Prompt diagnosis and airway management for primary thyroid lymphoma with compromised upper airway: a single-institution case series
Objectives. Primary thyroid lymphoma (PTL) is a rare malignant tumour. Prompt and accurate diagnosis and optimal airway management are crucial for PTL, especially when complicated with dyspnoea.
Methods. Eight patients with PTL and dyspnoea treated in Beijing Friendship Hospital from January 2015 to December 2021 were retrospectively reviewed.
Results. Three of four patients complicated with mild to moderate dyspnoea underwent chemotherapy after prompt diagnosis by fine needle aspiration cytology (FNAC) combined with cell block immunocytochemistry (CB-ICC) and flow cytometric immunophenotyping (FCI) or core needle biopsy (CNB) combined with immunohistochemistry (IHC) without open surgery. Total thyroidectomy was performed in one patient without other diagnostic methods because the FNAC result was inconclusive. Four patients with moderate to severe dyspnoea underwent tracheostomy and incisional biopsy without severe complications after tracheal intubation under the guidance of a fibreoptic bronchoscope performed without general anaesthesia.
Conclusions. For patients with mild to moderate dyspnoea suspected of PTL, FNAC along with FCI and CB-ICC or CNB along with IHC are recommended, in addition to prompt chemotherapy to avoid prophylactic tracheostomy. Patients with moderate to severe dyspnoea suspected of PTL should undergo tracheal intubation under the guidance of a fibreoptic bronchoscope without general anaesthesia, followed by tracheostomy with simultaneous thyroid incisional biopsy to reduce the risk of asphyxia during treatment.
Primary thyroid lymphoma (PTL) is a form of lymphoma in the thyroid gland. It is a rare malignant disease and accounts for 0.6%-5% of thyroid malignancies and approximately 2% of extranodal lymphomas 1,2. Patients usually present with a palpable nodule in the thyroid or a rapidly enlarging neck mass, causing local obstruction and infiltrative symptoms in more aggressive disease forms, including dysphagia, dyspnoea, stridor, hoarseness. 1-3. It can be difficult to distinguish PTL from anaplastic thyroid carcinoma or Hashimoto thyroiditis (HT), even by ultrasonography or histomorphology 1,4,5. However, the treatment and prognosis of the three conditions are quite different. Moreover, as PTL occurs relatively rarely, its accurate diagnosis is usually made after surgical resection, increasing the burden on patients and delaying optimal treatment 1-5.
When PTL is complicated with dyspnoea, a rapidly enlarging neck mass can even cause asphyxia. In such cases, prompt and accurate diagnosis is crucial, and airway management can be particularly difficult. Currently, no standard diagnostic and treatment protocols are available for PTL. There are only a few literature reports on such a condition, especially when complicated with dyspnoea. We, therefore, retrospectively analysed eight PTL patients with dyspnoea at our institution to summarise our experience in its diagnosis and airway management.
Materials and methods
We retrospectively reviewed the medical records of patients diagnosed with PTL and dyspnoea from January 2015 to December 2021 at Beijing Friendship Hospital, Capital Medical University, China. The electronic medical records database was searched with the keywords thyroid lymphoma and dyspnea. The exclusion criteria were: 1) a history of lymphoma in other parts of the body; 2) suspicious non-primary focus of thyroid when lymphoma was found; 3) dyspnoea not caused by PTL; 4) incomplete data on diagnosis and treatment process. Eight patient files were retrieved. We analysed the clinicopathological data, especially the diagnostic process and airway management, and summarised our experience (Tab. I).
All eight patients complained of a painless enlarged neck mass with local compression symptoms, including dyspnoea, stridor, hoarseness and dysphagia. Among these, four had pre-existing nodules. The course of sudden enlargement of the neck mass was 4-8 weeks, and symptoms of dyspnoea occurred from several days to three weeks before hospital admission. Among the eight patients enrolled, seven were females (85.7%), with a median age of 72.5 years (range: 50-83 years); the median follow-up time was 33 months (range: 2-78 months). Seven patients (85.7%) had a history of HT, and the remaining had not undergone HT-related laboratory tests. All the cases were non-Hodgkin lymphoma (NHL): the histologic subtype of six cases (75%) was diffuse large B-cell lymphoma (DLBCL), one was mucosa-associated lymphoid tissue (MALT) lymphoma with 30% transformation to DLBCL and one was angioimmunoblastic T-cell lymphoma (AITL). According to the Ann Arbor Staging Classification, five cases (62.5%) were staged as IE-IIE and three (37.5%) as IIIE-IVE. Mild dyspnoea was defined as tachypnea and shortness of breath, including failure to complete sentences. Moderate dyspnoea was defined as stridor and orthopnoea with intercostal, suprasternal and supraclavicular retractions. Severe dyspnoea was defined as restlessness and even cyanosis. Four cases (50%) had mild to moderate dyspnoea, and four (50%) had moderate to severe dyspnoea.
Fine needle aspiration cytology (FNAC) was the most commonly used initial diagnostic method for thyroid nodules in the clinic. However, concerning patients highly suspected of PTL only with mild dyspnoea, if routine blood evaluation and coagulation tests were normal without receiving antiplatelet or anticoagulation therapy, core needle biopsy (CNB) was preferred to obtain more tissues for diagnosis.
For the four cases with mild to moderate dyspnoea, FNAC was performed in three patients, which indicated a high suspicion of thyroid lymphoma in two patients (No. 1 and 2). Cell-block immunocytochemistry (CB-ICC) and flow cytometric immunophenotyping (FCI) of FNAC specimens were performed, resulting in a final diagnosis of DLBCL. FNAC results were inconclusive, and total thyroidectomy was performed for the remaining one, for whom the diagnosis of PTL was unsuspected pre-operatively. CNB was performed in one of the four cases (No. 3), and the final diagnosis was DLBCL based on morphology and immunohistochemistry (IHC).
The four cases with moderate to severe dyspnoea underwent an incisional biopsy simultaneous with tracheostomy. Three patients were diagnosed with DLBCL or AITL based on morphology and IHC; the remaining one (No. 6) was misdiagnosed with lymphocytic thyroiditis based on morphology. Unilateral thyroid lobectomy was then performed to obtain sufficient tissue from the central part of the lesion. The final diagnosis was MALT lymphoma with 30% transformation to DLBCL based on morphology and IHC.
Airway management and treatment
All patients were treated with supplemental oxygen during hospitalisation. Regarding the four cases with mild to moderate dyspnoea, three patients with suspected lymphoma were given intravenous methylprednisolone (40 mg daily) while awaiting biopsy results to avoid prophylactic tracheostomy (No. 1, 2, and 3). All four cases with moderate to severe dyspnoea underwent tracheostomy to prevent asphyxia. Before surgery, tracheal intubation was performed under the guidance of a fibreoptic bronchoscope without general anaesthesia (Fig. 1). The tumour was significantly reduced after two rounds of chemotherapy, and partial remission was achieved. In addition, decannulation and primary closure of tracheocutaneous fistulae (TCF) were performed in two cases (No. 5 and 6).
Chemotherapy was undertaken immediately after the final diagnosis based on histology, clinical stage, performance status, etc., except for one patient who refused further treatment (No. 7) and succumbed to the disease two months after tracheostomy. For the CD20+ B-cell NHL, CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) combined with rituximab and/or radiotherapy was the standard chemotherapy regimen. COP (cyclophosphamide, vincristine and prednisolone) combined with rituximab and/or radiotherapy was administered to some elderly patients with heart diseases (No. 1, 3 and 5). The standard chemotherapy regimen was 6-8 cycles, except for two elderly patients (patients No. 3 and 5) who could not endure the whole course of chemotherapy because of adverse reactions. Patient No. 3 succumbed to the disease due to a local invasion of the airway after 8 months; patient No. 5 died due to local and systemic relapse after 26 months. The remaining four patients remain in remission with no local or systemic relapse, with a follow-up of 40-78 months. Regarding the AITL patient (No. 8), he succumbed due to local and systemic dissemination of the disease 3 months after the final diagnosis, despite two courses of CHOP.
PTL is a rare malignant disease that commonly occurs in middle-aged and elderly women, typically presenting with a rapidly enlarging neck mass leading to compressive symptoms 1-3,6. Most thyroid lymphomas are of B-cell origin and predominantly of the diffuse large-cell type. The second most common histologic type is MALT lymphoma. T-cell lymphoma is extremely rare and has a relatively poor prognosis 6-8. The risk of developing thyroid lymphoma is 67 times greater in patients with HT than those with colloid goiter 9, and as high as 90% of subjects with PTL have a positive history of HT 10,11. In our cohort, similar to the previously reported literature, the median age was 72.5 years (range: 50-83 years); seven of eight cases (85.7%) were females, with seven (85.7%) having a history of HT. Histologic subtypes included DLBCL (75%), MALT lymphoma (12.5%), and AITL (12.5%). PTL should always be suspected in elderly women with a history of HT complaining of a rapidly enlarging thyroid mass.
Recent onset of symptoms or rapid enlargement of a painless pre-existing thyroid mass is the hallmark of PTL and anaplastic thyroid carcinoma 2,3,6,7,11. It can be difficult to distinguish PTL from anaplastic thyroid carcinoma, even by ultrasonography or histomorphology. As PTL occurs relatively rarely, the diagnosis is often overlooked 1-5. In our cohort, the course of sudden enlargement of the neck mass was 4-8 weeks, and the symptoms of dyspnoea occurred from several days to three weeks before hospital admission. Four patients were complicated with mild to moderate dyspnoea and the others with moderate to severe dyspnoea. Since the treatment and prognosis of PTL and anaplastic thyroid carcinoma are quite different, and the upper airway obstruction can be life-threatening, prompt and accurate diagnosis is crucial.
Airway management is a primary concern for patients with moderate to severe dyspnoea in whom thyroid lymphoma is suspected. Incisional biopsy is performed for the diagnosis simultaneous with tracheostomy. FNAC is usually performed for the initial diagnostic workup of a thyroid nodule, especially in patients with mild to moderate dyspnoea suspected of having thyroid lymphoma, due to its advantages since it is less invasive and does not tend to aggravate dyspnoea. However, cytology has limitations in diagnosing thyroid lymphoma. It is difficult to differentiate thyroid lymphoma from lymphocytic thyroiditis and anaplastic carcinoma, especially in patients with a history of HT 2,4,5. Cases of high-grade thyroid lymphoma can be confused with anaplastic carcinoma 4,6, but for low-grade (MALT) thyroid lymphoma, cytology and histology may be insufficient for diagnosis 2,5. This happened, for example, in case No. 6 of our series, in which an incisional biopsy was performed simultaneous with tracheostomy, and it was still misdiagnosed as HT by histology. She had to undergo unilateral thyroid lobectomy, and the final diagnosis was MALT lymphoma by IHC. Obtaining specimens only from the superficial surface of the thyroid without IHC at the same time may lead to misdiagnosis. In recent years, FCI and CB-ICC have been gradually applied in clinical practice because they are feasible on FNA specimens and very useful in suspected cases of NHL, especially when an open biopsy is not possible. NHL can be sub-classified in most cases 4,12-15. However, this is not a routine procedure, and the yield from FNAC may not be representative or insufficient for further diagnosis 6,16. CNB could obtain more tissue for thyroid lymphoma, with a higher diagnostic sensitivity than FNA (93% vs 71%, p = 0.006) 2. However, several potential complications have been reported, such as haematoma, voice change, infection, oedema, vasovagal reaction, haemoptysis and dysphagia 16. When PTL is associated with airway compromise, CNB may exacerbate dyspnoea or even cause asphyxia due to secondary haemorrhage and airway oedema. Based on the above factors, we need to weigh the pros and cons in real-time in clinical practice. It is imperative to fully communicate with patients about the possible risks and benefits of diagnostic methods. In our unit, FNAC is a routine diagnostic method for thyroid nodules without the need for coagulation screening, as the most commonly used initial diagnosis method in the clinic. For patients who were clinically highly suspected of PTL only with mild dyspnoea, if routine blood evaluation and coagulation tests were normal without receiving antiplatelet or anticoagulation therapy, CNB would be preferred to obtain more tissues for diagnosis. In our cohort, three patients underwent FNAC, with two suspected of thyroid lymphoma; the third was inconclusive. Using FCI along with CB-ICC, two patients (No. 1 and 2) were diagnosed with DLBCL. Redo biopsy was avoided, and appropriate chemotherapy was administered in time without prophylactic tracheostomy. Case No. 3 of our series was promptly diagnosed with DLBCL by CNB along with IHC. Regarding patients with moderate to severe dyspnoea, it is necessary to perform an incisional biopsy from the centre of the lesion and combine several diagnostic methods to avoid misdiagnosis. Multidisciplinary cooperation with a pathologist is also important to reach an accurate diagnosis.
Appropriate glucocorticoids can be administered for patients suspected of PTL, pending final diagnosis. Glucocorticoid administration can rapidly improve symptoms, which may be an important clinical finding, aiding in the diagnosis of PTL 17. It is possible to avoid prophylactic tracheostomy, especially in patients with mild to moderate dyspnoea (patients No. 1, 2, and 3). Tracheostomy under local anaesthesia or routine tracheal intubation is risky when a considerable thyroid mass compresses the upper airway. In patients with moderate to severe dyspnoea suspected of PTL, we suggest that tracheal intubation should be carried out under the guidance of a fibreoptic bronchoscope without general anaesthesia. After general anaesthesia, tracheostomy should be performed with thyroid incisional biopsy simultaneously to reduce the risk of asphyxia during treatment. Usually, DLBCL responds relatively well to chemotherapy, and the tumour size can be reduced dramatically after several courses 17. In our cohort, four patients with moderate to severe dyspnoea underwent tracheostomy without severe complications. Except for one case of abandonment of chemotherapy and one case of AITL with poor response to chemotherapy, the other two patients underwent decannulation and primary closure of TCF under local anaesthesia after two courses of chemotherapy. The benefits of tracheostomy obviously outweighed the possible risk of asphyxia during treatment and the economic burden. It should be emphasised that the large cervical mass can increase the distance between the cervical skin and the anterior tracheal wall, increasing the risk of post-operative tube displacement or accidental extubation. Therefore, we recommend tracheostomy instead of routine tracheotomy. The isthmus of the thyroid should be excised and the surrounding skin defatted and sutured to the tracheostoma circumferentially, making reintubation safer in the event of accidental extubation, with less susceptibility to maceration and infection around the tracheostoma.
The value of surgery in diagnosis and treatment is controversial. Those favouring surgery conclude that lobectomy or total thyroidectomy facilitates obtaining a large amount of tissue from the central part of the lesion, contributing to a more accurate diagnosis, especially in low-grade lymphomas (as observed in patient No. 6). At the same time, thyroidectomy may have a therapeutic value for high-risk patients with lymphoma showing low-grade malignancy, who are unlikely to endure chemotherapy or radiation therapy 1. Patients who have undergone complete resection of the lymphoma often have a better course than those without resection 18. A study of 62 patients from the Mayo Clinic concluded that thyroidectomy with adjuvant chemotherapy provided a long-term cure for PTL within the thyroid capsule 19. The opponents argue that the role of surgery for thyroid PTL in stages IE and IIE is still unclear, as survival rates do not seem to improve when radical surgery is added to other treatment modalities 7. Based on our experience, most PTL cases complicated with dyspnoea have relatively high-grade histology and advanced stage, and thyroidectomy may increase the risk of laryngeal nerve paralysis and post-operative hypoparathyroidism due to the infiltration of local tissues. Therefore, as therapy surgery may not be very beneficial. Meyer-Rochow et al. 20 demonstrated a clear transition from excisional surgery to surgery as a diagnostic procedure during the 1980s due to the impact of FNAC. Graff-Baker et al. 19 reported that the use of excisional surgery for PTL has declined from 81% of patients in 1973-1987 to 61% in 1997-2005 in the United States. Hyejung-Cha et al. 21 reported that surgery was not the main treatment option after 2006, and non-surgical treatment, including chemotherapy and/or RT, has become the mainstay of treatment in recent years, depending on the histologic subtype.
Therefore, nowadays, the mainstay treatment for PTL is considered to be chemotherapy and/or radiotherapy, with the outcomes depending on the stage of disease, infiltration of local organs, histology and the patient’s performance 18,19,22. Treatment combinations should be tailored to each patient with adjustments for these prognostic factors. In our cohort, those patients who underwent the whole course of chemotherapy (patients No. 1, 2, 4, and 6) achieved complete remission without relapse after 40-78 months. Those patients who failed to complete the whole course of chemotherapy or had no further treatment (patients No. 3, 5, and 7) suffered relapses or rapid progression and death. However, regarding AITL (patient No. 8), he succumbed to the disease 3 months after the final diagnosis, despite undergoing chemotherapy.
PTL should always be suspected in elderly women with a history of HT, complaining of a rapidly enlarging thyroid mass. For patients with mild to moderate dyspnoea suspected of PTL, FNAC along with FCI and CB-ICC or CNB along with IHC are recommended as the preferred diagnostic tools. Chemotherapy should be instituted promptly to avoid prophylactic tracheostomy. For patients with moderate to severe dyspnoea suspected of PTL, tracheal intubation should be performed without general anaesthesia under the guidance of a fibreoptic bronchoscope. Tracheotomy should then be performed with simultaneous thyroid incisional biopsy to reduce the risk of asphyxia during treatment. Appropriate glucocorticoids can be administered before a final diagnosis is reached to avoid prophylactic tracheostomy, especially in patients with mild to moderate dyspnoea. Because of the rarity of this disease, multicentric prospective studies with large groups of patients are needed to confirm our findings.
Conflict of interest statement
The authors declare no conflict of interest.
This work was supported by Key Science and Technology Program of Beijing Municipal Commission of Education (grant number KZ202110025035), Research and Development Project of Scientific Research Instruments and Equipment of Chinese Academy of Sciences-major instruments project (grant number YJKYYQ20180039) and Digestive Medical Coordinated Development Center of Beijing Municipal Administration of Hospitals (grant number XXZ0604).
AZ, LL: conceived and designed the research; AZ, MZ: retrieved patients’ data; AZ, YD, SY: prepared figures and tables; AZ, LL: drafted, edited, and revised the manuscript. All Authors read and approved the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.
This study was approved by the Institutional Ethics Committee of Beijing Friendship Hospital, Capital Medical University. The research was conducted ethically, with all study procedures being performed in accordance with the requirements of the World Medical Association’s Declaration of Helsinki. Written informed consent was obtained from each patient for study participation and data publication.
Figures and tables
|No.||Age/sex||Degree of dyspnoea||Stage||HT||Diagnostic procedures||Histology||Therapy||Follow-up (months)||Recurrence/death|
|1||77/F||Moderate||IIE||Yes||FNAC+FCI +CB-ICC||DLBCL||Methylprednisolone R-COP*7||52||No/no|
|2||63/F||Moderate||IE||Yes||FNAC+FCI +CB-ICC||DLBCL||Methylprednisolone R-CHOP*6||78||No/no|
|4||59/F||Mild||IIE||Yes||FNAC; SE||DLBCL||TT R-CHOP*6||61||No/no|
|6||68/F||Moderate to Severe||IIE||Yes||IB; SE+IHC||MALT lymphoma, 30% transformation to DLBCL||Tracheostomy UTL; R-CHOP*8||40||No/no|
|8||83/M||Moderate To Severe||IIIE||Yes||IB+IHC||AITL||Tracheostomy; CHOP*2||3||-/yes|
|F: female; M: male; HT: Hashimoto thyroiditis; FNAC: fine needle aspiration cytology; CB-ICC: cell block immunocytochemistry; FCI: flow cytometric immunophenotyping; SE: surgical excision; IB: incisional biopsy; TT: total thyroidectomy; UTL: unilateral thyroid lobectomy; DLBCL: diffuse large B-cell lymphoma; MALT: mucosa-associated lymphoid tissue; AITL: angioimmunoblastic T cell lymphoma; R-CHOP: rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone; R-COP: rituximab combined with cyclophosphamide, vincristine, and prednisolone.|
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