Surgical Management of Differentiated Thyroid Cancer

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1 Vanderbilt University Surgical Grand Rounds May 7, 2010 Surgical Management of Differentiated Thyroid Cancer Carmen C Solórzano, MD, FACS Associate Professor Endocrine and Surgical Oncology Vanderbilt University Nashville, TN

2 37,200 Thyroid cancer cases in deaths 7 HIGH PREVALENCE >300,000 individuals with thyroid cancer in the 4 USA SEER 2000 Incidence/100,000

3 Trends in Incidence of Thyroid Cancer ( ) and Papillary Tumours by Size ( ) in the USA (SEER) Thyroid cancer has the fastest rising incidence of all major cancers in the USA >350% since 1950 Davies, L. et al. JAMA 2006;295:

4 Thyroid Cancer Incidence and Mortality deaths per 100,000 in 2003

5 Increasing Incidence: Why? Radiation Iodine excess/deficient states Reproductive/hormonal factors Early detection of subclinical disease but the incidence has increased across all tumor sizes

6 Outline Risk factors and molecular mechanisms/markers Natural history, patterns of failure and pretreatment staging Surgical treatment Rationale for adjuvant therapy

7 The Thyroid Nodule Prevalence- 5% of US population (15 million) 50% if thyroid examined by Ultrasonography Thyroid carcinoma is uncommon: Lifetime risk of thyroid cancer 0.83% women and 0.33% men ATA guidelines 2009 Horner- SEER review

8 Thyroid Cancer Risk factors- Environmental Exposure to radiation is the only established environmental risk factor 1-Medical sources 2-Acute environmental exposure: nuclear fallout, weapons

9 1 100 thyroid cancer cases in 1,000,000 Nagataki Thyroid 2002 I 131, 131, KBq/m2 Belarus Chernobyl

10 Thyroid Cancer Risk factors- Genetic: Familial syndromes -5% of cancers Unknown gene Isolated familial non-medullary thyroid cancer WRN Werner s APC familial adenomatosis polyposis (cribiformmorular PTC) PTEN PTEN-Hamartoma syndrome Few patients with these syndromes develop thyroid cancer

11 Thyroid Cancer Molecular mechanisms/markers: Activation of BRAF -(PTC) Rearrangements of RET/PTC -(radiation exposure and younger pts) Activation of RAS- (FVPTC) Rearrangement of PAX8/PPARˠ -(FTC) Others: differential expressed genes, epigenetic changes

12 JCEM 94(6): 2092, FNA specimens (328 patients) Panel of mutations: BRAF, RAS, RET/PTC and PAX8/PPARˠ Only 28% of the indeterminate FNA tested positive

13 RET-Ras-BRAF-MEK RET-B catenin TRK-PI3K-AKT MDM-p53-PTEN Epigenetic silencing Single-nucletide polymorph Alternative splicing Gene expression abnl Zeiger, Curr Opinion in Onc 2010

14 Outline Risk factors and molecular mechanisms/markers Natural history, patterns of failure and pretreatment staging Surgical treatment Rationale for adjuvant therapy

15 Papillary Thyroid Cancer- has follicular cell differentiation, formation of papillae and/or distinctive nuclear changes FNA specimen

16 Sub-types Papillary Thyroid Cancer Follicular variant (most common type) Tall cell variant (aggressive) Columnar cell variant (aggressive): prominent nuclear stratification Diffuse sclerosing variant

17 Presenting Features 30 and 50 yrs of age (mean 45 yrs) Female predominance: 60% to 80% Primary tumors: 1 to 4 cm 28% multi-focal Extra-thyroidal invasion of adjacent soft tissues: about 15% 30-40% may have lymphadenopathy at presentation 2% distant metastases

18 Natural history and patterns of treatment failure Generally indolent tumor with low metastatic potential Recurrence 30% (loco-regional or distant mets) Death in approximately 8%: pulmonary mets and/or airway obstruction Overall 10 year survival: Papillary 93% Follicular 85% Hundahl Cancer 1998 Hurthle 76%

19 Many Staging Classifications The most predictive prognostic factors: Age Extent of tumor Presence of distant metastasis Histology- variants MACIS (Mayo) AJCC/TNM EORTC AMES, AGES, Munster, Ankara Clinical Class, OSU, MSKCC NTCTCS, Murcia, Noguchi, UAB&MDA, CIH Tokyo

20 6th T= specify solitary/multifocal T1a=<1cm and T1b 1.1-2cm

21 Cancer-Specific Survival for PTC TNM 6th 5 year 10 year 15 year I II III IVA IVB IVC MACIS I= < II= III= IV =>

22 Case 25 yo female: 2 cm thyroid mass no symptoms

23 Firm mass in right lobe no palpable adenopathy

24 Palpation is inadequate for evaluation of the thyroid and/or cervical adenopathy

25 7-13 MHz ULTRASOUND: Evaluates thyroid and lymph nodes BEFORE operative procedure

26 Ultrasound -Thyroid Features that may predict cancer: Hypo-echoic Calcifications Irregular borders Vascularity Taller>Wider Invasion? Kim EK AJR 2002 Papini JCEM 2002 Jabiev, Ann Surg Onc 2009 Mendez, Ann Surg Onc 2008

27 Lymph nodes- Ultrasound Central compartment Lateral compartment Cystic lymph node = Papillary cancer!

28 Evaluation of lymph nodes and the contra-lateral Lobe by surgeon- performed ultrasound (SUS) 72 pts with thyroid cancer in one lobe by FNA Evaluation of the contralateral lobe and lymph nodes Non-palpable lymph node mets in 24% A non-palpable thyroid nodule was found in the contralateral lobe in 38% 56% were malignant (vs. 14% if no nodule present) Solorzano Am Surg 2004; 70: 576

29 Ultrasound by the Surgeon or Radiologist Detects lymph node or soft tissue metastases in cervical compartments believed to be negative on physical exam in up to 30-50% of patients May prevent persistent or recurrent disease Excellent pre- and post-op op Diagnostic/Surveillance tool calcium Kouvaraki Surgery 2004; 136:1183 and 2003; 134:946

30 Mapping of Lymph Nodes II III IV Central VI Lateral V VII

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32 What happened to the thyroid scan? Fine needle aspiration biopsy

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34 Fine Needle Aspiration Cancer Rate (histology) Carcinoma (5-8%) 96-98% Cancer Benign (65-75%) up to 4-7% Cancer Non-diagnostic or inadequate (5-10%) 11% cancer Indeterminate (10-20%) 20-40% Ca Follicular or Hurthle cell neoplasm Suspicious for carcinoma Yang Cancer 2007;111: Yassa Cancer 2007;111:

35 Distribution of FNA results- when the patient visits this surgeon % N=797 patients with FNA s from unpublished data 2010 (1/2003-1/2010)

36 797 patients with FNA s who underwent thyroidectomy Unpublished data 1/2003-1/2010 FNA result vs. Histopathology Tertiary Referral Center # pts 98% 49% # #FN= 37% #HN= 36% #Susp PTC= 92% 16% 24%

37 Bethesda System for Reporting Non-diagnostic Benign NCI- Thyroid FNA State of the Science Conference 2007 Thyroid Cytopathology Atypia of undetermined significance/ Follicular lesion of undetermined significance (FLUS) Follicular neoplasm or suspicious for a follicular neoplasm (specify if Hurthle/Oncocytic) Suspicious for malignancy Malignant

38 Thyroid 2009 vol 19(11), p1159

39 Papillary Thyroid Cancer Staging Case 25 yo female: 2 cm R thyroid nodule FNA Suspicious for a Follicular Neoplasm US: Lateral (II,III,IV,V) lymph nodes not involved, additional small (8mm) thyroid nodule opposite thyroid lobe

40 Ultrasound (and physical exam findings) May be used to alter surgical decision making (total thyroidectomy vs. lobectomy) in patients with indeterminate FNA

41 180 patients with indeterminate FNA 137 Hurthle/Follicular, 43 suspicious PTC Adverse nodule features on SUS: Micro-calcifications Irregular borders Hypoechoic Taller>Wider Mendez et al. Ann Surg Onc 15(9):2487, 2008

42 Adverse thyroid nodule features on SUS in patients with indeterminate FNA SUS features Malignant Benign Total 0 17(29%) 41(71%) (35%) 33(65%) (71%) 11(29%) (89%) 3(11%) (100%) 0(0%) 5 Total 92(51%) 89(49%) 180 Mendez, Ann of Surg Onc 2008

43 Risk factors and molecular mechanisms of tumor development Natural history/patterns of failure Pretreatment staging Outline Surgical treatment Rationale for adjuvant therapy

44 Treating Thyroid Cancer Start with the end in mind!!! Normal post-op op ultrasound and undetectable Tg

45 Goals of Surgical Therapy Remove the primary tumor, disease extension beyon thyroid capsule, and affected cervical lymph nodes Accurately stage disease Facilitate radioiodine therapy when appropriate Permit accurate long-term surveillance for recurrence Minimize the risk of recurrence and metastasis Limit the disease-and treatment-related morbidity and mortality

46 Thyroid Cancer Risk stratification for M0 patients Low risk High Risk < 40 Age > 40 Female Sex Male < 2 cm Size > 2 cm NO Extra-thyroidal invasion YES? Lymph Nodes Multiple + AGES, AMES, MACIS, etc

47 Death from PTC, the most common form of thyroid cancer, is very rare, and therefore, death should not be used as a valid endpoint for assessment of treatment Cervical recurrence occurs 20% low risk 69% high risk

48 Extent of Surgery Total Thyroidectomy vs. Lobectomy Total Lobe Improved in high risk Lower in high/low Allows delivery Use in follow-up Survival Recurrence Radioactive Iodine Thyroglobulin Complications Lower

49 Mortality Recurrence Total Thyroidectomy improves survival and recurrence in patients with MACIS high risk PTC Mayo clinic 2002 ( )

50 Mayo experience low-risk AMES % Recurrence AMES low-risk M0 Men < 41, woman < 51 Older patients with: T < 5 cm intrathyroidal, M UL 22 BL UL=unilateral lobectomy BL=bilateral lobectomy 8 UL 14 BL 19 any site local regional 2 UL Recurrence Site BL 6 Hay, Surgery 1998;124:958 N = 1,656,

51 52,173 patients; 83% total thyroidectomy For all tumors >1cm, and for tumors 1-2 cm, total thyroidectomy associated with improved survival Reinforces the current common practice Ann Surg 2007

52 25 yo with FNA indeterminate Follicular variant PTC multifocal (2.2 cm) Lymph nodes in the central neck appeared normal- should they be removed prophylacticly?

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54 Pattern of LN metastasis (micro-metastases, H+E negative) 80 patients total thyroid and central and ipsilateral lateral neck dissection 53% had lymph node micro-metastases by Immunohistochemistry Upper 1/3 tumors upward lymphatic flow Lower 1/3/isthmus tumors downward flow Early thyroid cancer micromets do not cross the midline and remain in the ipsilateral side of the tumor Qubain, Surgery 2002:131:249-56

55 level II,III lateral Pre-tracheal Para-tracheal <1cm tumors- 26% micro-mets >1.1cm-66% micro-mets

56 Pattern of LN metastasis (H+E positive) 134 patients total thyroid, central and lateral neck dissection The ipsilateral lateral compartment involved as often as the central (lat 29% vs. central 32%); re-ops (lat 21% vs. central 37%) The ipsilateral central compartment most common Marchens WJS 2002;26:22-8 site for LN mets Patients who have central lymph node mets have at least a 70% chance of ipsilateral lateral LN involvement Marchens, Surgery 2009; 145;175-81

57 Lymph Node Metastases in PTC Cervical LN metastases are quite common 20-50% Micro-metastases -present in 90% Lymph node metastases in PTC significantly correlate with persistence and recurrence of PTC Lymph node metastases and their effect on mortality remains controversial

58 Lymph Node Metastases in PTC Making evidence based recommendations for the treatment of LN metastases is challenging Studies are retrospective Indolent disease Heterogeneity of literature (use of ultrasound, terminology, prophylactic vs. therapeutic etc)

59 The argument against prophylactic (elective) LN dissection of the central compartment Lymph node metastases have no impact on cause specific mortality or recurrence More radical surgery greater morbidity (hypoparathyroidism and permanent nerve injury) Roh Ann Surg 2007;245:604 Bardet Eur J endo 2008 Palestini Langenbeck s Arch 2008 Henry Langenbeck s Arch 1998

60 The argument in favor of prophylactic (elective) LN dissection of the central compartment Even experienced surgeons can not tell if lymph nodes are affected May reduce recurrence/persistence May improve survival Re-operations in the central neck are morbid Noguchi Arch Surg 1998;133:276 White W J Surg 2007; 31:895 Sywak, Surgery 2006 Tisell et al. WJS 20: , 1996 Zaydfudim et al. Surgery 144: 1070, 2008

61 Historical Perspective 1950 s Frazell, Foote Jr, Crile Jr-? the need for radical and then prophylactic neck dissections 1970 s- Shiro Noguchi- 90% of PTC patients already have lymph node micromets-? the need for routine dissections- unless gross disease, >40 yo or >1.5 cm Ernest Mazzaferri- neck dissections do not influence recurrence or survival- extent of thyroidectomy and RAI treatment does

62 Historical Perspective Cont s-the great debates Hay/Cady/Shaha about Total thyroid vs. lesser no mention of neck dissections 2000 s-ultrasound and Thyroglobulin- The goal posts have changed position! HAVE WE EVOLVED OR, HAVE WE MERELY COME FULL CIRCLE? Zeiger JSO 2010

63 Extent of Central LN Dissection The New Paradigm! R27 Prophylactic central compartment neck dissection (ipsilateral or bilateral) may be performed in patients with PTC with clinically uninvolved central neck lymph nodes, especially for advanced primary tumors (T3 or T4) Recommendation R27 should be interpreted in light of available expertise American Thyroid Association: Thyroid Cancer Guidelines-R27 Thyroid 2009

64 Extent of Central LN Dissection The New Paradigm! Prophylactic central neck dissection can be considered but is not required in all cases National Cancer Center Network-Guidelines 2010

65 Extent of LN Dissection The punch line! Obvious gross lymph node disease in the central compartment should be removed with a therapeutic central LN dissection Level VI central neck dissection can be achieved with low morbidity** Prophylactic (elective) central dissection? controversial ** in experienced hands Gemsenjager JACS 197: , 2003 Tisell et al. WJS 20: , 1996

66 Extent of LN Dissection The punch line continued! Lateral LN disease when evident clinically, on ultrasound or at the time of surgery should be treated with a functional compartment directed dissection (levels II-V) The level VI (central) lymph nodes should also be dissected NO BERRY PICKING Tisell et al. WJS 20: , 1996 Musacchio Am Surg. 2003;69(3):

67 Central and lateral neck dissection

68 Risk factors and molecular mechanisms of tumor development Natural history/patterns of failure Pretreatment staging Surgical treatment Outline Rationale for adjuvant therapy

69 Loco-regional recurrence Can be decreased by: Extent of the initial surgical procedure Thyroid remnant Adequate lymph node removal Radioactive Iodine (RAI) TSH suppression (oral LT4)

70 Rationale for RAI ablation -Eradicates residual, not-resected microscopic or gross tumor -Ablates any thyroid tissue to facilitate: Tg measurements RAI whole body scans (WBS) -May detect sub-clinical lung metastases -Improves survival in high risk patients

71 Recurrence following RAI Stage 2 and 3 Mazzaferri (T>1.5cm) N = 802 % Recurrence years N = 138 RAI no RAI Also TSH suppression Mazzaferri, Am J Med 1994;97:418

72 RAI ongoing controversies - No consensus on ablation dose of I Does it improve survival? - RAI ablation in low risk patients? May not be necessary!

73 Rationale for TSH suppression TSH is a growth factor for thyroid cancer Keeping TSH at a low level (<0.1mU/l) can decrease recurrence

74 TSH suppression not for all? National Thyroid Cancer Treatment Cooperative Registry n=617 PTC Thyroid 1998;8: Degree of TSH suppression in patients with high-risk papillary cancer correlated with time to progression No correlation in low risk patients

75 Overall survival in high risk differentiated thyroid cancer according to TSH score 100% TSH=Undetectable/subnormal 90% 80% 50% TSH=Normal or elevated 10% Years Jonklaas Thyroid 2006 Outcomes of patients with DTC following therapy

76 TSH suppression For high risk patients- YES <0.1 miu/l For low risk patients- NO Moderate suppression for intermediate risk Duration?

77 Conclusions Surgeons play a key role in the management of thyroid cancer Staging, performing or completing adequate thyroid cancer removal Member of the multidisciplinary team Help with surveillance and removal of recurrent disease

78 THANK YOU

79 52,173 patients in NCDB Ann Surg 2007

80 Emile Theodor Kocher Nobel Prize 1909 For his work on the physiology, pathology, and surgery of the thyroid gland

81 Resident performing endocrine surgery Nerve monitor Harmonic scalpel Parathyroid Autotransplant Medical student

82 Extent of lymph node dissection A current controversy! High incidence of cervical LN mets at diagnosis ACS CoC patient care evaluation study 5583 cases of thyroid cancer- Type % No LN evaluated % <1cm Papillary Follicular 77 6 Hurthle 71 3 Medullary Hundahl,, Cancer 2000; 89:

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84 DFS following RAI: U of Chicago U of C stage I and II (intrathyroidal or N1) with T > 1cm 120 % Disease Free (DFS) years RAI Surgery alone RAI no RAI DeGroot, JCEM 1990;71:414 N = approx. 200

85 DFS following TSH suppression TSH suppression as a determinant of recurrence: 70% papillary 120 % Disease Free years TSH < 0.1 (N=18) TSH > 1.0 (N=15) TSH <0.1 TSH>1.0 Pujol, JCEM 1996;81:4318. Stage of disease variable

86 Treating Thyroid Cancer Start with the end in mind!!!

87 Evaluation of Lymph Nodes and the Contralateral Lobe by SUS 72 patients with thyroid cancer SUS evaluation of contra-lateral lobe Non-palpable contra-lateral nodule found by SUS N=27(38%) No contra-lateral nodule found by SUS N=32 Total thyroidectomy N=25 Thyroid lobectomy N=2 Total thyroidectomy N=28 Thyroid lobectomy N=4 14/25 (56%) cancer in contralateral lobe nodule 4/28 (14%) cancer in contralateral lobe SUS identified non-palpable lymph node metastasis in 24%

88 Historical Perspective The general lack of a great body of material for prolonged follow-up studies emphasizes the need for extreme caution in making all-inclusive pronouncements of a prognostic nature about a form of cancer in which the most noteworthy attribute is extreme chronicity Frazell and Foote Cancer 1958;11:895 Memorial Center for Cancer and Allied Dz-NY