymphoma depends upon histology, type of treatment delivered, tumor extent/stage of the disease, and disease bulk International Prognostic Indices for the non-Hodgkin lymphomas is available to identity other prognostic factors. Prognosis is generally good for the patients with no adverse risk factors (Table).
Table :International Prognostic Index for the aggressive non-Hodgkin's lymphomas
International Prognostic Index
Serum lactate dehydrogenase concentration above normal
ECOG performance statusÂ 2
Ann Arbor stage III or IV
Number of extranodal disease sites >1
One point for each of the above characteristics, with total score ranging from zero to five.
Adapted from The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 1993; 329:987.
More than 80% of patients with stage IE or IIE disease achieve a complete remission after the initial therapy . Atleast 50% will relapse within five years, usually outside of the radiation field or in distant sites. Most relapses occur in distant sites [Table III]
Treatment outcomes of early stage thyroid lymphoma.
Localized disease stage I or II -- (n =51) 1
Five year failure-free survival rates
Combined modality therapy
Stage IE/IIE diffuse large B-cell thyroid lymphoma -- (n =32 with median follow-up of 62 months) 2
chemotherapy followed by RT ( n= 24) CR = 94%
5 -yr PFS*
5 - yr OS **
1. Ha CS; Shadle KM; Medeiros LJ; Wilder RB; Hess MA; Cabanillas F; Cox JD: Localized non-Hodgkin lymphoma involving the thyroid gland: Cancer 2001 Feb 15;91(4):629-35.
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.Â
2. Niitsu N; Okamoto M; Nakamura N; Nakamine H; Bessho M; Hirano M: Clinicopathologic correlations of stage IE/IIE primary thyroid diffuse large B-cell lymphoma. Ann Oncol. 2007 Apr 11; Division of Hematology, Department of Internal Medicine, Saitama Medical University, Saitama, Japan.
Multivariate analysis (age and local tumor control) of treatment outcomes of early stage thyroid lymphoma.
Stage IE or IIE thyroid lymphoma (n= 27)1
actuarial DFS* for patients <65
actuarial DFS for patients >65
actuarial DFS for patients with stage I
actuarial DFS for patients with stage II
DiBiase SJ; Grigsby PW; Guo C; Lin HS; Wasserman TH: Outcome analysis for stage IE and IIE thyroid lymphoma: Am J Clin Oncol 2004 Apr;27(2):178-84. Department of Radiation Oncology, University of Maryland, Baltimore, Maryland, USA.
*disease free survival