New York, the nation s thyroid gland. Christopher Morley ( ), "Shore Leave"

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2 New York, the nation s thyroid gland Christopher Morley ( ), "Shore Leave"

3 Thyroid Literature Medline Thyroid disease 136,053 Thyroid tumors 33,554 New Paper on Thyroid Disease Every 3 Hours New Paper on Thyroid Cancer Every 8 Hours Thyroid Google search Thyroid Cancer Google search 36 million 21 million

4 Controversies Prevalence Follow-Up Diagnosis Role of RAI Papillary Microcarcinoma Clinical Impact Treatment- Surgery/Observation Primary / Neck Nodes Completion Thyroidectomy

5 When a things ceases to be a subject of controversy, it ceases to be a subject of interest. William Hazlitt

6 87% of the increase is due to primary tumors < 2cm 49% of the increase is due to primary tumors < 1 cm Davies, Welch. JAMA. 2006; 295:

7 Papillary Microcarcinoma Definition World Health Organization Papillary thyroid cancer Less than or equal to 1 cm Includes variants of PTC Unifocal or multifocal Includes N1 disease Includes M1 disease Other Terminology Occult Thyroid Cancers Incidentalomas Papillary Microtumor Occult papillary carcinoma (<1-1.5 cm) occult sclerosing variant

8 Papillary microtumor (The Porto proposal, Must fill all below criteria) Size 1 cm or less, Unifocal lesion, Not involving thyroid capsule or showing extraglandular extension, Not showing aggressive histologic subtype (eg, tall cell subtype), Occurring in adults at least 18 years of age Incidentally found. Rosai et al Int J Surg Pathol 2003

9 Papillary Microcarcinoma Autopsy Studies 25-35% in Finland, and Japan 10-15% in Canada, Poland, Colombia 5-10% in the US Prevalence Thyroid Glands Removed for Benign Disease 6% in Japan 11% in Italy 10% in Canada In the US, at least 5-10% of healthy adults may harbor papillary thyroid cancer Yamamoto et al, Cancer 1990 Harach et al, Cancer 1985 Fukunaga et al, Cancer 1975 Fink et al, Mod Pathol 1996 Pelizzo et al, Tumori 1990

10 Papillary Microcarcinoma Common Clinical Presentations Incidental findings on neck imaging Occult disease in benign surgical specimen Cervical LN Mets at presentation Distant Mets at presentation

11 Incidentaloma of the Thyroid Clinical Imaging Routine physical exam Obstetrics Check up Pregnancy Prenatal CT MRI Trauma, cervical spine Ultrasound Carotid, breast PET Scan

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13 PET Incidentaloma PET Associated Incidental Neoplasms (PAIN) Focal vs Diffuse Uptake 50% malignancy in patients with focal uptake Oncocytic pathology, tall cell or insular tumors Katz, Shaha. J Am Coll Surg 2008.

14 Incidental Incidentaloma of Thyroid U/S of carotid U/S breast thyroid U/S sales rep self demonstration U/S tech learning on spouse or classmates A relative visiting sonographer Sonographers offer while waiting for spouse s U/S Family member with thyroid nodule or thyroid cancer

15 Natural History A sobering calculation Possible Insights Based on Autopsy and SEER Data US Population: 300 Million Assume 6% have micropapillary cancer Calculated prevalence: 18,000,000 Observed prevalence all thyroid cancer: 434,000 Cancers found <2.5%

16 Papillae <0.1 CM CLASSICAL PTC

17 2mm Follicular variant, infiltrative Infiltrative follicle

18 0.9 cm solid variant PTC

19 0.9 cm solid variant PTC (nested growth)

20 Papillary Microcarcinoma Outcome Expectations Survival 99.5% Local Recurrence 1 to 2% Nodal Recurrence 3 to 5% Distal Recurrence 1% Mortality.5%

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22 Papillary Microcarcinoma Clinical outcomes after observation 2 prospective studies, 584 patients Over 5 yrs of observation 7% increase of 3mm or more 1% risk of new LN mets No deaths Delayed therapy was effective Ito 201 0, Sugatani 201 0

23 Balancing benefit and risk Are we hurting more people than we are helping? We should identify and treat thyroid cancers that are likely to cause harm if our interventions will prevent or ameliorate that harm However, if we are identifying thyroid cancers that are likely to be harmless, or can be effectively treated at a later date, we may be exposing patients to risks of treatment that may outweigh the risks of treating low risk thyroid cancer. Differentiating those cases that gain a benefit from early detection and treatment from those that can be effectively managed with an active surveillance approach

24 Papillary Microcarcinoma Risk Factors Associated with Increased Risk of Recurrence Lymph node mets at presentation Extrathyroidal extension Vascular invasion High grade histology +/- Size of primary More than unifocal BRAF Hay et al, Surgery 1992 Baudin Cancer 1998 Mazaferri, Kloos, JCEM 2001 Appetecchia et al, J Exp Clinc Cancer Res 2002 Chow et al, Cancer 2003 Pellegriti et al, JCEM 2004 Pelizzo et al Nucl Med Commun 2004 Roti et al, JCEM 2006 Ito et al, Thyroid 2003

25 Overtreatment of Papillary MicroCa Surgical Overtreatment Total Prophylactic Node Dissection Adjuvant Overtreatment RAI Follow-Up- Overtreatment, minimal follow-up

26 Differentiated Thyroid Cancer SURVIVAL: Lobectomy vs. Total Low Risk Group PROPORTION SURVIVING 100% 99% Lobectomy n = 276 Total n = TIME (years)

27 The fact that total thyroidectomy can be performed safely does not necessarily mean that it is indicated in all patients with thyroid cancer... An operation not worth doing is not worth doing well. Collin Thomas Chapel Hill

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30 Let the punishment fit the crime.

31 Papillary Microcarcinoma Neck Nodes Incidence of Micro-Mets 20-25% No impact on outcome Pre-Op Ultrasound No prophylactic node dissection During surgery, evaluate central compartment Clearance only if suspicious nodes or frozen section positive Avoid nerve injury and hypoparathyroidism Less than 2% central compartment recurrence

32 Papillary Microcarcinoma Management Paradigm No worrisome features Worrisome features* Lobectomy Alone Observation Treatment and Follow Up Low Risk PTC Serial US Total thyroidectomy +/- RRA *LN +, DM +, vascular invasion, aggressive histology, extrathyroidal extension, family history thyroid cancer, radiation exposure

33 Year Papillary Carcinoma Papillary Microcarcinoma (%) (24%) (23%) (34%) (35%) (40%) Total (36%)

34 450 Surgeries per Year Number of Surgeries All Papillary Microcarcinoma Year

35 Characteristics of Patients with Papillary Microcarcinoma Age n % <45 yrs % 45 yrs % Gender n % Female % Male % Surgery n % Less than Total % Total Thyroid % Extra Thyroid Extension n % None % Microscopic % Macroscopic 20 2% Nodal Involvement n % N0/NX % N1a 107 9% N1b % Distant Metastasis at Presentation n % M % M1 11 1% Postoperative RAI n % No % Yes %

36 Oncologic Outcomes of Patients with Papillary Microcarcinoma Local Recurrence 0 0% Neck Recurrence 13 1% Lateral Neck* 10 1% Central Neck* 4 0% Distant Recurrence 2 0% Biochemical/RAI Recurrence** 26 2% Death with Disease*** 4 0% *1 patient recurred in the central and lateral compartment **1 patient developed a palpable neck recurrence, 7 patients treated with RAI ***All patients died with distant metastasis

37 Histologic Subtypes of Papillary Microcarcinoma ( ) Classical Type % Occult Sclerosing Variant 95 9% Follicular Variant 78 7% Tall Cell Variant 78 7% Tall Cell Features 44 4% Other, NOS 38 4%

38 -Recurrence free survival is defined by recurrence detected on biopsy, RAI imaging

39 -T1N0M0 Patients only -Recurrence free survival is defined by recurrence detected on biopsy, RAI imaging

40 Conservative Management Total thyroidectomy/lobectomy Therapeutic, but no prophylactic node dissection Completion thyroidectomy for Stage II-IV Radioiodine for stage II-IV (except for minimal central node involvement)

41 Good judgment comes from experience; and experience comes from bad judgment!

42 Radioiodine? Ross: No benefit Micropapillary Ca Mazzaferri: No benefit Stage I DeGroot: No benefit tumor <1 cm Hay: No benefit low risk patients SEER : 99.9% 15 year survival +/- RAI France: No benefit ATA Low Risk patients Ross et. Al Thyroid 2009; 19:1043; Mazzaferri et al, AJM 1981: ;

43 Microcarcinoma- An Unique Presentation and Biologic Behavior Small microscopic primary Bulky nodal mets Nodal disease- poorly differentiated?

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45 The rule of 20: Only 20% of the people will remember 20% of what you said 20 minutes after your lecture. Shaha s Aphorisms

46 Thyroid Cancer Good Low 20 yr survival 99% Treatment Lobectomy. Appropriate surgery based on extent of disease. Bad Intermediate 85% Total thyroidectomy. Select extent of thyroidectomy based on extent of disease. RAI in select cases. Ugly High 57% Total thyroidectomy. RAI. Ext RT in selected cases.

47 Commonplace clinical problems in surgery are approached in diametrically opposite ways - by surgeons with similar training backgrounds, having read the literature but interpreting the available information differently, based on unique personal experience, vision or surgical prejudice. -- Richard Simmons

48 Surgeon Complications Endocrinologist Institutional philosophy Nuclear Physician Thyroid ca patient (Internet) THE BOSS! Primum non nocere First do no harm

49 Thyroid Epidemic or Pandemic Call: ARSHAHA OR GO SHAHA

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53 Papillary Microcarcinoma AACE/AAES Guidelines Unilateral total lobectomy may be an appropriate definitive procedure for patients with minimal thyroid cancers. Minimal PTCs are defined as cancers smaller than 1 cm, which do not extend beyond the thyroid capsule and are not metastatic or angioinvasive. AACE/AAES medical/surgical guidelines for clinical practice: management of thyro Cobin et al. Endocrine Practice 7 (3): 2001

54 Papillary Microcarcinoma European Thyroid Association Guidelines Apart from solitary well differentiated thyroid cancer less than 1 cm in diameter with no evidence for nodal or distant metastases and no history of previous radiation exposure that may be operated on by less than total thyroidectomy, the standard surgical treatment is total (near-total) thyroidectomy. European consensus for the management of patients with differentiated thyroid carcinoma of the fo Pacini et al. European J of Endo 154: 2006

55 Papillary Microcarcinoma European Thyroid Association Guidelines completion thyroidectomy should be proposed in the case of a large tumor, multifocality, extrathyroidal extension, and/or vascular invasion, evidence of local or distant metastases, previous history of radiation exposure or unfavorable histology. European consensus for the management of patients with differentiated thyroid carcinoma of the fo Pacini et al. European J of Endo 154: 2006

56 All histologic subtypes (classical, follicular variant, tall cell) can be seen in subcentimeter papillary carcinoma.

57 0.8 cm tall cell variant Tall cells with obvious PTC nuclear features

58 Question #1: Is the thyroid cancer epidemic real or imagined? Unfortunately, it is real Significant increase in the incidence of new cases Both genders, all races and most countries Almost exclusively PTC The vast majority of cases less than 1-2 cm in size

59 What is causing the increased incidence? Why are we finding so many new cases? Increased Disease Detection FNA, US, and Careful Pathology Examination Identifying previously sub-clinical disease Always been present, but unknown True increase in the number of thyroid cancer cases New cases found in addition to background subclinical disease Unknown (unappreciated) risk factor for development of PTC Environmental risk factors other than ionizing radiation?

60 Papillary Microcarcinoma Clinical outcomes after observation 2 prospective studies, 584 patients Over 5 yrs of observation 7% increase of 3mm or more 1% risk of new LN mets No deaths Delayed therapy was effective Ito 201 0, Sugatani 201 0

61 Papillary Microcarcinoma A prospective trial of active surveillance Intra-thyroidal papillary microcarcinoma Offer active surveillance (US 6-12 months for 5 yrs) AND FNA for genotyping (Sequenome, others) Identify barriers to acceptance and continuation Develop communication tools and strategies Identify molecular predictors of disease progression

62 Balancing benefit and risk Are we hurting more people than we are helping? We should identify and treat thyroid cancers that are likely to cause harm if our interventions will prevent or ameliorate that harm However, if we are identifying thyroid cancers that are likely to be harmless, or can be effectively treated at a later date, we may be exposing patients to risks of treatment that may outweigh the risks of treating low risk thyroid cancer. Differentiating those cases that gain a benefit from early detection and treatment from those that can be effectively managed with an active surveillance approach

63 Entity: Mimics of papillary microcarcinoma Feature shared with microcarcinoma - Solid cell nest -Micro stellate pattern - Multifocal sclerosing -Micro stellate pattern thyroiditis -Hashimoto s thyroiditis Clear nuclei

64 Papillary microcarcinoma Behavior 133 patients with follow up. Follow up (median, range): 9.9 yrs ( yrs).

65 Disease specific survival one D.O.D (0.7%). Proportion Surviving yr DSS=99% Follow up time (months)

66 Papillary microcarcinoma Behavior D.O.D: 1/133 (0.7%). Recurrent but alive: 3/133 (2.2%). Persistent disease: 2/133 (1.5%).

67 3667 Patients Received Primary Treatment at MSKCC Between 1986 and Papillary Carcinoma 3425 Tumors with Dimensions Recorded 1242 Papillary Microcarcinomas

68 -Neck recurrence was only considered if biopsy proven -Recurrence free survival is defined by recurrence detected on biopsy, RAI imaging