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Recurrent well-differentiated thyroid carcinoma
Oral Oncology 49 (2013) 689–694
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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Recurrent well-differentiated thyroid carcinoma Matthew J.R. Magarey, Jeremy L. Freeman ⇑ Department of Otolaryngology Head & Neck Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Canada
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Article history: Available online 25 April 2013 Keywords: Recurrent thyroid carcinoma Thyroglobulin Ethanol Central neck dissection
s u m m a r y The incidence of Well-differentiated Thyroid Carcinoma (WDTC) has been increasing over the past several decades. Consequently, so has the incidence of recurrence, which ranges from 15% to 30%. Factors leading to increased risk of recurrence are well described. However, the impact of local and regional recurrence is not well understood, but distant recurrence dramatically reduces 10-year survival to 50%. Recurrent WDTC has several established options for treatment; Observation, Radioactive Iodine (RAI), Surgery and External Beam Radiotherapy (EBRT). Novel treatments such as radiofrequency ablation (RFA) and percutaneous ultrasound-guided ethanol injection (PUEI) are beginning to gain popularity and have promising early results. A review of the current literature, outcome measurements and a strategy for revision surgery within the central neck compartment are discussed within this manuscript. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Well-Differentiated Thyroid Carcinoma (WDTC) has had an increasing incidence over the past several decades. Consequently, the incidence of recurrent disease has also been on the rise. This is most likely due to improved surveillance with high-resolution ultrasonography (HRUS) and monitoring with serum thyroglobulin (Tg) allowing detection of low-volume disease. Despite this, the death rate from WDTC has remained relatively unchanged over this time.1 WDTC remains prognostically favourable in comparison to other forms of malignancy, with disease-specific death rates as low as 1.3%.2 Recurrence can be identified based on clinical findings, biochemical activity, or radiological studies. Locations for recurrence can be divided into central recurrence, in the thyroid bed or central compartment lymph nodes; lateral neck recurrence in lymph nodes or soft tissues and distant metastases. The significance of nodal recurrence on morbidity and survival is presently unclear, particularly for low-volume disease. Due to the favourable prognosis of WDTC, traditional means of staging cancer based on overall survival have now been replaced in many institutions with stratification based on risk of recurrence, as seen in the most recent American Thyroid Association (ATA) guidelines.3 Contemporary literature has focused on management decisions with an aim to control recurrent disease while minimising morbidity to the patient. This manuscript aims to outline the epidemiology, patterns of dis-
⇑ Corresponding author. Address: Temmy Latner/Dynacare Chair in Head and Neck Oncology, Mount Sinai Hospital, 600 University Avenue – Suite 401, Toronto, Ontario, Canada M5G 1X5. Tel.: +1 416 586 5141; fax: +1 416 586 8600. E-mail address: [email protected] (J.L. Freeman). 1368-8375/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.03.434
ease, and current treatment options for those patients found to have recurrent WDTC.
Rates of recurrence The current literature quotes recurrence rates of WDTC up to 30%, the majority of which will occur within 10 years of primary surgery.4–6 Another large audit of cases spanning 60 years from a single institution shows a recurrence rate over 25 years of 14%. Of these recurrences, almost 80% occurred during the first 10 years. The recurrence rate was relatively stable over the last 50 years of the audit.7 This may well be due to improved pre-operative screening and more well defined surgical techniques for dealing with primary surgical management of WDTC. Factors leading to a higher likelihood of recurrence include increasing age, male gender, increasing tumour size, extra-thyroidal extension, nodal disease at time of primary surgery and aggressive histological type.3,8–10 Most of this data relates to papillary thyroid carcinoma (PTC), which is by far the more common of the WDTC. Studies specifically looking at follicular thyroid carcinoma (FTC) are less frequent in the literature, however a German study from 2002 looked specifically at this issue. They found that of 186 patients with FTC, recurrence rates were 43.5%, of which more than half occurred in the first three years after initial diagnosis. Most of these recurrences were distant recurrences to lung and bone, which would be expected given the biological behaviour of FTC. The study found that only tumour size > 4 cm and initial lymph node metastases were risk factors for recurrence.11 The impact of locoregional recurrence on survival remains a matter of debate, as no clear link between nodal recurrence and
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mortality has yet been established. A recently published retrospective study from France looking at occult nodal disease, locoregional recurrence, distant metastases and disease-specific survival in 201 patients found that with multivariate analysis, only distant metastases had an impact on disease specific survival.12 Another recently published study from Japan with an average 10-year follow-up shows the rates of nodal, lung and bone recurrence at 7%, 2% and 0.6% respectively.13 The same author has also shown that age at recurrence, and extrathyroidal extension of the primary tumour, have an impact on survival, but that locoregional recurrence does not.14 At the recent ATA meeting in Quebec City 2012, the Memorial Sloan Kettering group displayed their experience of 799 patients from 1985 to 2005 showing that all of the disease related deaths were due to distant recurrence, and that no patients died from uncontrolled locoregional recurrent disease. Pattern of recurrence WDTC can recur loco-regionally or distantly. Numerous articles in the literature discuss the pattern of lymph node spread from WDTC. It is generally accepted that the first echelon to develop metastatic disease is the central compartment, following with ipsilateral lateral neck nodes.15 Despite this, some investigators have found similar rates of central and lateral neck nodal involvement,16 and others have found lower rates of central compartment involvement.9 Central node involvement has been shown to be a predictor of lateral node involvement in a recent study,17 however the debate regarding prophylactic central neck dissection (CND) continues. This debate is unlikely to ever gain clear evidence supporting either argument given the recent finding of trial feasibility from the ATA.18 A single surgeon study found that close to 60% of recurrent WDTC involved both the central and lateral neck compartments.19 Regarding lateral neck involvement, a single institutional audit20 and a metaanalysis,21 both show that when the lateral neck is involved, nodal disease is not just confined to levels III and IV, but also involves II and V in a significant number of cases. Distant recurrence occurs most commonly in lung and bone, but can occur at other distant sites. It has been shown that the location of recurrence has a prognostic significance for patients with recurrent WDTC,22 and that distant recurrence reduces 10-year survival to 50%.14 Surveillance Follow up of patients after surgery for WDTC consists of numerous modalities that may be employed. The most common is serum Tg levels. Stimulated thyroglobulin (StimTg) may also be used to further quantify an equivocal random Tg level. HRUS is also a commonly used screening tool for detecting tumour recurrence. These two modalities are the recommended tools for patient follow-up following surgery with or without radioactive iodine ablation (RAI) for WDTC.3 Other modalities that can be used to further investigate possible recurrences detected using Tg and HRUS, are fine-cut axial CT scan, MRI, FDG-PET, and occasionally I-131 scans. The combination of two or more of these modalities has significantly improved detection of recurrence beyond that of clinical examination alone.3 In addition to the detection of recurrent WDTC, the biological behaviour of the tumour can be inferred by these various investigations. As tumour mass displays less iodine uptake it often becomes more PET avid. This may represent de-differentiation of the tumour cells and increased metabolic activity. There is some suggestion that this has a negative influence on treatment outcomes.23 The topic of follow up and surveillance is covered in greater detail in another chapter in this journal.
Options for treatment The traditional treatment options for recurrent WDTC currently include: 1. 2. 3. 4.
Observation Radioactive Iodine I-131 Ablation (RAI) Surgical resection of the involved regions External Beam Radiation Therapy (EBRT)
When a patient presents with recurrent WDTC it can be a time of significant anxiety for both the patient and the treating physician. A balance must be achieved between providing adequate information and reassurance to the patient, while reducing morbidity and mortality. Time spent with the patient and their family will help them to understand the rationale for the different treatment options and help them to feel that they are a part of the decision making process. Observation is a valid option if the recurrence is deemed to be low-volume, or clinically low-risk. Stability of both serum Tg and the size of any lesions observed over time would make further treatment less appealing for both the patient and the physician. The 2009 ATA guidelines recognises the need to develop methods to identify which small nodal metastases can be observed rather than treated.3 In one study looking at 191 patients with residual thyroid bed nodules 1 cm or less, only 9% increased in size over five years. Absence of suspicious US appearance, and stability of serum Tg increased the likelihood of stability of thyroid bed nodule size.24 Farrag et al. have suggested that only those patients with rising Tg should undergo surgery for thyroid bed nodules.25 A Tg doubling time of less than one year has been found to be a valuable negative prognostic indicator by some groups.26 Clayman et al. also suggest observation for patients with lesions in the central compartment less than 1 cm, and for all patients under 45 years of age. Progression of disease should be observed before surgery is recommended.27 Observation of all low-volume disease, and inactive larger volume disease should be discussed with patients presenting with recurrence as a reasonable option. Many patients will be pleased to avoid further surgical procedures if they feel that ongoing surveillance will confirm stability of recurrent lesions. Although the ATA guidelines currently suggest surgery is favoured for locoregional recurrence,3 RAI may be used in cases of recurrent WDTC, particularly when disease is unable to be located on anatomical imaging studies, or it has been located in high-risk areas and has been deemed surgically unresectable (such as beside an only functioning recurrent laryngeal nerve). It is also an option in patients with distant metastases who would not be offered a cure through surgical resection. Ongoing use of RAI in the face of iodine refractory masses on scintigraphy, or persisting serum Tg levels may not be supported due to the potential side effects of what may be a non-efficacious treatment. These side effects include injury to the lacrimal glands and salivary glands causing xerophthalmia, xerostomia and potential dental caries. Radiation induced malignancy to tissues such as breast, stomach and bone marrow must also be considered.28 Despite widespread use of RAI, recent review articles have supported a more selective use, suggesting that the effectiveness of RAI may be limited and that a number of cases may prove resistant to such treatment.28,29 The ATA guidelines do suggest that bulky disease or disease located on anatomical studies should be managed with surgery and that RAI should be used in these cases in an adjunctive manner.3 Surgery for recurrent WDTC is a well-published topic that has, over the last several years, lead to well defined algorithms for management of this clinical scenario.25,27 The major risks associated with revision surgery in the thyroid bed, central compartment
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and lateral neck include injury to the recurrent laryngeal nerves, permanent hypoparathyroidism and injury to the spinal accessory nerve.30 Several series published in the last five years have shown rates of permanent RLN injury from 0% to 4.7% and permanent hypoparathyroidism from 0% to 7%. One series compares CCND with initial thyroidectomy, to revision CCND for recurrent disease and finds little difference between most complications. There was actually a lower rate of temporary hypocalcaemia with revision CCND.5 Although the outcome measurements vary between these series, and the follow-up period ranges from 2 to 20 years, reported cure rates are 36–90%.5,19,25,27,31–34 Outcome measurements will be discussed further in another section of this manuscript. The surgical technique used by the senior author to complete a revision central compartment neck dissection (CCND) will be also discussed at the end of this article. External Beam Radiation Therapy must also be considered as another adjuvant therapy, particularly in non-iodine avid lesions, and locally invasive lesions. It has proven useful in the postoperative setting for local control of disease and can prolong further recurrent disease that may otherwise impact on quality of life. Several studies have shown an improvement in disease-free survival and overall survival in cases with known microscopic residual invasive disease or inoperable disease. However, factors such as gross residual disease and high-risk histological sub-types have proven more resistant to EBRT.35,36
Novel options for treatment In recent years, a greater appreciation for selective treatment, or minimally invasive treatment of WDTC recurrence has lead to the development of newer techniques that target only the areas of confirmed disease. These newer therapies aim to ablate the disease, while minimising both the costs and morbidities associated with surgical clearance of an entire lymphatic tissue region. The 2009 ATA guidelines conclude with a statement regarding small cervical lymph node metastases, stating ‘‘Perhaps techniques will be developed to safely remove or destroy small cervical nodal metastases, which in some cases would otherwise progress to overt, clinically significant metastases’’.3 Both radiofrequency ablation (RFA) and ultrasound-guided percutaneous ethanol injection (UPEI) have gained popularity in health care centres around the world with promising results.37–42 The Mayo Clinic has over 20 years experience using UPEI and has reported excellent outcomes at the ATA meeting in Quebec City 2012, and at the ETA meeting in Pisa 2012. Together with other published series, the response rate of involved lymph nodes is between 93% and 100% (taking reduced size and Doppler blood flow as evidence of successful treatment).39–42 Lymph nodes treated measure up to 3 cm in greatest diameter, and have been described in positions close to important structures such as the RLN, Carotid artery and jugular vein. Thyroglobulin measurements have also shown a significant reduction following UPEI, highlighting the success of such treatments.40,42 Complications arising from UPEI and RFA include mild to moderate discomfort at the time of injection and temporary hoarseness in a limited number of patients. All of the above series report no major complications. One potential complication that is of concern to both authors, but has not been discussed in any publication is the potential for significant fibrosis in the neck should subsequent surgery become necessary. This is an issue that may need further clarification in the literature prior to widespread adoption of this technique. The cost of UPEI is another factor that would encourage health centres to consider the technique in their armamentarium for treatment of recurrent thyroid cancer. Costs for UPEI in the United States of America have been quoted at $836–1583 per treatment,
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compared to surgical costs of $9800–12,000 for a neck dissection, or total hospitalisation costs of $35,000–45,000 for full surgical treatment.39,43 Outcome measures for recurrent well-differentiated thyroid carcinoma In the series of papers reviewed in this manuscript, there is a wide range of reported outcome variables for the treatment of recurrent WDTC. These range from undefined ‘‘postoperative surveillance’’, through normalisation of Tg levels, to cause-specific survival. WDTC is a slowly progressive disease with a very low death rate, and long-term follow-up must be maintained to see any change in outcome when measuring survival. This is no more apparent than in a recent paper from Japan which showed 5, 10 and 20 year cause-specific survival from locally recurrent WDTC to be 86%, 76% and 36%.34 The difficulty in following patients for this extended period of time, and the rate at which new treatments are emerging for WDTC, render survival as an outcome, although interesting from an academic view, not an ideal measure for comparison. Most contemporary literature is beginning to accept biochemical remission as evidence of successful treatment of disease.19,25,27,31–34 However, within this group of reports, even the Tg levels that are stated as ‘‘remission’’ vary from ‘‘undetectable’’ to <2 ng/ml. Yim et al. specifically looked at StimTg as an outcome measure following reoperation for recurrent WDTC, using a StimTg level < 1 ng/ml as biochemical remission. This paper found that a postoperative StimTg level > 5 ng/ml reduced clinical disease-free survival at five years from 94% to 74%.33 When both Tg levels, and clinical or radiological evidence of disease were used in the same paper, higher rates of recurrent or persistent disease were found with Tg levels.19,31,33 This is likely to be due to the fact that low volume disease will contribute to a rising Tg level before the disease becomes clinically apparent. The authors feel that a StimTg level < 2 ng/ml represents normalisation of Tg levels, and is an achievable, reproducible result that can allow meaningful comparison between established and novel treatments for recurrent WDTC. Of course this must be interpreted in light of Tg Antibodies, which if present, render the Tg levels irrelevant. Revision central compartment neck dissection Although there are several methods in the literature describing revision central compartment neck dissection (CCND), this manuscript will highlight the technique of the senior author (JLF) which has been previously published.44 A video presentation of this technique will be presented at the World Congress for Thyroid Cancer, Toronto, July 2012. A review of 82 consecutive cases performed by the senior author has been published, showing that this particular approach to CCND for recurrent WDTC is a safe and efficacious procedure.19 The senior author also has approximately 180 additional unpublished cases of revision CCND with similar results. After appropriate pre-operative workup, including imaging, and full consent, the patient is positioned, prepared and draped in the usual manner for a standard thyroidectomy procedure. Intraoperative nerve monitoring is used for revision cases, although it must be stressed that this is used as an adjunct, and not in place of primary visual identification of the nerve. Confirmation of a functioning nerve at first identification and again at completion of surgery is useful. The previous thyroidectomy scar is excised and the incision carried below the platysmal layer where subplatysmal flaps are raised from the anterior thyroid notch superiorly to the sternal notch inferiorly, and to both the sternocleidomastoid muscles laterally. The anterior strap muscles are firstly separated in the
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midline, and then divided horizontally at their midpoint, and these muscles are raised off the trachea superiorly and inferiorly to fully expose the thyroid bed. The ‘‘pinch-burn’’ technique using ophthalmic bipolar forceps is the preferred method of raising the strap muscles from the underlying tissue (see Fig. 1). The superior surface of the carotid vessels are identified at the level of the thyroid cartilage, and the soft tissue overlying them is dissected to expose the vessels passing inferiorly into the upper mediastinum. This is an important step as the carotid vessels remain in a relatively constant position in a previously operated neck. The carotid arteries are used as a ‘‘shield’’ to protect the recurrent laryngeal nerves, which will lie deep to these structures, while the soft tissue dissection occurs in a more superficial layer (see Fig. 2). Once the carotid arteries are exposed along their length, the recurrent laryngeal nerves (RLN) are then identified using blunt dissection using cylindrical dental cotton sponges held in a Kelly clamp. This is achieved at an inferior level close to where the nerves emerge from under the carotid arteries. This manoeuvre serves a dual purpose. Firstly, this is a more constant position for the nerves in a previously operated neck, and secondly, this region is less likely to have been violated with previous surgery, which will limit the amount of dissection thru the fibrotic tissue around the nerves. This will maximise the chances of correctly identifying the nerves while minimising the likelihood of injury. Again, it must be stressed that locating the nerves is primarily a visual task, with intraoperative nerve monitoring used to confirm a functioning nerve after visual identification. The soft tissue is then dissected away from the nerves using a dissecting mosquito forcep. This is achieved following an inferior to superior direction, up to the level of insertion under the cricothyroid muscle (see Fig. 3). Once the RLN is free along the entire length, attention is turned to the inferior parathyroid glands, which are often located at the superior aspect of the thymus gland. The thymic tissue, in continuity with the parathyroid glands, is dissected away from the pretracheal tissues and reflected anteriorly away from the field of dissection. The dissection is achieved using a combination of blunt
Figure 1 Dissection of the sternohyoid and sternothyroid muscles using monopolar cautery.
Figure 2 Retrograde dissection of the right common carotid artery down to the innominate artery in the upper mediastinum.
Figure 3 Identification of the right recurrent laryngeal nerve inferiorly in the neck in a region not previously dissected.
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recurrent WDTC. Understanding all options, and their relative benefits will provide the best outcome for patients. References
Figure 4 Final anatomy including bilateral carotid arteries and recurrent laryngeal nerves and the normal position of the parathyroid glands. The inferior parathyroid glands are attached to the superior thymic tissue. Parathyroid glands are marked with an asterix ().
dissection and bipolar diathermy. Leaving the parathyroid gland attached to the thymus preserves the blood supply, decreasing the likelihood of postoperative hypoparathyroidism. The superior parathyroid glands are usually found just lateral and posterior to the insertion of the recurrent laryngeal nerve as it passes deep to the cricothyroid muscle (see Fig. 4). At this stage, the dissection should have exposed all of the central compartment tissue from thyroid cartilage to well below the sternal notch (preferably to the innominate artery), and from both carotid arteries laterally. The lymphatic tissue can be carefully dissected away from around the RLN in continuity with the lower paratracheal tissue and pretracheal tissue. The entire central compartment tissue can then be removed en-bloc as a single specimen. At the end of the dissection, RLN function is confirmed with the nerve monitor, and the parathyroid glands are inspected. Should any gland appear to have a compromised blood supply, it can be removed, cut into small pieces with a #15 blade, and reimplanted into well vascularised muscle (the authors prefer the ipsilateral sternocleidomastoid).
Summary Detection and treatment of WDTC aims to remove all evident disease at the time of initial presentation. Despite improvements in pre-operative screening and clear surgical algorithms, recurrence continues to cause concern for both treating physicians and patients. When faced with WDTC recurrence, all options for treatment need to be considered, and discussed with the patient. The authors hope that a clear, step-wise approach to revision surgery will provide confidence in disease clearance while minimising morbidity. Newer techniques for treating low-volume recurrent disease will soon find their place among other established treatments. A multi-disciplinary approach is essential when facing
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Contents lists available at SciVerse ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Recurrent well-differentiated thyroid carcinoma Matthew J.R. Magarey, Jeremy L. Freeman ⇑ Department of Otolaryngology Head & Neck Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Canada
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Article history: Available online 25 April 2013 Keywords: Recurrent thyroid carcinoma Thyroglobulin Ethanol Central neck dissection
s u m m a r y The incidence of Well-differentiated Thyroid Carcinoma (WDTC) has been increasing over the past several decades. Consequently, so has the incidence of recurrence, which ranges from 15% to 30%. Factors leading to increased risk of recurrence are well described. However, the impact of local and regional recurrence is not well understood, but distant recurrence dramatically reduces 10-year survival to 50%. Recurrent WDTC has several established options for treatment; Observation, Radioactive Iodine (RAI), Surgery and External Beam Radiotherapy (EBRT). Novel treatments such as radiofrequency ablation (RFA) and percutaneous ultrasound-guided ethanol injection (PUEI) are beginning to gain popularity and have promising early results. A review of the current literature, outcome measurements and a strategy for revision surgery within the central neck compartment are discussed within this manuscript. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Well-Differentiated Thyroid Carcinoma (WDTC) has had an increasing incidence over the past several decades. Consequently, the incidence of recurrent disease has also been on the rise. This is most likely due to improved surveillance with high-resolution ultrasonography (HRUS) and monitoring with serum thyroglobulin (Tg) allowing detection of low-volume disease. Despite this, the death rate from WDTC has remained relatively unchanged over this time.1 WDTC remains prognostically favourable in comparison to other forms of malignancy, with disease-specific death rates as low as 1.3%.2 Recurrence can be identified based on clinical findings, biochemical activity, or radiological studies. Locations for recurrence can be divided into central recurrence, in the thyroid bed or central compartment lymph nodes; lateral neck recurrence in lymph nodes or soft tissues and distant metastases. The significance of nodal recurrence on morbidity and survival is presently unclear, particularly for low-volume disease. Due to the favourable prognosis of WDTC, traditional means of staging cancer based on overall survival have now been replaced in many institutions with stratification based on risk of recurrence, as seen in the most recent American Thyroid Association (ATA) guidelines.3 Contemporary literature has focused on management decisions with an aim to control recurrent disease while minimising morbidity to the patient. This manuscript aims to outline the epidemiology, patterns of dis-
⇑ Corresponding author. Address: Temmy Latner/Dynacare Chair in Head and Neck Oncology, Mount Sinai Hospital, 600 University Avenue – Suite 401, Toronto, Ontario, Canada M5G 1X5. Tel.: +1 416 586 5141; fax: +1 416 586 8600. E-mail address: [email protected] (J.L. Freeman). 1368-8375/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.03.434
ease, and current treatment options for those patients found to have recurrent WDTC.
Rates of recurrence The current literature quotes recurrence rates of WDTC up to 30%, the majority of which will occur within 10 years of primary surgery.4–6 Another large audit of cases spanning 60 years from a single institution shows a recurrence rate over 25 years of 14%. Of these recurrences, almost 80% occurred during the first 10 years. The recurrence rate was relatively stable over the last 50 years of the audit.7 This may well be due to improved pre-operative screening and more well defined surgical techniques for dealing with primary surgical management of WDTC. Factors leading to a higher likelihood of recurrence include increasing age, male gender, increasing tumour size, extra-thyroidal extension, nodal disease at time of primary surgery and aggressive histological type.3,8–10 Most of this data relates to papillary thyroid carcinoma (PTC), which is by far the more common of the WDTC. Studies specifically looking at follicular thyroid carcinoma (FTC) are less frequent in the literature, however a German study from 2002 looked specifically at this issue. They found that of 186 patients with FTC, recurrence rates were 43.5%, of which more than half occurred in the first three years after initial diagnosis. Most of these recurrences were distant recurrences to lung and bone, which would be expected given the biological behaviour of FTC. The study found that only tumour size > 4 cm and initial lymph node metastases were risk factors for recurrence.11 The impact of locoregional recurrence on survival remains a matter of debate, as no clear link between nodal recurrence and
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mortality has yet been established. A recently published retrospective study from France looking at occult nodal disease, locoregional recurrence, distant metastases and disease-specific survival in 201 patients found that with multivariate analysis, only distant metastases had an impact on disease specific survival.12 Another recently published study from Japan with an average 10-year follow-up shows the rates of nodal, lung and bone recurrence at 7%, 2% and 0.6% respectively.13 The same author has also shown that age at recurrence, and extrathyroidal extension of the primary tumour, have an impact on survival, but that locoregional recurrence does not.14 At the recent ATA meeting in Quebec City 2012, the Memorial Sloan Kettering group displayed their experience of 799 patients from 1985 to 2005 showing that all of the disease related deaths were due to distant recurrence, and that no patients died from uncontrolled locoregional recurrent disease. Pattern of recurrence WDTC can recur loco-regionally or distantly. Numerous articles in the literature discuss the pattern of lymph node spread from WDTC. It is generally accepted that the first echelon to develop metastatic disease is the central compartment, following with ipsilateral lateral neck nodes.15 Despite this, some investigators have found similar rates of central and lateral neck nodal involvement,16 and others have found lower rates of central compartment involvement.9 Central node involvement has been shown to be a predictor of lateral node involvement in a recent study,17 however the debate regarding prophylactic central neck dissection (CND) continues. This debate is unlikely to ever gain clear evidence supporting either argument given the recent finding of trial feasibility from the ATA.18 A single surgeon study found that close to 60% of recurrent WDTC involved both the central and lateral neck compartments.19 Regarding lateral neck involvement, a single institutional audit20 and a metaanalysis,21 both show that when the lateral neck is involved, nodal disease is not just confined to levels III and IV, but also involves II and V in a significant number of cases. Distant recurrence occurs most commonly in lung and bone, but can occur at other distant sites. It has been shown that the location of recurrence has a prognostic significance for patients with recurrent WDTC,22 and that distant recurrence reduces 10-year survival to 50%.14 Surveillance Follow up of patients after surgery for WDTC consists of numerous modalities that may be employed. The most common is serum Tg levels. Stimulated thyroglobulin (StimTg) may also be used to further quantify an equivocal random Tg level. HRUS is also a commonly used screening tool for detecting tumour recurrence. These two modalities are the recommended tools for patient follow-up following surgery with or without radioactive iodine ablation (RAI) for WDTC.3 Other modalities that can be used to further investigate possible recurrences detected using Tg and HRUS, are fine-cut axial CT scan, MRI, FDG-PET, and occasionally I-131 scans. The combination of two or more of these modalities has significantly improved detection of recurrence beyond that of clinical examination alone.3 In addition to the detection of recurrent WDTC, the biological behaviour of the tumour can be inferred by these various investigations. As tumour mass displays less iodine uptake it often becomes more PET avid. This may represent de-differentiation of the tumour cells and increased metabolic activity. There is some suggestion that this has a negative influence on treatment outcomes.23 The topic of follow up and surveillance is covered in greater detail in another chapter in this journal.
Options for treatment The traditional treatment options for recurrent WDTC currently include: 1. 2. 3. 4.
Observation Radioactive Iodine I-131 Ablation (RAI) Surgical resection of the involved regions External Beam Radiation Therapy (EBRT)
When a patient presents with recurrent WDTC it can be a time of significant anxiety for both the patient and the treating physician. A balance must be achieved between providing adequate information and reassurance to the patient, while reducing morbidity and mortality. Time spent with the patient and their family will help them to understand the rationale for the different treatment options and help them to feel that they are a part of the decision making process. Observation is a valid option if the recurrence is deemed to be low-volume, or clinically low-risk. Stability of both serum Tg and the size of any lesions observed over time would make further treatment less appealing for both the patient and the physician. The 2009 ATA guidelines recognises the need to develop methods to identify which small nodal metastases can be observed rather than treated.3 In one study looking at 191 patients with residual thyroid bed nodules 1 cm or less, only 9% increased in size over five years. Absence of suspicious US appearance, and stability of serum Tg increased the likelihood of stability of thyroid bed nodule size.24 Farrag et al. have suggested that only those patients with rising Tg should undergo surgery for thyroid bed nodules.25 A Tg doubling time of less than one year has been found to be a valuable negative prognostic indicator by some groups.26 Clayman et al. also suggest observation for patients with lesions in the central compartment less than 1 cm, and for all patients under 45 years of age. Progression of disease should be observed before surgery is recommended.27 Observation of all low-volume disease, and inactive larger volume disease should be discussed with patients presenting with recurrence as a reasonable option. Many patients will be pleased to avoid further surgical procedures if they feel that ongoing surveillance will confirm stability of recurrent lesions. Although the ATA guidelines currently suggest surgery is favoured for locoregional recurrence,3 RAI may be used in cases of recurrent WDTC, particularly when disease is unable to be located on anatomical imaging studies, or it has been located in high-risk areas and has been deemed surgically unresectable (such as beside an only functioning recurrent laryngeal nerve). It is also an option in patients with distant metastases who would not be offered a cure through surgical resection. Ongoing use of RAI in the face of iodine refractory masses on scintigraphy, or persisting serum Tg levels may not be supported due to the potential side effects of what may be a non-efficacious treatment. These side effects include injury to the lacrimal glands and salivary glands causing xerophthalmia, xerostomia and potential dental caries. Radiation induced malignancy to tissues such as breast, stomach and bone marrow must also be considered.28 Despite widespread use of RAI, recent review articles have supported a more selective use, suggesting that the effectiveness of RAI may be limited and that a number of cases may prove resistant to such treatment.28,29 The ATA guidelines do suggest that bulky disease or disease located on anatomical studies should be managed with surgery and that RAI should be used in these cases in an adjunctive manner.3 Surgery for recurrent WDTC is a well-published topic that has, over the last several years, lead to well defined algorithms for management of this clinical scenario.25,27 The major risks associated with revision surgery in the thyroid bed, central compartment
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and lateral neck include injury to the recurrent laryngeal nerves, permanent hypoparathyroidism and injury to the spinal accessory nerve.30 Several series published in the last five years have shown rates of permanent RLN injury from 0% to 4.7% and permanent hypoparathyroidism from 0% to 7%. One series compares CCND with initial thyroidectomy, to revision CCND for recurrent disease and finds little difference between most complications. There was actually a lower rate of temporary hypocalcaemia with revision CCND.5 Although the outcome measurements vary between these series, and the follow-up period ranges from 2 to 20 years, reported cure rates are 36–90%.5,19,25,27,31–34 Outcome measurements will be discussed further in another section of this manuscript. The surgical technique used by the senior author to complete a revision central compartment neck dissection (CCND) will be also discussed at the end of this article. External Beam Radiation Therapy must also be considered as another adjuvant therapy, particularly in non-iodine avid lesions, and locally invasive lesions. It has proven useful in the postoperative setting for local control of disease and can prolong further recurrent disease that may otherwise impact on quality of life. Several studies have shown an improvement in disease-free survival and overall survival in cases with known microscopic residual invasive disease or inoperable disease. However, factors such as gross residual disease and high-risk histological sub-types have proven more resistant to EBRT.35,36
Novel options for treatment In recent years, a greater appreciation for selective treatment, or minimally invasive treatment of WDTC recurrence has lead to the development of newer techniques that target only the areas of confirmed disease. These newer therapies aim to ablate the disease, while minimising both the costs and morbidities associated with surgical clearance of an entire lymphatic tissue region. The 2009 ATA guidelines conclude with a statement regarding small cervical lymph node metastases, stating ‘‘Perhaps techniques will be developed to safely remove or destroy small cervical nodal metastases, which in some cases would otherwise progress to overt, clinically significant metastases’’.3 Both radiofrequency ablation (RFA) and ultrasound-guided percutaneous ethanol injection (UPEI) have gained popularity in health care centres around the world with promising results.37–42 The Mayo Clinic has over 20 years experience using UPEI and has reported excellent outcomes at the ATA meeting in Quebec City 2012, and at the ETA meeting in Pisa 2012. Together with other published series, the response rate of involved lymph nodes is between 93% and 100% (taking reduced size and Doppler blood flow as evidence of successful treatment).39–42 Lymph nodes treated measure up to 3 cm in greatest diameter, and have been described in positions close to important structures such as the RLN, Carotid artery and jugular vein. Thyroglobulin measurements have also shown a significant reduction following UPEI, highlighting the success of such treatments.40,42 Complications arising from UPEI and RFA include mild to moderate discomfort at the time of injection and temporary hoarseness in a limited number of patients. All of the above series report no major complications. One potential complication that is of concern to both authors, but has not been discussed in any publication is the potential for significant fibrosis in the neck should subsequent surgery become necessary. This is an issue that may need further clarification in the literature prior to widespread adoption of this technique. The cost of UPEI is another factor that would encourage health centres to consider the technique in their armamentarium for treatment of recurrent thyroid cancer. Costs for UPEI in the United States of America have been quoted at $836–1583 per treatment,
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compared to surgical costs of $9800–12,000 for a neck dissection, or total hospitalisation costs of $35,000–45,000 for full surgical treatment.39,43 Outcome measures for recurrent well-differentiated thyroid carcinoma In the series of papers reviewed in this manuscript, there is a wide range of reported outcome variables for the treatment of recurrent WDTC. These range from undefined ‘‘postoperative surveillance’’, through normalisation of Tg levels, to cause-specific survival. WDTC is a slowly progressive disease with a very low death rate, and long-term follow-up must be maintained to see any change in outcome when measuring survival. This is no more apparent than in a recent paper from Japan which showed 5, 10 and 20 year cause-specific survival from locally recurrent WDTC to be 86%, 76% and 36%.34 The difficulty in following patients for this extended period of time, and the rate at which new treatments are emerging for WDTC, render survival as an outcome, although interesting from an academic view, not an ideal measure for comparison. Most contemporary literature is beginning to accept biochemical remission as evidence of successful treatment of disease.19,25,27,31–34 However, within this group of reports, even the Tg levels that are stated as ‘‘remission’’ vary from ‘‘undetectable’’ to <2 ng/ml. Yim et al. specifically looked at StimTg as an outcome measure following reoperation for recurrent WDTC, using a StimTg level < 1 ng/ml as biochemical remission. This paper found that a postoperative StimTg level > 5 ng/ml reduced clinical disease-free survival at five years from 94% to 74%.33 When both Tg levels, and clinical or radiological evidence of disease were used in the same paper, higher rates of recurrent or persistent disease were found with Tg levels.19,31,33 This is likely to be due to the fact that low volume disease will contribute to a rising Tg level before the disease becomes clinically apparent. The authors feel that a StimTg level < 2 ng/ml represents normalisation of Tg levels, and is an achievable, reproducible result that can allow meaningful comparison between established and novel treatments for recurrent WDTC. Of course this must be interpreted in light of Tg Antibodies, which if present, render the Tg levels irrelevant. Revision central compartment neck dissection Although there are several methods in the literature describing revision central compartment neck dissection (CCND), this manuscript will highlight the technique of the senior author (JLF) which has been previously published.44 A video presentation of this technique will be presented at the World Congress for Thyroid Cancer, Toronto, July 2012. A review of 82 consecutive cases performed by the senior author has been published, showing that this particular approach to CCND for recurrent WDTC is a safe and efficacious procedure.19 The senior author also has approximately 180 additional unpublished cases of revision CCND with similar results. After appropriate pre-operative workup, including imaging, and full consent, the patient is positioned, prepared and draped in the usual manner for a standard thyroidectomy procedure. Intraoperative nerve monitoring is used for revision cases, although it must be stressed that this is used as an adjunct, and not in place of primary visual identification of the nerve. Confirmation of a functioning nerve at first identification and again at completion of surgery is useful. The previous thyroidectomy scar is excised and the incision carried below the platysmal layer where subplatysmal flaps are raised from the anterior thyroid notch superiorly to the sternal notch inferiorly, and to both the sternocleidomastoid muscles laterally. The anterior strap muscles are firstly separated in the
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midline, and then divided horizontally at their midpoint, and these muscles are raised off the trachea superiorly and inferiorly to fully expose the thyroid bed. The ‘‘pinch-burn’’ technique using ophthalmic bipolar forceps is the preferred method of raising the strap muscles from the underlying tissue (see Fig. 1). The superior surface of the carotid vessels are identified at the level of the thyroid cartilage, and the soft tissue overlying them is dissected to expose the vessels passing inferiorly into the upper mediastinum. This is an important step as the carotid vessels remain in a relatively constant position in a previously operated neck. The carotid arteries are used as a ‘‘shield’’ to protect the recurrent laryngeal nerves, which will lie deep to these structures, while the soft tissue dissection occurs in a more superficial layer (see Fig. 2). Once the carotid arteries are exposed along their length, the recurrent laryngeal nerves (RLN) are then identified using blunt dissection using cylindrical dental cotton sponges held in a Kelly clamp. This is achieved at an inferior level close to where the nerves emerge from under the carotid arteries. This manoeuvre serves a dual purpose. Firstly, this is a more constant position for the nerves in a previously operated neck, and secondly, this region is less likely to have been violated with previous surgery, which will limit the amount of dissection thru the fibrotic tissue around the nerves. This will maximise the chances of correctly identifying the nerves while minimising the likelihood of injury. Again, it must be stressed that locating the nerves is primarily a visual task, with intraoperative nerve monitoring used to confirm a functioning nerve after visual identification. The soft tissue is then dissected away from the nerves using a dissecting mosquito forcep. This is achieved following an inferior to superior direction, up to the level of insertion under the cricothyroid muscle (see Fig. 3). Once the RLN is free along the entire length, attention is turned to the inferior parathyroid glands, which are often located at the superior aspect of the thymus gland. The thymic tissue, in continuity with the parathyroid glands, is dissected away from the pretracheal tissues and reflected anteriorly away from the field of dissection. The dissection is achieved using a combination of blunt
Figure 1 Dissection of the sternohyoid and sternothyroid muscles using monopolar cautery.
Figure 2 Retrograde dissection of the right common carotid artery down to the innominate artery in the upper mediastinum.
Figure 3 Identification of the right recurrent laryngeal nerve inferiorly in the neck in a region not previously dissected.
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recurrent WDTC. Understanding all options, and their relative benefits will provide the best outcome for patients. References
Figure 4 Final anatomy including bilateral carotid arteries and recurrent laryngeal nerves and the normal position of the parathyroid glands. The inferior parathyroid glands are attached to the superior thymic tissue. Parathyroid glands are marked with an asterix ().
dissection and bipolar diathermy. Leaving the parathyroid gland attached to the thymus preserves the blood supply, decreasing the likelihood of postoperative hypoparathyroidism. The superior parathyroid glands are usually found just lateral and posterior to the insertion of the recurrent laryngeal nerve as it passes deep to the cricothyroid muscle (see Fig. 4). At this stage, the dissection should have exposed all of the central compartment tissue from thyroid cartilage to well below the sternal notch (preferably to the innominate artery), and from both carotid arteries laterally. The lymphatic tissue can be carefully dissected away from around the RLN in continuity with the lower paratracheal tissue and pretracheal tissue. The entire central compartment tissue can then be removed en-bloc as a single specimen. At the end of the dissection, RLN function is confirmed with the nerve monitor, and the parathyroid glands are inspected. Should any gland appear to have a compromised blood supply, it can be removed, cut into small pieces with a #15 blade, and reimplanted into well vascularised muscle (the authors prefer the ipsilateral sternocleidomastoid).
Summary Detection and treatment of WDTC aims to remove all evident disease at the time of initial presentation. Despite improvements in pre-operative screening and clear surgical algorithms, recurrence continues to cause concern for both treating physicians and patients. When faced with WDTC recurrence, all options for treatment need to be considered, and discussed with the patient. The authors hope that a clear, step-wise approach to revision surgery will provide confidence in disease clearance while minimising morbidity. Newer techniques for treating low-volume recurrent disease will soon find their place among other established treatments. A multi-disciplinary approach is essential when facing
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