Thyroid nodules are the most common endocrine metabolic disorders and are mostly accidental nodules. In addition to detailed history taking and physical examination, high resolution ultrasound, thyroid stimulating hormone level determination and fine needle aspiration biopsy are the basis of thyroid nodule diagnosis.
Endocrinologists should master the indications for thyroid puncture biopsy. When the pathology report cannot distinguish benign from malignant, molecular or genetic diagnosis should be chosen for further clarification, and appropriate treatment plan should be selected according to different results. In this article, a typical thyroid nodule was diagnosed as papillary thyroid carcinoma and treated surgically, so that clinicians can pay more attention to and standardize the treatment of thyroid nodules.
Case introduction
The patient was 37 years old, Han nationality, and was seen in the outpatient clinic of the Department of Endocrinology and Metabolism of our hospital for “thyroid nodules found in health checkup for 2 months”. 2 months ago, thyroid nodules were found in the patient’s health checkup (the details are unknown). There was no history of thyroid disease or positive family history.
Outpatient thyroid function (thyroid function) showed: thyroid stimulating hormone (TSH) 2.020 mU/L (reference value 0.27-4.2 mU/L, same below), free thyroxine (FT4) 13.99 pmol/L (12.0-22.0), thyroglobulin (Tg) 19.67 μg/L (1.4-78), anti-thyroglobulin antibody (TgAb) 20.27 IU. TgAb) 20.27 IU/ml (<115) and anti-thyroid peroxidase antibody (TPOAb) <5.00 IU/ml (<34).
Ultrasound of the thyroid gland showed that the anterior-posterior diameter of the right lobe of the thyroid gland was about 12 mm, the upper and lower diameters were about 46 mm, and the left lobe was about 9 mm, the upper and lower diameters were about 46 mm, the left and right diameters were about 15 mm, and the thickness of the isthmus was about 2 mm. The echogenicity of the thyroid gland parenchyma was homogeneous, and a weakly echogenic nodule of about 6 mmx6 mmx6 mm was detected in the middle part of the right lobe. The echogenicity was heterogeneous, with several dotted pieces of strong echogenicity and dotted lines of blood flow signal in the periphery, but no significant blood flow signal was seen inside. No mass echogenicity was seen in the left lobe and isthmus, and no large lymph nodes were seen in the neck bilaterally.
Diagnostic hint: solid occupancy of the right lobe of the thyroid with calcification, nature to be determined. Thyroid imaging (99mTc04 5mCi) was unremarkable. Outpatient physical examination: pulse 74 beats/min, blood pressure 112/76 mmHg (1 mmHg=0.133kPa). There were no scars on the neck, no localized vascular varicosities, and no skin breakdown. There was no significant enlargement of the thyroid gland, the bilateral thyroid gland was of medium quality, no significant masses were found, and the lymph nodes in the neck were not found to be grown. Cardiopulmonary and abdominal investigations were negative. Physiologic reflexes were present and pathologic signs (I).
Clinical response questions
(a) What is the further management plan for this thyroid nodule?
Characteristics of this patient’s thyroid nodule: This patient’s thyroid nodule was found accidentally during a health check-up, also known as an accidental or incidental thyroid nodule, with no hyperthyroidism (hyperthyroidism) or hypothyroidism (hypothyroidism) related manifestations, no symptoms of nodule compression, no history of thyroid disease or positive family history, and normal thyroid function, Tg, TgAb and TPOAb results. The thyroid function, Tg, TgAb and TPOAb were normal. The nodules were not palpated during thyroid palpation. Ultrasound of the thyroid gland revealed a nodule <1 cm in diameter with poorly defined borders and several punctate calcifications, but no other special findings. The thyroid image was normal.
(b) What is the next step in the management of this patient?
1. Diagnostic thinking of thyroid nodules in relevant guidelines and consensus: In recent years, guidelines and consensus on thyroid nodules point out that high-resolution ultrasound, TSH level measurement and fine-needle aspiration biopsy (FNAB), especially ultrasound-guided fine-needle aspiration biopsy of the thyroid gland (UGFNAB), are the basis for the diagnosis of thyroid nodules.
First, the first step in the diagnosis of thyroid nodules should be to take a detailed history and physical examination, including: age, sex, relevant medical and family history, symptoms and signs, etc. Risk factors for malignant thyroid nodules include: history of head and neck radiation: medullary thyroid carcinoma (MTC), multiple endocrine adenomatosis type 2 (MEN2), papillary thyroid cancer, and family history of certain thyroid cancer syndromes (e.g., Cowden syndrome, Carney syndrome, Wener syndrome, and Gardner syndrome); age <14 years or >70 years The nodules should be rapidly growing, hard, irregularly shaped, and poorly mobile; pathologically enlarged lymph nodes in the neck; persistent dysphagia, dysphonia, and dyspnea (vocal cord and other lesions should be excluded).
Second, based on history and physical examination, patients should be screened for thyroid ultrasound: all patients with thyroid disease, especially those at high risk for thyroid malignancy; patients with palpable thyroid nodules and multinodular goiter: those with cervical lymph node lesions suggestive of malignant lesions; and other tests such as computed tomography (CT), magnetic resonance imaging (MRI), or positron emission computed tomography (PET). Ultrasound of the thyroid gland should be performed before the detection of incidental thyroid nodules by other tests such as computed tomography (CT), magnetic resonance imaging (MRI) or positron emission computed tomography (PET) and before preparing for FNAB or UGFNAB. High-resolution ultrasound is the most sensitive tool for detecting thyroid disease and can describe the location, size, number, morphology, texture, margins, envelope, blood supply, presence or absence of calcification and its relationship to surrounding tissues, assist in diagnosing difficult cases, differentiate between thyroid nodules or diffuse goiter, screen cases for thyroid FNAB and assist in selecting the type and length of biopsy needles, and also Baseline sizes of thyroid tissue and nodules can be obtained to facilitate treatment and dynamic follow-up observations.
The evaluation of thyroid nodules is also combined with laboratory findings. All thyroid nodules should be tested for TSH, FT3 and FT4 if TSH is decreased, and FT4 and TPOAb if TSH is increased.
TPOAb: mainly for the diagnosis of autoimmune thyroiditis.
TgAb: limited to ultrasound and clinical findings predisposing to chronic lymphocytic thyroiditis with normal TPOAb.
Tg: not recommended for the diagnosis of thyroid nodules and cannot identify the benignity or malignancy of thyroid nodules, but can be used as an indicator to monitor postoperative recurrence of differentiated thyroid cancer, provided that TgAb is normal.
Thyrotropin receptor antibody: for patients with reduced TSH.
Calcitonin: basal state serum calcitonin levels may be used for the initial assessment of thyroid nodules: basal calcitonin levels should be measured prior to surgery for nodular goiter.
Calcitonin must be measured for those with a family history or clinical suspicion of MTC or MEN2.
If calcitonin levels are elevated, they should be retested, and pentagastrin or calcium stimulation tests may increase diagnostic accuracy if interfering factors are removed
If parathyroid adenoma in the thyroid gland is considered by ultrasound, blood calcium and parathyroid hormone should be measured.
How can the benignity or malignancy of a nodule be initially determined from ultrasound findings? The following ultrasound findings in the thyroid gland suggest that the nodule may be benign: simple cystic nodule: a nodule with multiple small vesicles occupying more than 50% of the volume of the nodule with a spongy appearance. The following ultrasound findings are likely to indicate a malignant nodule: solid hypoechoic nodules; nodules with an abundant blood supply (normal TSH); irregular margins, absent halos; microcalcifications, diffuse pinpoint or clustered calcifications; and abnormal ultrasound imaging of the cervical lymph nodes (rounded lymph nodes, irregular or blurred borders, uneven internal echogenicity, internal calcifications, poorly demarcated cortex and medulla, missing lymphatic portals or cystic changes). cystic changes). It is important to emphasize that these imaging changes are only a preliminary estimate of the benignity or malignancy of the thyroid nodule, especially for the purpose of UGFNAB, and the diagnosis must be based on pathology.
FNAB is the most sensitive and specific method to further accurately assess the benignity and malignancy of thyroid nodules. Currently, the most important cause of false-negative cytologic diagnosis is improper sampling, and UGFNAB can improve the success rate of sampling and diagnostic accuracy compared to FNAB under palpation. The sensitivity of preoperative diagnosis of thyroid cancer by UGNNAB is 83%, specificity is 92%, positive prediction rate is 75%, false negative rate is 5%, and false positive rate is 5%. However, the cytomorphology alone cannot distinguish follicular carcinoma from follicular cell adenoma and medullary carcinoma of the thyroid.
UGFNAB should be performed in the following groups.
(1) Nodules larger than 10 mm in diameter: nodules of any size detected by ultrasound with extraperitoneal growth or abnormal cervical lymph nodes.
(2) Those with a history of neck radiation in childhood or adolescence.
(3) First-degree relatives of differentiated thyroid cancer, MTC or MEN2
(4) Those with previous thyroid cancer surgery: those with elevated calcitonin levels without interfering factors.
(5) Those with a diameter of less than 10 mm with ultrasound finding of malignant tendency or with 2 or more ultrasound suspected malignant high-risk factors
(6) Nodules that increase in size by more than 50% or increase in maximum diameter by more than 20% during follow-up.
(7) Nodules with height greater than the transverse diameter; cystic nodules with a solid portion greater than 50% and nodules >20 mm in diameter. in addition, intracystic sclerotherapy should be preceded by puncture for pathological examination.
However, UGFNAB is not routinely performed in the following cases.
(1) “hot nodules” with autonomic uptake confirmed by thyroid nuclide imaging.
(2) Ultrasonically indicated nodules that are purely cystic in nature.
(3) nodules that are highly suspicious of malignancy based on ultrasound images.
To improve the accuracy of UGFNAB, the following methods can be used.
(1) At least 2 punctures for sampling at multiple sites of the same nodule.
(2) Taking the material at the site where ultrasound suggests suspicious signs.
(3) sampling at the solid site of a cystic nodule, along with cytology of the cystic fluid
(4) When cervical lymphadenopathy is suspected, FNAB should include thyroid nodules and cervical lymph nodes.
If the diagnosis is not clear from the first UGFNAB, the procedure may be repeated once. In partial thyroid or neck masses, ultrasound-guided coarse needle aspiration biopsy (CNB) of the thyroid may be used if UCFNAB cytology is uncertain, and CNB is also feasible in the following cases: suspected undifferentiated tumor, thyroid lymphoma, pathologic lymph nodes, and other malignant diseases of the neck. Some authors believe that pathologist-directed puncture improves the success rate of puncture. The hallmark of successful puncture is the presence of at least six or more glandular vesicles in the specimen.
With the use of genetic and molecular biology techniques, new corroborating evidence has been provided for thyroid nodules in which some pathological findings cannot be distinguished as benign or malignant. Common specific gene alterations such as p53, Ras, met, erb2, p27, etc., RET gene mutations for MTC, BRAF and RET/PTC gene alterations are diagnostic for PTC.
Calcitonin, carcinoembryonic antigen and chromogranin A are diagnostic markers for MTC. Keratin is meaningful for differentiating degenerative carcinoma from sarcoma and lymphoma, while flow cytometry and immunocytology provide help for the diagnosis of non-Hodgkin’s lymphoma of the neck.
2. Diagnosis of the first case: According to the above guidelines and consensus, we formulated the next management measures manually from the patient’s thyroid ultrasound performance and laboratory test results. The patient’s laboratory tests showed normal thyroid function, Tg, TgAb and TPOAb results, but the ultrasound results showed a nodule with a diameter of 6 mmx6 mmx6 mm and a malignant tendency (the internal echogenicity was not homogeneous, and the border was not clear, and several spots of strong echogenicity were visible, i.e. calcification).
After UGFNAB, the pathological findings showed unexplained cellular atypical changes in the right lobe of the thyroid gland on puncture smear and cell block, which did not clearly indicate whether the nodule was malignant. The results suggested: HBME-1 (+), CK19 (+), Galectin-3 partial (+); gene test results: positive for BRAF (V600E) point mutation and negative for RET/PTC fusion gene: the diagnosis was papillary carcinoma.
(C) What is the final treatment modality for this patient?
1. Guidelines and consensus on the principles of treatment of thyroid nodules.
(1) Malignant thyroid nodules with a clear diagnosis should be treated surgically, and the appropriate surgical procedure should be selected according to the number, size, extent of invasion and surrounding lymph nodes of the nodules.
(2) For cytologically benign nodules, the following treatment modalities are available.
(1) Follow-up: Clinical, ultrasound and TSH examinations should be performed every 6-18 months for benign thyroid nodules. If clinical or ultrasound suspicion of malignancy is present, repeat UGFNAB should be performed, or repeat UGFNAB should be performed routinely every 6-l8 months; if nodules are found to be significantly growing during follow-up, i.e., nodule volume increases by more than 50%, or at least 2 diameter lines increase by more than 20% ( and more than 2 mm), UGFNAB should be performed.
Special attention should also be paid to the presence of symptoms, signs (e.g., hoarseness, dyspnea/swallowing difficulties, nodal fixation, enlarged cervical lymph nodes, etc.) and ultrasound signs suggestive of nodal malignancy. (i) For cystic solid nodules, the decision to perform UGFNAB is based on the growth of the solid portion.
(ii) Levothyroxine suppression therapy: this is not recommended as a routine treatment for benign thyroid nodules. (b) In young patients with small nodular goiter, levothyroxine or iodine supplementation is feasible if autonomic functional lesions can be excluded.
If TSH is normal, levothyroxine is not recommended to prevent recurrence after lateral thyroidectomy. partial TSH suppression regimens (TSH controlled at the lower limit of the normal range, i.e., 0.4-0.6 mU/L) have similar efficacy in reducing nodule volume compared with complete TSH suppression regimens (TSH controlled at <0.1 mU/L).
(iii) Indications for surgery in benign nodules: the presence of nodule-related local pressure symptoms, history of previous external radiation, progressive nodule enlargement, ultrasound findings suggestive of suspected malignant tendency, nodule diameter >4 cm and cosmetic needs may be selected for surgical treatment.
Lobectomy with isthmus is recommended for single nodule goiters and (sub)total thyroidectomy for multi-nodular goiters (MNGs). While completely removing the thyroid nodules. Preserve as much normal thyroid tissue as possible. The use of total/near-total thyroidectomy is recommended with caution. TSH suppressive therapy is not recommended to prevent nodule recurrence after benign thyroid nodule surgery. Surgery is recommended for nodules suspected by FNAB biopsy, and the next therapeutic step is decided based on intraoperative frozen sections
④ Radioactive iodine therapy: Indications are high-functioning or symptomatic goiter, previously treated with surgery or at risk of surgery.
Prior to treatment, non-thyrotoxic MNGs should undergo UGFNAB, avoid iodine-containing contrast agents, iodinated drugs prior to radioiodine administration, discontinue antithyroid drugs for at least l week prior to use, and repeat only after 1 week of treatment.
It is contraindicated in pregnant and lactating women, and women of childbearing age should undergo a pregnancy test prior to treatment. If the hyperthyroidism does not resolve and the nodules do not shrink after 4-6 months of treatment, the patient should consider giving radioactive iodine treatment again or taking other treatment methods, taking into account the patient’s clinical manifestations, relevant laboratory test results and thyroid nuclear imaging review. If hypothyroidism occurs after treatment, levothyroxine replacement therapy should be given promptly.
(v) Ultrasound-guided ethanol percutaneous injection (PEI): this method is more effective in the treatment of benign cystic thyroid nodules and complex nodules with one large fluidic cyst; isolated firm nodules and MNGs with or without high function should not be treated with PEI.
(6) Image-guided thermal ablation: nodules with symptoms of compression or cosmetic needs, and those who do not want to perform surgical treatment or are at risk of surgery can be treated with this method, which is not used as routine treatment for thyroid nodules.
The patient was diagnosed as papillary thyroid carcinoma by pathology, genetics and molecular biology in the outpatient clinic, and was admitted to the Department of Thyroid and Breast Surgery of our hospital.
Intraoperatively, there was a 0.6 cmx0.8 cm mass in the middle part of the right lobe of the thyroid gland with a medium quality, clear border and intact envelope. No nodule was seen in the left lobe of the thyroid gland. There were no obvious enlarged lymph nodes in the right central region or in front of the trachea.
The intraoperative frozen pathology showed that there was no definite tumor in the pre-tracheal lymph nodes and papillary carcinoma was detected in the right lobe of the thyroid gland. The patient’s postoperative condition was stable and her pronunciation was normal. The intraoperative frozen and postoperative paraffin sections of the remaining tissues diagnosed: papillary carcinoma in the right lobe and isthmus of the thyroid gland without invasion of the envelope, 4 lymph nodes, and no cancer. After surgery, he was given “Eugenol 50μg qd” as replacement therapy.
The patient was discharged with a diagnosis of micro papillary carcinoma of the right lobe of the thyroid gland (T1NOMO). The patient is currently being followed up.
Diagnosis and treatment experience
1. Thyroid nodules are the most common endocrine metabolic disease, not diabetes mellitus as commonly believed.
With continuous advances in ultrasound technology, the detection rate of thyroid nodules continues to increase. From March 2009 to August 2010, the Chinese Medical Association Endocrinology Branch conducted a thyroid disease epidemiological survey in ten cities in China. The epidemiological survey found that the prevalence of solitary thyroid nodules was 11.6% and that of multiple thyroid nodules was 7%.
2. Most thyroid nodules are accidental nodules.
Most thyroid nodules have no obvious clinical symptoms, but are mostly found by accidental discovery of a neck mass or by palpation or ultrasound during a health check. The histological features of the nodules are often not obviously correlated with the clinical manifestations. If thyroid nodules are combined with hyperthyroidism or hypothyroidism, they may show corresponding clinical symptoms.
The determination of the benignity and malignancy of thyroid nodules is the key to diagnosis and treatment.
The clinical management and prognosis of benign and malignant thyroid nodules are different, and the impact on patients’ quality of life and the medical costs involved are also significantly different, so the identification of benign and malignant nodules is the core issue of thyroid nodule diagnosis and treatment. Detailed history taking and physical examination, high-resolution ultrasound, and relevant laboratory tests are all suggestive for the determination of benign and malignant nodules, while UGFNAB cytology, molecular markers or genetic tests play a decisive role in the final diagnosis.
4. The importance of molecular diagnosis when UGFNAB pathology is difficult to determine the benignity and malignancy of thyroid nodules.
If the pathology report cannot confirm benign or malignant lesions or critical lesions, molecular markers or genetic testing can greatly increase the accuracy of diagnosis, especially the genetic diagnosis of follicular cell carcinoma and medullary carcinoma is decisive before surgery and has a suggestive effect on the patient’s prognosis.
Of course, in most cases, UCFNAB pathology is reliable for the diagnosis of benign and malignant thyroid nodules; therefore, the purpose of this article is in no way to deliberately devalue the importance and accuracy of UGFNAB for diagnosis, but rather to highlight the importance of molecular diagnosis in this setting by selecting this particular case.
5. Risk of determining benign and malignant thyroid nodules with a positive thyroid antibody with prednisone treatment test.
Prednisone treatment is effective in subacute thyroiditis with thyroid nodules when accompanied by elevated blood Tg. However, prednisone treatment is not effective in all benign diseases, such as nodular goiter; conversely, while prednisone treatment is ineffective in most malignant thyroid nodules, prednisone treatment is effective in cervical lymphatic disease (e.g., thyroid lymphoma) and should be noted. Therefore, prednisone treatment trials are clearly risky for determining the benignity and malignancy of thyroid nodules and should not be used.
6. The biggest problem for endocrinologists is their unfamiliarity with the indications for puncture.
Thyroid nodules are very common in clinical practice, and how to properly diagnose and treat them is a problem in front of endocrinologists and thyroid surgeons. It seems that all endocrinologists can perform ultrasound examination of thyroid nodules, but after getting the ultrasound results, how to proceed to the next step, whether to follow up and observe or to perform puncture, some endocrinologists seem to be hasty in their treatment and are not familiar with the indications for puncture.
The reasons for this may be the lack of awareness of people at risk for malignant thyroid nodules, the lack of detailed history taking and physical examination, the lack of ability to read thyroid ultrasound and laboratory results, etc. It is also related to the lack of attention to thyroid pathology in some hospitals and the lack of patience of physicians to continue searching for suspicious lesions. The evolving ultrasound technology, pathology technology, molecular biology technology and genetic technology provide powerful weapons to differentiate benign and malignant thyroid nodules, and all endocrinologists need to do is to fully understand and master the indications for puncture, so that thyroid nodules can be diagnosed and treated correctly and timely.
In conclusion, in clinical practice, regardless of the presence or absence of symptoms of thyroid nodules detected by physical examination or ancillary tests, patients with high risk of malignant nodules or those with malignant tendencies suggested by ultrasound and other tests should undergo further pathological or molecular diagnosis in order to receive timely treatment and avoid misdiagnosis or underdiagnosis.