Perioperative management - Restthyroidectomy with partial central lymph node dissection on the left

In the case described here, the completion surgery for total thyroidectomy was performed due to a suspicious thyroid nodule in the left lobe, after the patient had undergone right-sided hemithyroidectomy years ago for a 1 cm papillary thyroid carcinoma.

The surgery described here may be indicated for benign, suspicious, or malignant thyroid changes:

• Nodules with sonographic features of a higher malignancy risk (EU-TIRADS [European Thyroid Imaging and Reporting Data System] category 4 - 5
  LINK TIRADS
   
• In case of a positive or suspicious fine needle aspiration result with follicular neoplasia or suspected malignancy in cytology (from Bethesda stage 3/4) 
  LINK Bethesda
   
• Unclear nodule after radiation of the neck region or radiation exposure
   
• Autonomy
   
• Papillary and follicular thyroid carcinoma T1a to T4
  
  Note 1
  
  Follicular thyroid carcinoma (FTC) is a thyroid malignancy originating from follicular cells that do not show the characteristic nuclear criteria of papillary thyroid carcinoma. The tumors are usually encapsulated and, unlike adenomas, show invasive growth in the form of complete capsular breakthrough. In a minimally invasive tumor without or with only slight evidence of angioinvasion and a size <4 cm, a primary or secondary total thyroidectomy is not required. 
  
  Note 2
  
  Clinically, prognostically, and therapeutically, tumors with multifocal, aggressive, or metastatic tumor biology must be distinguished from low-risk tumors. 
  In differentiated thyroid carcinomas, primary or secondary total thyroidectomy is also recommended in the case of distant metastasis, particularly to enable postoperative radioiodine therapy.
  
  In the case of an organ capsule-exceeding T4a tumor, a cervicovisceral resection should generally be considered.
  LINK TNM
   
• Poorly differentiated thyroid carcinoma (PDTC)
  
  was first defined by the WHO in 2004 as a distinct entity, prognostically standing between differentiated and undifferentiated carcinomas. Even in the case of distant metastasis, complete tumor resection with total thyroidectomy and postoperative radioiodine therapy should be performed. However, radioiodine uptake is often limited.
   
• Undifferentiated (anaplastic) carcinomas (UTC) (T4a N0/1 M0/1).
  
  • If resectable, thyroidectomy as radical tumor resection in bilateral involvement plus multimodal therapy LINK TNM
     
• Medullary thyroid carcinoma (with central compartment resection in case of pathological calcitonin levels)
  
  Medullary thyroid carcinoma (MTC) accounts for about 5% of all thyroid carcinomas and is characterized by several specific features: The much more common differentiated thyroid carcinomas (DTC) originate from the thyroid hormone-producing cells themselves and therefore take up iodine. In contrast, MTC is derived from the calcitonin-producing C-cells. These are located between the cavity structures of the thyroid tissue and do not take up iodine. Thus, the possibility of classical radioiodine therapy, which often enables a cure in malignant thyroid cells even in advanced disease, is eliminated.
  
  MTC secretes calcitonin (Ctn) and carcinoembryonic antigen (CEA). It can only be cured by surgery. In about 75% of cases, it occurs sporadically and in about 25% hereditarily as part of multiple endocrine neoplasia type 2 (MEN2) in association with pheochromocytomas and/or primary hyperparathyroidism. In suspected MEN2, appropriate diagnostics (plasma, urine metanephrines, serum calcium, parathyroid hormone) should be performed before surgery to exclude or confirm pheochromocytoma or hyperparathyroidism.
  
  In biochemically proven MTC (in women from 30 pg/ml, in men from 60 pg/ml calcitonin), total thyroidectomy is recommended, as 10% of sporadic MTCs also occur multifocally (bilaterally).
  
  Thyroidectomy should be supplemented by central and possibly lateral cervical lymph node dissection, as early local/regional metastasis can occur, and even micro-MTCs (≤ 10mm) can be associated with lymph node metastases (exception: lack of desmoplasia evidence in frozen section). At the latest, with a basal Ctn > 200 pg/ml, contralateral lateral lymph node dissection should also be performed.
  
  In suspected MTC as part of MEN2, a germline analysis of the RET gene should be performed, and the molecular genetic proof of an activating pathogenic germline variant of the RET gene is evidence of an MEN2 syndrome. All affected individuals with MTC should receive genetic counseling.
  
  •  Post-op incidental finding after non-total thyroidectomy: no reoperation if calcitonin is below the detection limit.

Nodal positive thyroid carcinomas

In nodal-positive thyroid carcinomas, total thyroidectomy with dissection of the first lymph node station in the so-called central compartment is the procedure of choice.

The central compartment includes the anatomical space between the carotids on both sides as the lateral boundary, the hyoid bone cranially, and the brachiocephalic vein caudally.

The organ-related components of the central neck area are the two thyroid lobes, the short straight neck muscles (sternohyoid muscle, sternothyroid muscle), and the central lymph nodes (pre- and paratracheal, prelaryngeal).

In nodal-positive PTC and MTC, total thyroidectomy with central lymph node dissection is the standard.

• Manifest hyperthyroidism: Before elective thyroid surgery, the patient must be euthyroid to minimize the risk of a thyrotoxic crisis.LINK Hyperthyroidism
• Cardiopulmonary risk assessment
• General anesthesia intolerance
• Coagulation disorder or use of anticoagulants

Guidelines recommend an individual benefit-risk analysis before elective surgeries: If the operative bleeding risk clearly outweighs the potential cardiovascular benefit, the aspirin therapy should be interrupted.
In cases of higher-grade anticoagulation such as P2Y₁₂-ADP receptor antagonists (e.g., Clopidogrel), NOACs (e.g., Xarelto), or Vitamin K antagonists (e.g., Falithrom or Marcumar), an interdisciplinary consultation should develop a therapy concept regarding the indication for anticoagulation, the possibility of bridging with heparin, and the operative bleeding risk.

• An asymptomatic nodular goiter and a scintigraphically hypofunctioning ("cold") nodule without suspicion of malignancy are not indications for surgery.

Medical History

• local symptoms of thyroid enlargement, nodule growth (cervical pressure or globus sensation, swallowing difficulties, and dyspnea, especially under exertion)
   
• voice changes/hoarseness, recurrent laryngeal nerve palsy
   
• symptoms of hyperthyroidism
   
• medications (iodine-containing preparations, antithyroid drugs)
   
• family medical history
   
• previous radiation in the neck area: A confirmed etiological factor for the development of differentiated thyroid carcinoma is exposure to ionizing radiation, which is why patients with thyroid nodules should be specifically asked about previous radiation to the head-neck region.
   
• Pre-existing cervical spine problems (head reclination during positioning!)

Physical Examination

• palpation (size, consistency of thyroid lobes, nodules, swallowing mobility, palpable lymph nodes)
   
• endocrine ophthalmopathy

Vocal Cord Function Testing

• A preoperative ENT laryngoscopy to assess vocal cord mobility is essential.
   
• It can detect pre-existing damage to the recurrent laryngeal nerve, e.g., after previous surgery or in malignancy.
   
• It allows for a situation-adapted surgical strategy.
   
• It is the basis of perioperative quality assurance
   
• Pre- and postoperative laryngoscopy and intraoperative neuromonitoring form the basis of perioperative quality assurance and are an inseparable diagnostic unit. Neuromonitoring is not usable without knowledge of clinical laryngeal function! LINK IONM

Laboratory Tests

• usual preoperative laboratory parameters depending on underlying disease, coagulation, calcium, PTH
   
• TSH, thyroid hormones: fT3, fT4
  The most important in-vitro parameter is TSH, whose pathological change is based on a long-standing thyroid dysfunction. Note: A low concentration suggests hyperthyroidism, a high concentration suggests hypothyroidism. In these cases, additional determination of thyroid hormones (fT3 and fT4) is mandatory, while with normal TSH and clinical euthyroidism, it can be omitted.
   
• thyroid antibodies for the diagnosis of immunothyropathy and thyroiditis
  
  
  • Antibodies against TSH receptor (TRAK) should be determined if a clear distinction between Graves' disease and non-immunogenic hyperthyroidism is not possible based on clinical examination and imaging.
     
  • Antibodies against thyroid peroxidase (anti-TPO) are determined when autoimmune thyroid disease is suspected; they are elevated in 95% of patients with Hashimoto's thyroiditis (autoimmune thyroiditis) and in 70% of patients with Graves' disease.
     
  • Antibodies against thyroglobulin (anti-TG) are less specific, determined additionally when autoimmune thyroiditis is suspected, especially if anti-TPO is negative.
     
• Determination of basal calcitonin level.
  Calcitonin (Ctn) is a highly specific tumor marker for medullary thyroid carcinoma (MTC). German guidelines recommend a one-time determination before any thyroid surgery to detect C-cell changes in early form. The level of basal calcitonin allows conclusions about the stage of the disease and helps plan the extent of resection.
  From a threshold of ≥ 30 pg/ml Ctn for women and ≥ 60 pg/ml for men, an MTC is likely enough to justify further treatment steps.
  Lymph node metastases in the lateral lymph node compartment seem to occur only at a calcitonin level above 85/100 pg/ml and simultaneous evidence of desmoplasia. Otherwise, lateral lymph node dissection can be omitted. 25% of tumors are familial, e.g., leading tumor in MEN 2a. Therefore, molecular genetic clarification is always recommended in suspected MTC.
   
• Note: Smoking, proton pump inhibitors, renal insufficiency, and chronic alcohol consumption can lead to slightly to moderately elevated calcitonin levels (control under abstinence if necessary).

Ultrasound with TI-RADS Classification (Thyroid Imaging Reporting and Data System)

Preoperative neck ultrasound is of great importance in surgical planning. It is the basic examination method for assessing thyroid morphology.

The standardization of thyroid nodule findings allows for an assessment of dignity or risk stratification of the nodule, as required by guidelines.

Nodular findings of the thyroid are described in detail under documentation of the following criteria:

• Size (specify diameter in all 3 planes)
• Echogenicity (hypoechoic, isoechoic, hyperechoic, anechoic, and complex echo)
• cystic components
• micro- or macrocalcifications
• presence of a hypoechoic rim (halo sign)
• margin delineation (sharp versus blurred)
• configuration (asymmetric, "taller than wide")
• vascularization

The following sonographic criteria are associated with a significantly increased likelihood of malignancy:

• Hypoechogenicity
• blurred margins
• non-oval shape
• "Taller-than-wide" shape: nodule is more pronounced in depth than in width in the axial section.
• Presence of microcalcifications
  LINK TIRADS

Note:

Ultrasound can also assess the relationship to neighboring structures, lymph node status, and possible retrosternal extension.

Thyroid Scintigraphy

Scintigraphy with the tracer 99m-Technetium pertechnetate (Tc-99m) has a discrimination limit of about 1cm for lesions that are either more, equally, or less storing than the surrounding tissue and are thus described as scintigraphically warm/hot (with simultaneous suppression of surrounding tissue), indifferent, or cold.

Notes:

• The scintigraphy, together with ultrasound, is the basic examination method in the evaluation of thyroid nodules.
• Autonomous areas that are no longer subject to regulatory control by TSH can be unmasked by suppression scintigraphy (with orally administered thyroxine).
• Even with a normal TSH value, functionally autonomous nodules can be present. These should not be punctured.
• Scintigraphically cold nodules that are sonographically anechoic correspond to cysts and are considered benign.
• Non-anechoic cold nodules require clarification

Optional Preoperative Diagnostics

Magnetic Resonance Imaging/Native Computed Tomography

• In retrosternal goiter, to assess the extent of the retrosternal portion, facilitating preoperative planning of a possibly necessary thoracic surgical access route (sternotomy).
   
• in pronounced local compression symptoms
   
• in organ-overlapping growth
  
  Note 1: These two examinations have no role in the initial assessment of thyroid nodules.
  
  Note 2: In differentiated thyroid carcinoma (DTC), MRI should be preferred to avoid contrast exposure.
  Computed tomography has the disadvantage that contrast with contrast medium must be avoided, partly due to the risk of iodine-induced hyperthyroidism, and partly to avoid iodine contamination in anticipation of radioiodine therapy. After exogenous iodine intake, iodine receptors are blocked for a longer period, making radioiodine therapy and thyroid scintigraphy impossible.

PET-CT

• Molecular whole-body imaging in advanced tumors for recurrence and metastasis diagnostics with functional tracers such as dopamine (18F-DOPA), somatostatin analogs (68Ga-DOTATOC) in MTC, and fluorodeoxyglucose (18F-FDG) in PDTC (Poorly Differentiated Thyroid Carcinoma), which often does not store radioiodine.

Scintigraphy with ⁹⁹ᵐTc-MIBI with Washout Index as a Semi-Quantitative Method

For the assessment of the dignity of thyroid nodules, sestamibi scintigraphy is used clinically off-label. Off-label use must be disclosed. MIBI scintigraphy should only be used in scintigraphically hypofunctional nodules from 1 cm in size and suspicious sonomorphology (TIRADS 4 and 5) and evidence of a follicular neoplasm (Bethesda 3/4).

Imaging with ⁹⁹ᵐTc-MIBI can be used especially when fine needle aspiration is indicated but not possible or has not yielded conclusive results.

The predictive negative predictive value with rapid washout is good, follow-up controls are required.

Fine Needle Aspiration Cytology

Based on clinical, sonographic, and scintigraphic criteria, risk nodules are identified, which are then further clarified by fine needle aspiration. Since multinodular thyroid changes are common in Germany, it is advisable to limit the need for aspiration to non-autonomous nodule areas >1 cm – depending on sonographic features.
Fine needle aspiration (FNA) of a suspicious thyroid nodule serves to assess the risk of malignancy. It is particularly indicated when non-surgical treatment of the lesion is considered.

In the following scenarios, an indication for aspiration of thyroid nodules may arise:

• Patients with clinical signs of thyroid carcinoma when cytological diagnosis is important for surgical planning.
   
• Nodules depending on size from EU-TIRADS classification class 3: class 3 (> 2 cm), class 4 (> 1.5 cm), class 5 (> 1 cm)
   
• Nodules of any size with extracapsular growth or unclear cervical lymph nodes (here, the lymph node should also be aspirated if necessary)
   
• Nodules of any size in patients with a history of neck radiation without evidence of autonomy
   
• First-degree relative of a patient with papillary or medullary thyroid carcinoma or multiple endocrine neoplasia type 2

Note: In MTC, Ctn determination is superior to cytology. Due to the special importance of calcitonin screening, FNA is generally not required for the preoperative diagnosis of MTC. The assessment of a desmoplastic stromal reaction in histology is no longer reliably possible after FNA, so FNA should not be performed with elevated Ctn.

Aspiration should be explicitly avoided in nodules that correspond to scintigraphically focal autonomies, as well as in nodules that do not exhibit any sonographic criteria suspicious for malignancy. 

Cytologically, many tumor entities can be diagnosed with high accuracy. Follicular neoplasia requires histological clarification.

The indication for surgery is based on cytology in cases of follicular neoplasia, detection of specific mutations, or other evidence or proof of malignancy.

Detection of benign findings in FNA can avoid unnecessary surgeries. Detection of malignant cells significantly influences the surgical strategy (hemithyroidectomy versus thyroidectomy, extent of lymph node dissection).

In encapsulated follicular tumors, differentiation between follicular adenoma and carcinoma is not possible by FNA. Similarly, FNA cannot distinguish between a non-invasive encapsulated follicular variant of papillary thyroid tumor (NIFTP) and papillary thyroid carcinoma. Molecular pathological additional investigations can increase the sensitivity and specificity of FNA but are not yet routinely used.

The most common papillary carcinoma, accounting for over 80% of all differentiated thyroid carcinomas, can be diagnosed with high reliability.

Cytopathological Evaluation of FNA

The Bethesda classification is a 6-grade system designed exclusively for thyroid aspiration and is largely evidence-based. The advantage of this system lies in the clear assignment of malignancy probability in the individual groups. Moreover, this classification allows for international comparability due to its international use.

LINK Bethesda Classification

In suspected transmural infiltration, additionally panendoscopy, tracheoscopy, and esophagoscopy

Euthyroidism

• no special preparation

Hypothyroidism

• Information on preoperative treatment of hypothyroidism can be found at: 
  LINKHypothyroidism

Hyperthyroidism
Every patient with hyperthyroidism undergoing elective thyroid surgery should have a stable euthyroid metabolic state before the operation.

• The safest method is the administration of an antithyroid drug over several weeks.
   
• In cases of manifest hyperthyroidism, additionally, iodine blockade through short-term administration of high-dose iodide (Plummer's) 5 - 10 days preoperatively to inhibit hormone release from the thyroid, reduce thyroid perfusion (less bleeding risk), and prevent a thyrotoxic crisis during surgery. Always after initiating medical thyrostatic therapy, otherwise risk of iodine-induced hyperthyroidism.
   
• In mild forms of hyperthyroidism, a few days of treatment with beta-blockers may be sufficient.

Information on preoperative treatment of hyperthyroidism can be found at:
 LINK Preoperative Hyperthyroidism

increased cardiopulmonary risk

• Assessment of surgical risk through further diagnostics (stress ECG, heart echo, coronary angiography, lung function)

Fine needle aspiration/ intraoperative frozen section

• One-stage primary surgery requires preoperative fine needle aspiration cytology and/or the possibility of intraoperative frozen section diagnosis.
   
• The intraoperative frozen section cannot reliably predict the malignancy of encapsulated tumors. The diagnosis of a PTC in the frozen section is possible if pronounced papillary structures and typical cell nuclei are visible – however, it is often uncertain, especially in small or atypical tumors. The frozen section can guide the surgical strategy but does not replace the final diagnosis in the paraffin section.
   
• The metastatic potential/lymph node metastasis potential in MTC can be assessed intraoperatively histopathologically by the extent of intratumoral desmoplasia (desmoplastic stromal reaction) and the breach of the thyroid capsule. MTC without desmoplasia do not show lymph node metastases.

• Bleeding/Postoperative bleeding/Hematomas
• Wound infection/Wound healing disorder
• Thromboembolism
• Position-related cervical spine complaints
• Vocal cord paralysis/Dysphonia
• Dysphagia
• Hypocalcemia requiring substitution and follow-up
• Permanent hypoparathyroidism
• Thyroid hormone substitution
• Need for radioiodine therapy under exogenous or endogenous TSH stimulation
• Tumor follow-up

For large goiters extending into the mediastinum and before reoperation, rare complications should also be mentioned:

• Injuries to the sympathetic nervous system (Horner's syndrome)
• Injuries to the trachea or neck vessels
• Injury to the esophagus, pleura with tension pneumothorax, thoracic duct with chyle fistula

Intubation anesthesia for thyroid surgeries LINK

• The removal of the thyroid gland is performed in a supine position with padded shoulders and a slightly reclined (hyperextended) head. The normal pillow is replaced by a round pillow, or the head section of the operating table is slightly tilted downward.
• Ensure access to the head for tube adjustment during IONM in the course of the operation.
  both arms are adducted.
• Knee or heel cushion

• Surgeon stands to the right of the patient (in case of nerve preparation on the left, possibly switch to the left side as in the film example)
• 1st assistant opposite the surgeon, possibly 2nd assistant towards the head
• instrumenting OR nurse on the left (at the patient's abdominal level)

• Vessel sealing devices ("vessel sealing [VS] devices"): VS devices help optimize the safety and technical efficiency of thyroid surgery. They reduce blood loss, minimize the risk of hematomas and postoperative bleeding. They enable rapid and bloodless dissection, thereby shortening the operation time. Smaller incisions lead to more cosmetically pleasing results. Typical risks when using these devices arise from heat generation near sensitive structures. Generally, a distance of 2–3mm during activation is sufficient.
   
• Hooks: Four-pronged, small Roux hooks; if necessary, special retraction systems instead of the second assistant
   
• Clamps: fine Overholt clamps, small Pean clamps
   
• Suture material: absorbable braided 3-0, 4-0; if necessary, non-absorbable monofilament thread 5-0 for ligating the tissue remnant near the larynx, absorbable skin suture, if necessary, clips
   
• Neuromonitoring equipment, then also vessel loop for retracting the vagus nerve
   
• if necessary, Redon drainage CH 8
   
• recommended: surgical loupes for the surgeon

Postoperative Analgesia

• NSAIDs, possibly also opioid-containing analgesics

Follow the link here to PROSPECT (Procedures Specific Postoperative Pain Management).

Follow the link here to the current guideline Treatment of acute perioperative and post-traumatic pain.

Medical Follow-up Treatment:

• Close clinical monitoring in the first 4 to 6 postoperative hours to detect/exclude bleeding.
• Removal of any Redon drains on the first postoperative day
• Laryngoscopy before discharge, but at the latest within 7 days after discharge
• Laboratory Tests
  • Serum calcium and parathyroid hormone levels 12-24 hours postoperatively to detect parathyroid dysfunction and initiate early medication therapy.
  • In case of hypocalcemia symptoms, serum calcium levels < 2.00 mmol/l or PTH < 15 pg/ml, oral substitution with calcium 3 x 1 g and calcitriol 2 x 0.5 µg per day for 14 days.
  • The PTH level correlates best with the need for calcium/vitamin D substitution. PTH ≥ 15 pg/ml -> Safe discharge possible, PTH < 10 pg/ml -> Calcium/Vitamin D substitution, PTH between 10 and 15 gray area -> Follow-up 48 hours postoperatively for safe assessment is advisable, substitution should be continued until then.
  • Close monitoring to prevent iatrogenic hypercalcemia. Gradual tapering of substitution is recommended.
     
• Thyroid Hormone Substitution
  
  After a complete thyroidectomy, manifest hypothyroidism occurs within two to four weeks without hormone substitution. In the case of a benign diagnosis, it is therefore advisable to start L-thyroxine administration a few days postoperatively. The average substitution dose of L-thyroxine is 1.7 micrograms/kg/day according to a recent study, with a target TSH value of 0.5 to 2.0 mU/l. A TSH check after 6-8 weeks is advisable to adjust the dosage if necessary.
  
  In the case of a malignant diagnosis, a target TSH value in the lower normal range (0.5 to 2.0 mU/l) should be aimed for after a lobectomy or thyroidectomy without radioiodine therapy. TSH-suppressive therapy should not be performed.
  
  For planned radioiodine therapy, see below.

Thrombosis Prophylaxis:

The need for thrombosis prophylaxis in thyroid surgery depends on individual risk.

• In low-risk cases (young patient, no risk factors, short surgery), routine medication prophylaxis is not recommended, but early mobilization is advised.
   
• Increased risk (age > 60 years, obesity, coagulation disorder, previous DVT, longer surgery duration) pharmacological prophylaxis with low molecular weight heparin (LMWH) or fondaparinux, usually starting in the evening pre- or postoperatively with simultaneous early mobilization (preferably on the day of surgery or the first postoperative day).
   
• Duration of prophylaxis is generally until full mobilization, usually 1–5 days postoperatively
   
• The decision on thrombosis prophylaxis strongly depends on the individual risk profile, not automatically on the type of surgery.
   
• Careful consideration of thrombosis versus bleeding risk! Too aggressive anticoagulation should be avoided.
   
• Note: Renal function, HIT II (history, platelet control)
  Follow the link here to the current guideline: Prophylaxis of Venous Thromboembolism (VTE)

Mobilization: already on the day of surgery

Physical Therapy: for posture-related cervical spine complaints, if necessary, physical measures 

Dietary Progression: full diet on the day of surgery

Bowel Regulation: generally not required

Discharge: possible from the 2nd postoperative day if uncomplicated

Incapacity for Work: varies individually, approximately 10 - 14 days after discharge, significantly longer if radioiodine therapy is indicated

Completion Surgery

Due to the lack of pre- and intraoperative identification possibilities of FTC, the question of completion surgery with adjuvant radioiodine therapy arises after the postoperative histological diagnosis, assessing the risk of tumor persistence or recurrence. Surgery is indicated in the presence of distant or lymph node metastases, a widely invasive FTC, or evidence of angioinvasion (≥4 vessels). Risk factors include a size ≥4 cm, age >55 years, and incomplete tumor resection.

If the completion surgery includes the previously operated side, the procedure is recommended within 4 days or at an interval of 3 months after the initial surgery. In the case of incomplete primary tumor resection, surgery should be performed promptly.

In the case of only contralateral surgery after hemithyroidectomy during the initial surgery, current data do not indicate an increased risk of complications. Due to scarring/adhesions ventrally, a primarily lateral approach is recommended for completion. Completion surgeries without the use of IONM are not recommended.

If an MTC is found incidentally, a completion surgery can be omitted if calcitonin is not elevated in the first 2 weeks after resection and genetic testing excludes hereditary MTC. 

Radioiodine (131I) Therapy for Ablation of Postoperative Residual Thyroid Tissue

Ablative 131Iodine therapy is standard for differentiated thyroid carcinoma following surgery. Exceptions are papillary microcarcinoma without risk factors and low-malignant FTC types (low-risk group).

Only after adjuvant radioiodine therapy do the 131Iodine whole-body scintigraphy and thyroglobulin measurement under rhTSH (recombinant human thyroid-stimulating hormone) stimulation become sensitive and specific examination methods to ensure therapeutic success.

The sensitivity of whole-body scintigraphy depends on the TSH level; a basal TSH > 30 mU/l is favorable. This TSH level can be achieved 3 - 5 weeks after thyroidectomy, 4 – 5 weeks after discontinuation of levothyroxine (T4) medication, or after exogenous stimulation with recombinant human TSH (rhTSH).

In high-risk patients, TSH secretion should be endogenously stimulated, provided there are no contraindications for hypothyroidism.

In patients with comorbidities such as cardiopulmonary diseases, diabetes mellitus, renal insufficiency, neurological and psychiatric disorders, and bilateral recurrent laryngeal nerve palsy (risk of glottis edema in case of severe hypothyroidism), a multi-week hormone withdrawal with the consequence of manifest hypothyroidism is not advisable, and exogenous TSH stimulation with rhTSH is the method of choice.

The results of 131Iodine therapy are better the smaller the tumor mass and the higher the degree of differentiation. Moreover, 131Iodine therapy has good palliative effects in inoperable and not completely surgically removable tumors if radioiodine uptake is present. 

6 – 8 months after ablative radioiodine therapy, it should be assessed using diagnostic 131Iodine whole-body scintigraphy and thyroglobulin levels under rhTSH stimulation whether the desired elimination of thyroid remnant tissue has been achieved and whether there are indications of iodine-accumulating metastases.

Thyroglobulin (Tg)

Thyroglobulin is an important marker for the synthetic performance of the thyroid gland. It primarily serves the postoperative follow-up of papillary or follicular thyroid carcinomas. 

Only after thyroidectomy and ablative 131Iodine therapy is thyroglobulin a sensitive and specific tumor marker for differentiated thyroid carcinoma, with sensitivity enhanced by thyroid hormone withdrawal or stimulation with rhTSH. 

The treatment of differentiated thyroid carcinoma is well standardized with the sequence of surgery, 131Iodine therapy, and levothyroxine medication.

Follow-up

The further follow-up concept, including the extent of morphological and functional imaging, is strongly oriented towards a reassessment of individual risk by measuring the rhTSH-stimulated thyroglobulin level – combined with a 131I whole-body scintigraphy – approximately 6 – 8 months after ablative radioiodine therapy. For many patients, follow-up is then reduced to ultrasound, measurement of Tg levels with modern assays (including Tg recovery and Tg antibodies), and determination of thyroid function parameters.

Note: Anti-Tg antibodies interfere with the determination of thyroglobulin and make the value unreliable in the presence of positive antibodies.
Therefore, anti-Tg antibodies must be determined in parallel with each Tg measurement to correctly assess the significance. In the presence of positive antibodies, the anti-Tg antibody titer itself becomes the follow-up parameter.

Follow-up includes the review and medication adjustment of thyroid hormone substitution or suppression, as well as the diagnosis and treatment of typical complications of primary therapy. This includes ultrasound of the thyroid bed and neck soft tissues including lymph nodes, determination of the tumor marker thyroglobulin and thyroglobulin antibodies, and laboratory testing of thyroid hormone therapy.

TSH Value Adjustment in the Long-term Course of Patients with Differentiated Thyroid Carcinoma

Thyroglobulin is measured stimulated or unstimulated depending on the situation.
Stimulated Tg is more sensitive and is mainly used in the first follow-up phase or when recurrence is suspected.
Unstimulated Tg is generally sufficient in long-term asymptomatic patients with negative anti-Tg antibodies.

After the response evaluation 6 - 12 months after initial therapy (surgery ± radioiodine therapy), the following scenarios may arise:

Excellent Response

• In patients with an excellent response, a TSH value of 0.5 – 2.0 mU/L should be aimed for. An excellent response is defined as Tg < 0.2 ng/mL (unstimulated) or < 1 ng/mL (stim.) without evidence of antibodies, no imaging evidence of recurrence/metastases.

Biochemically Incomplete Response

• In patients with a biochemically incomplete response Tg ≥1 ng/mL (unstim.) or > 10 ng/mL (stim.), a TSH value of 0.1 – 0.5 mU/L should be aimed for, considering possible risk factors. The term "biochemically incomplete response" in differentiated thyroid carcinoma refers to the assessment of therapeutic response based on thyroglobulin levels (Tg) and possibly anti-Tg antibodies – i.e., biochemical markers, without imaging evidence of a tumor.

Structurally Incomplete Response

• In patients with a structurally incomplete response, a TSH value of < 0.1 mU/L should be aimed for, considering possible risk factors. An incomplete response here refers to the detection of tumor or metastases in imaging.

Note: The mentioned TSH ranges are target values that should be approximately achieved. Frequent changes in thyroid hormone dosage should be avoided.

Medullary Thyroid Carcinoma

In biochemical cure (Ctn level postoperatively not measurable low), semi-annual follow-ups with neck ultrasound, Ctn, and CEA determination should be performed in the first 2 years. Thereafter, if no Ctn increase has occurred, annual checks or even longer intervals can be adopted. The prognosis is very good.

Note: Carcinoembryonic Antigen (CEA) is the second tumor marker in MTC. It should not be used for preoperative diagnosis. It is a more stable marker compared to Ctn for tumor monitoring and can be used in follow-up control in metastatic MTC.

Anaplastic Thyroid Carcinoma

Due to the poor prognosis, follow-up is symptom-oriented.