INTRODUCTION

Primary thyroid lymphoma is a rare dis­order accounting for about 2% of all ma­lignant lymphomas in general and less than 5% of thyroid malignancies (Sippel et al. 2002). Approximately 50-80% of pri­mary thyroid lymphomas is of B-cell origin; which is the diffuse large cell type. The mucosa-associated lymphoid tissue (MALT) lymphomas, the more indolent lymphomas, account for 6 - 27% of thy­roid lymphomas (Widder & Pasieka 2004). The most common clinical presentation of thyroid lymphoma is a rapidly enlarging thyroid mass associated with compres­sive symptoms (Sippel et al. 2002; Abdel et al. 2001) namely dyspnea, dysphagia and pain. Patients are usually elderly with a peak incidence in the sixth decade (Ha et al. 2001)and have a female prepon­der­ance (Sippel et al. 2002; Tupchong et al. 1986; Charles et al. 2002). These tu­mours are noted to be almost always arising in the background of Hashimoto’s thyroiditis (Sippel et al. 2002).

Management of thyroid lymphomas has evolved over the last 20 years from hav­ing the surgeons as major players for removal of obstructive symptoms to the more cur­rent approach of non-invasive chemothe­rapy and external beam radia­tion. Never­theless, surgery still plays an important role as demonstrated by sev­eral studies (Sippel et al. 2002; Widder & Pasieka 2004). Optimal treatment for primary thy­roid lymphoma continues to be a co­lourful debate amongst clinicians.

CASE REPORT

Patient 1

A 65-year-old Chinese man was referred for a progressively enlarging thyroid mass of 4 months’ duration, associated with hoarseness of voice and respiratory obstructive symptoms. He had no history of fever, night sweats, loss of weight or loss of appetite.

On physical examination, he was a well built gentleman with a large neck swell­ing. His blood pressure was 130/80 mmHg and pulse rate was 90 per minute. There were multiple enlarged cervical lymph nodes but no other abnormalities were found. His full blood count and se­rum biochemistry was normal except for a mild elevation of lactate dehydroge­nase (LDH) levels (644 U/L).

Assessment by the otolaryngologist re­vealed a large multinodular goiter with retrosternal extension and bilateral vocal cord involvement. Fine needle aspiration cytology of the anterior thyroid swelling showed features consistent with poorly differentiated malignant tumour with pos­sibilities that include malignant lymphoma and anaplastic carcinoma.

Following the biopsy, he developed sudden onset of acute obstructive respi­ratory symptoms which led to an emer­gency debulking of his thyroid mass and tracheostomy. The histopathological ex­amination of the thyroid tissue showed diffuse infiltration by large malignant cells arranged in sheets. The malignant cells exhibit pleomorphic vesicular nuclei and occasional prominent nucleoli. Immuno­histochemically, the malignant cells ex­pressed B cell markers (CD20 and CD79α) and were negative for creatinine kinase and T cell markers (CD3 and CD45Ro) and this confirmed the diagno­sis of diffuse large B-cell lymphoma with extra thyroidal extension.

Staging bone marrow aspiration and trephine biopsy showedno marrow infil­tration by lymphoma cells. Computed tomography (CT) scan of the neck and thorax showed a large thyroid mass with retrosternal extension, multiple cervical lymphadenopathy, narrowing of the vocal cord and thickening of the larynx due to lymphomatous infiltration of the larynx.

The patient was started on chemothe­rapy consisting of rituximab, cyclophos­phamide, doxorubicin, vincristine and prednisolone (R-CHOP) two weeks after debulking of his tumour. During the post chemotherapy period, he developed up­per gastro-intestinal bleeding, left tem­poro-parietal infarct, and nosocomial pneumonia with Methicillin Resistant Staphylococcus aureus. However, he recovered from the complications after a prolonged stay in the hospital. After com­pleting his sixth R-CHOP, a gallium scan was performed which showed an in­creased in uptake in the right side of the superior mediastinum and hilar region. He was given another two cycles of R-CHOP, but a repeat gallium scan showed persistent uptake with similar pattern and intensity and then radiotherapy was planned as the next choice of treatment for this patient.

Patient 2

A 68-year-old Malay lady who initially presented with a sudden increase in thy­roid gland size, associated with pain and acute upper airway obstruction. An ur­gent CT scan showed a thyroid mass with retrosternal extension and left inter­nal jugular vein invasion with thrombosis. There was no mediastinal lymph node enlargement. She did not present with any B symptomssuch as fever, night sweats or loss of significant body weight. An emergency mod­ified radical neck dis­section was per­formed and the left inter­nal jugular vein was ligated. The histo­pathological ex­amination revealed diffuse large B-cell lymphoma of the thyroid gland (Figure 1).

One week later, she developed left arm swelling and pain. An ultrasound Doppler showed evidence of left subclavian and axilary vein thrombosis. She was started on warfarin tablets 2 mg daily and was referred to our centre for chemotherapy. However, she only turned up at our hos­pital two weeks later with dysphagia to solid food, neck swelling and left neck pain. Physical examination showed a large left neck swelling which was firm and tender. There was also a thyroidect­omy scar present. Her blood pressure was 160/90 mmHg and her pulse rate was 95 beats per minute. Examination of other systems was normal. Her full blood count and serum biochemistry were nor­mal except for a highly elevated lactate dehydrogenase level (> 12,000 U/L) and a slightly increased serum uric acid (577 umol/L). Her thyroid function test showed hypothyroidism (free T4: <5.15 pmol/L, thyroid stimulating hor­mone: 69.41 µIU/ml). No bone marrow assessment was done previously. 

A direct laryngoscopy showed a swol­len epiglottis and left vocal cord palsy. The patient was planned for a tracheos­tomy prior to chemotherapy. Unfortu­nately, she collapsed in the ward a day after admission, was resuscitated, and required intensive care unit nursing. A CT angiography showed pulmonary embol­ism involving the right main, ascending and descending pulmonary arteries. Her stay in the intensive care unit was com­plicated by bleeding following anticoagu­lant therapy, a deteriorating renal func­tion, septicaemia with Staphylococcus aureus and hypothyroidism. Her renal function deteriorated further and she continued to bleed despite continuous support with blood products. Her coagu­lation profile was persistently prolonged (PT: 22.4 seconds, INR: 1.85, APTT: >180 seconds). CT scan of the brain showed gross oedema secondary to hy­poxic brain injury. She finally succumbed to her illness one week post admission.

DISCUSSION

Malignant tumours of the thyroid in gen­eral are not very common. The incidence accounts for 1-2 cases per 100,000 people (Sippel et al. 2002). Of these, thyroid lymphomas only account for less than 5% of thyroid malignancies and 2% of all malignant lymphomas (Sippel et al. 2002). They commonly present with a rapidly enlarging neck mass, often caus­ing obstructive symptoms as in both of the cases presented. It occurs more fre­quently in women than men (Sippel et al. 2002; Tupchong et al. 1986; Charles et al. 2002),in keeping with the predilection of thyroid disease for women in general.

Thyroid lymphoma is frequently asso­ciated with Hashimoto’s thyroiditis (Abdel et al. 2001) which is not evident in both cases mentioned. There are however, case series which report the association of thyroiditis to be between 25-75% (Abdel et al. 2001). It is hypothesized that chronic antigenic stimulation secondary to autoimmune disorders leads to chronic proliferation of lymphoid cells, which eventually undergo mutation resulting in clonal proliferation and development of lymphoma (Moshynska & Saxena 2008). However, not all patients with Hashi­moto’s thyroiditis develop lymphoma of the thyroid gland.

The International Prognostic Index (IPI) is used to predict the risk of dis­ease re­currence and overall survival by taking into account factors such as age, stage of disease, performance status, number of extranodal sites, and the presence or ab­sence of an elevated se­rum lactate dehy­drogenase (LDH) (The International Non-Hodgkin's Lymphoma Prognostic Factors Project 1993). This is used gen­erally to predict survival in patients with non-Hodg­kin’s lymphoma. Based on this system, both patients de­scribed above have an IPI score of 2 (age and elevated LDH) which places them in the low/intermediate risk. A study done by Ha et al. (2001) tested the usefulness of the IPI in predicting the prognosis of patients with thyroid lym­phoma. The 5-year sur­vival rate for pa­tients with an IPI of 0 was 86% versus 50% for patients with an IPI of greater than 0. The data included pa­tients treated with radiation alone, che­mothe­rapy alone, or combined-modality ther­apy. A different study (Abdel et al. 2001) of 60 patients with thyroid lym­phoma showed that me­diastinal involve­ment and performance status was the most important indepen­dent prognostic fac­tors influencing re­lapse-free survival and overall survival.

Primary thyroid lymphoma is uncom­mon and its optimum management has always been a controversial issue. As the number of cases is small, mainly in the form of case reports, there is lack of ran­domized prospective studies and thus different treatment protocols are being practised. In the past, surgery played a major role in the diagnosis and treatment of thyroid lymphoma (Abdel et al. 2001). This still hold true for cases of localized mucosa-associated thyroid (MALT) lym­phoma where there is a complete re­sponse rate of more than 90% (Widder & Pasieka 2004). Surgery also plays an impor­tant role in the early control of symptoms especially in patients with se­vere airway obstruction or those with se­vere pain (Sippel et al. 2002). A retros­pective study of 46 cases by Tupchong et al. (1986) showed that patients with total macro­scopic removal of the tumour had the highest rate of local control and has a long survival rate when compared to those receiving radiotherapy alone. How­ever, in these cases the disease was li­mited to the thyroid and cervical lymph nodes.

The more common type of thyroid lym­phoma is diffuse large B-cell lymphoma (DLBCL) which is aggressive and usually presents with disseminated disease as shown in the present cases. The surgical risks for these patients are considerable which includes operative mortality, nerve injuries (recurrent laryngeal), hypopara­thyroidism and possible damage to the trachea, esophagus and large vessels. With the advent of fine needle aspiration cytology, flow cytometry and immuno­histochemical analysis; it is possible to avoid unnecessary surgical intervention for tissue diagnosis (Charles et al. 2002). Furthermore, combination therapy of radiation and chemotherapy without ex­tensive surgery is associated with an equal or a superior 5 year survival rate without the additional risks of surgery (Abdel et al. 2001).

In the present cases, both patients un­derwent emergency thyroidectomy to relieve the obstructive symptoms. In the first case, the patient received a combi­nation of rituximab and CHOP. Rituximab is a chimeric monoclonal antibody that targets CD20 antigen expressed on B-cells. The use of rituximab in combination with the standard chemotherapy protocol has been shown to have significant sur­vival benefit and improvement of patient outcome in DLBCL (Feugier et al. 2005). In this randomized study, rituximab com­bined with CHOP was compared to CHOP alone in patients aged more than 60 years with diffuse large B-cell lym­phoma and CD20-positivity. The combi­nation of rituximab and CHOP improved rates of complete response, failure-free survival, and survival. Although this study does not look at primary thyroid lym­phoma per se, it may be assumed that rituximab will benefit any lymphomas with CD20 positivity as it specifically targets these antigens that are present on B-cells. Our patient received 8 cycles of the combination chemotherapy and survived for 12 months from the time of presenta­tion.

The second case was more compli­cated since the patient had concomitant thrombosis, initially involving the left in­ternal jugular vein which developed into a left subclavian and axillary thrombosis post-operatively. Following that, she de­veloped pulmonary embolism in the ward. The acute coronary syndrome that she had prior to collapse may have been due to another thrombosis within the co­ronary vessels itself. This added to the difficulty in her management. Anticoagu­lant was needed to prevent further thromboembolism but she developed bleeding complications. If chemotherapy was started earlier, she might have be­nefited from the reduced tumour burden. The bulk of her tumour may have contri­buted to the stasis of blood within her vessels and caused the repeated epi­sodes of thrombosis. A second surgery was not an option at this time as she was haemodynamically unstable. Her progno­sis may have been better if chemothe­rapy was started immediately after de­bulking of her tumour initially.

 We describe two cases of primary thy­roid lymphoma that presented with an enlarging thyroid mass and had to un­dergo emergency thyroidectomy. Both had similar presentations but with differ­ent outcomes. Treatment options for pri­mary thyroid lymphoma include com­bined therapy with surgery playing a mi­nimal role for diagnosis but a crucial role for compromised airway secondary to an enlarging thyroid mass. Addition of a mo­noclonal antibody may increase survival risk for patients who are rapidly diag­nosed and commenced early treatment.