RAJI SHAMAILEH,MD PERIE ADORABLE-WAGAN, MD

OBJECTIVES
Review

the incidence of autonomously hot nodule in a poorly differentiated thyroid carcinoma To briefly discuss the clinical behavior of this uncommon form of Insular Thyroid Carcinoma To discuss the management of Poorly differentiated thyroid cancer To discuss the current therapeutic approach and treatment strategy of this aggressive thyroid cancer

IDENTIFYING DATA
71

year old male

Married

Nueva

Ecija

July

3, 2011

CHIEF COMPLAINT

ANTERIOR NECK MASS

5 YEARS PTA
During an annual PE, an anterior neck mass was noted. Patient had no hoarseness, difficulty of breathing or dysphagia Patient consulted with endocrinologist
Thyroid ultrasound

Thyroid function test:

TSH: 0.00 FT3: 2.82 FT4: 1.68

Complex mass with calcification, almost completely replacing the left thyroid lobe. Measuring 6.7x6.52x5.34cm. A hypoechoic solid nodule on the right lobe measuring 1.93x1.58cm. A complex mass is likewise noted in the inferior isthmus measuring 3.33x3.61x2.77 cm

Thyroid Scintigraphy:
Large multinodular goiter with probable autonomously functioning toxic adenoma in the inferior left lobe with concurrent goitrous thyroiditis with multinodular degeneration

HISTORY OF PRESENT ILLNESS

Started on Methimazole (Tapazole) 5mg/tab twice a day x 2 weeks

6 months FNAB done showing

colloid cyst Given options for surgery

7 months later Radioactive iodine therapy. Post RAI TSH showed TSH 2.657 and FT4 0.6ng/dl.

3 YEARS PTA

Follow up UTZ: thyroid gland remained enlarged with the complex mass noted on the left thyroid measured 5.95cm x 4.02cm x 3.73cm compared to previous 6.7 x 6.5 x 5.3cm.
Patient advised another biopsy but was lost to follow up

HISTORY OF PRESENT ILLNESS

Repeat FNAB of the thyroid nodule which showed Follicular neoplasm. Patient was advised thyroidectomy but refused.

7 months PTA

Patient decided to undergo thyroidectomy thus admitted

2 months PTA

REVIEW OF SYSTEMS
HEENT: no headache,no dizziness,no seizures, no visual changes or eye pain, no photophobia, eye pain, no protruding eye, nor diplopia, no tinnitus, no hearing loss, no nose bleeding, no hoarseness, no dysphagia. Respiratory: no shortness of breath, (+) cough, no hemoptysis Cardiovascular: no easy fatigability, no palpitation ,No chest pain, no paroxysmal nocturnal dyspnea

REVIEW OF SYSTEMS
Gastrointestinal: No increased bowel motility, (+) regular bowel movement,no abdominal pain, nausea,vomiting, no change in the caliber of stool, no melena, no hematochezia Genitourinary: no dysuria, no hematuria, no urinary frequency Neuromuscular: no tremors, no proximal muscle weakness Metabolic : no heat intolerance,(-) weight loss, regular appetite

PAST MEDICAL HISTORY

HTN

4 years, on Losartan 50mg/tab OD

on Simvastatin 20mg/tab OD

Dyslipidemia

CKD secondary to Hypertensive Nephrosclerosis Crcl 49ml/min COPD

Seretide 50/500mcg BID

Non diabetic

FAMILY MEDICAL HISTORY

Hypertension No family history of DM or thyroid disease

PERSONAL AND SOCIAL HISTORY

Previous smoker of 10 pack years

PHYSICAL EXAM

General Survey

elderly, ambulatory male, not in distress

Vital signs

BP 140/80 HR 60 RR 18 T 36.2 Ht. 160cm wt. 60kg

BMI: 23.4k/m2

PHYSICAL EXAMINATION

HEENT

No widening of the palpebral fissure No lid lag or retraction Flat neck veins Enlarged anterior neck mass.
Left lobe of the thyroid gland 5x6cm firm, and hard Right lobe 4x2 cm soft, smooth, no palpable thyroid nodule

No palpable cervical lymphadenopathy

PHYSICAL EXAMINATION

HEART: adynamic precordium, regular rate rhythm, no murmur appreciated Respiratory: clear lungs, no rales, no wheezing Abdomen: soft, flat, normoactive bowel sound, no tenderness

Extremities: no tremors, good radial pulse, no edema, no cyanosis

COURSE IN THE WARDS

Thyroidectomy intraOp findings: Intrathoracic extension of the thyroid gland dissected (4cm) and separated from the thymus and a multinodular thyroid gland with 6cm widest Admission diameter. Frozen section showed poorly differentiated thyroid carcinoma

Asymptomatic Ionized calcium post operative showed 4.40mg/dl. Patient started on Calcium Day 1 post carbonate one tab 3x a day

op

Post Op day 3

Hospital Acquired Pneumonia Official histopath result released

Discharged improved on the 8th HD

HISTOPATHOLOGICAL FINDINGS
Poorly differentiated carcinoma (syn. Insular carcinoma) with minor (less than 5%) component of tall cell papillary carcinoma involving the left and right thyroid lobes with extensive vascular and capsular invasion, and with intrathoracic extension Hurtle cell adenoma (1.5cm) diameter right lobe with background of nodular colloid goiter with fibrocalcifications.

FOLLOW UP

3 weeks post OP

PET CT: revealed tumor residuals in the left infrahyoid region and superior mediastinum, multiple pulmonary nodule and right hilar lymphadenoapthy.

4 weeks post OP

Patient readmitted and subjected to RAI therapy 200mci levothyroxine 100mcg once a day post RAI. Whole body scan showed functioning residuals in the anterior cervical region and superior mediastinum, s/p total thyroidectomy. With evidence of distant functioning radiophilic metastases in both lung bases. No radio avid focus in the right hilar region Patient discharged and advised follow up after 4 weeks with repeat TSH, FT4 and FT3.

INTRODUCTION
Malignant thyroid nodules do not take up radionuclides Appear as cold areas in thyroid scintigraphy.

However, on rare occasions malignancy may be found in functional nodules. We describe the unexpected diagnosis of malignancy in a patient with a hyperfunctioning thyroid nodule, which had been treated with radioiodine therapy

ATA GUIDELINES ON THYROID NODULES AND DTC

In a patient with a Hyperfunctioning thyroid nodule, what is the incidence of malignant transformation?

INCIDENCE CARCINOMA WITH AUTONOMOUS THYROID NODULE

ln the literature, autonomous differentiated thyroid cancers are very rare and primarily reported as sporadic cases Difficult to determine the real incidence of cancer in hyperfunctioning thyroid nodules

Recently published series, 88% of microcarcinomas diagnosed between 1993 and 2007 were incidental and 6% of incidental papillary carcinomas were found at surgery performed for a hot nodule.2

HORMONES 2008, 7(2):175-179 2 Archives of Iranian Medicine, Volume 14, Number 2, March 2011 2

How does malignant transformation occurs?

PATHOGENESIS
The etiopathogenesis of coexisting hyperthyroidism and carcinoma is still unknown. Activating TSHR mutations have been identified in patients with concomitant AFTN and thyroid carcinomas1 Autonomous thyroid adenomas, mutations in the TSH receptor gene (TSHR) and in the Gs protein gene (GNAS1) have been identified to be the cause of the majority of the cases2,3

Tfayli et al.THYROID Volume 20, Number 9, 20101 Azevedo 2Arq Bras Endocrinol Metab. 2010 Russo et al JCEM 19973

Detection of an Activating Mutation of the Thyrotropin Receptor in a Case of an Autonomously Hyperfunctioning Thyroid Insular Carcinoma
DIEGO RUSSO, SALVATORE TUMINO, FRANCO ARTURI, PAOLO VIGNERI, GIUSEPPE GRASSO, ALFREDO PONTECORVI, SEBASTIANO FILETTI, AND ANTONINO BELFIORE

Journal of Clinical Endocrinology and Metabolism 2007

Mutation of the TSHR gene may explain the activation of differentiated thyroid functions in an aggressive and metastatic insular carcinoma that presented as an AFTN causing hyperthyroidism.

GENETIC EVENTS IN THYROID TUMORIGENESIS

FOLLICULAR ADENOMA

TSH R TOXIC ADENOMA GS

RAS :20% PPAR- PAX 8 FOLLICULAR CELL RAS: 40% RET/PTC TRK RAS, BRAF PAPILLARY CARCINOMA p53 p53 FOLLICULAR CARCINOMA

ANAPLASTIC CARCINOMA

Vasco V. et al JCEM 2003

CLASSIFICATION OF
THYROID CARCINOMA
THYROID CARCINOMA OF FOLLICULAR THYROID ORIGIN

WELL DIFFERENTIATED POORLY DIFFERENTIATED

UNDIFFERENTIATED

INSULAR

LARGE CELL TYPE

CANCER CONTROL 2005

INSULAR THYROID CARCINOMA

Uncommon pathologic entity Many of the tumors have been documented as case reports in the literature Exact incidence of insular carcinoma remains unknown Relatively new distinct subtype of thyroid carcinoma Criteria for diagnosis is not uniform among pathologists Incidence 3% of the primary thyroid carcinomas

ANNALS OF SURGERY 2000 Vol. 231, No. 3, 329338

INSULAR THYROID CARCINOMA

Incidence varies Japan: less than 1% of thyroid North America 23% of thyroid cancer Northern Italy 15% Variations: Geographic (environmental) influences Due to differences in histopathological interpretation International consensus meeting was held in Turin, on March 2006, to develop uniform diagnostic criteria for poorly differentiated carcinomas
Asioli et al Modern Pathology (2010) 23, 12691278

INSULAR THYROID CARCINOMA

PDTCs are rather aggressive Tumors with low Tg production, which respond poorly to RAI, and are often positive on FDG-PET scanning. 25% of patients with PDTC retain the ability to concentrate RAI These RAI-avid PDTCs do not have high metabolic activity and are usually negative on FDG-PET scanning

Nature clinical practice ONCOLOGY November 2007 vol 4 no 11

CLINICAL CHARACTERISTIC
Age: 41-86y, 2/3 female (2.2:1) Enlarging neck mass Dysphagia Dyspnea Euthyroid 7/60 (11.6%)

Cold nodule: 18/23 : 78.3%

Hot nodule 2/21 (9.5%)
Cometa et al Throat Journal May 2003

CLINICAL COURSE
PDTCs is usually aggressive with higher recurrence rate Higher rate of distant metastases Higher rate of local extrathyroidal invasion than well-differentiated thyroid tumors. PDTCs tend to be FDG-PET-positive, and not RAIavid Until we can confidently identify those PDTCs that will not respond to RAI, we routinely offer RAI therapy in the management of these patients

Nature clinical practice ONCOLOGY November 2007 vol 4 no 11

TREATMENT STRATEGY
Rarity of this tumor Difficult to draw conclusions from the literature as to the best treatment option for PDTC. Surgical management of this entity is the principal treatment approach. Total thyroidectomy: due to the aggressiveness tumor Central compartment with possible modified radical neck dissection: 50% of PDTCs having regional nodal metastases

Patel et al. Cancer Control. 2006

What is the role of postoperative RAI remnant ablation?

POSTOPERATIVE RAI

Remnant ablation

Adjuvant therapy

ATA GUIDELINES ON THYROID NODULES AND DTC

What is the treatment response to postoperative RAI therapy?

POSTOPERATIVE RAI THERAPY

PDTCs

arise from follicular epithelium and thus have the distinct potential to concentrate iodine Percentage of PDTCs having sufficient RAI concentration to allow postoperative RAI therapy is unknown. Although prospective evidence for its use and efficacy is not available

Patel et al. Cancer Control. 2006

POSTOPERATIVE RAI THERAPY

Most

authors advocate the use of RAI and L-thyroxine Differentiated epithelial function Aggressive behavior High rates of regional and distant metastases

Patel et al. Cancer Control. 2006

RADIOACTIVE IODINE THERAPY

Common

feature to all insular carcinomas presence of cells that arise from follicular epithelium. Distinct potential to concentrate radioiodine. This allows postoperative radioiodide imaging and the potential for adjuvant radioiodine therapy.

RADIOACTIVE IODINE THERAPY

Until

the recent reclassification in 1984 Insular carcinomas as a distinct thyroid cancer Poorly differentiated neoplasms : Not be expected to localize 131I

Justin et al

30 year old female diagnosed Insular thyroid carcinoma Received RAI 100mCi WBS post RAI therapy showed no distant metastases Low Thyroglobulin levels 3 months post op 2 years after no evidence of locoregional spread

RADIOACTIVE IODINE THERAPY

Percentage of PDTCs having sufficient RAI concentration to allow postoperative RAI therapy is unknown 85% radioavidity Prospective evidence for its use and efficacy is not available Most authors advocate the use of RAI and Lthyroxine Function with aggressive behavior, with high rates of regional and distant metastases

Cancer Control. Patel. April 2006, Vol. 13, No. 2

What is the role of PET scan in the management of Thyroid carcinoma?

18FDG

PET

Localize

disease in Tg- positive in thyroid cancer, RAI scan negative patients Initial staging and follow up of high risk patients with PDTC unlikely to concentrate RAI To identify sites of disease that may be missed with RAI scanning and conventional imaging Initial staging and follow up of invasive or metastatic disease hurtle cell carcinoma
ATA Guidelines on Thyroid Nodule and DTC.Thyroid 2009

18FDG

PET

Powerful

prognostic tool for identifying which patients with known distant metastases are at highest risk for disease specific mortality Selection tool to identify those patients unlikely to respond to additional RAI therapy Measurement of postreatment response following EBRT, surgical resection and embolization or systemic therapy
ATA Guidelines on Thyroid Nodule and DTC.Thyroid 2009

18

F-FDG PET

18

F-FDG PET is not ideal for the routine detection of well differentiated The combination of 18FDG PET and 131I helped to detect 93% of lesions.

Al-Nahhas et al: 18FDG PET in Diagnosis and Follow-up of Thyroid malignancy (Review)

What is the long term outcome of patient with Insular Thyroid Carcinoma?

Pellegriti et al. CANCER November 15, 2002 / Vol 95 / No. 10

Pellegriti et al. CANCER November 15, 2002 / Vol 95 / No. 10

Pellegriti et al. CANCER November 15, 2002 / Vol 95 / No. 10

RADIOACTIVE IODINE UPTAKE

Pellegriti et al. CANCER November 15, 2002 / Vol 95 / No. 10

Pellegriti et al. CANCER November 15, 2002 / Vol 95 / No. 10

TREATMENT MODALITY
Aggressive and are associated with a poorer patient outcome Warrant an initial aggressive treatment, including: 1.)Total thyroidectomy plus central lymphadenectomy 2.) Followed by prophylactic radioiodine therapy RAI therapy clinically effective only in a minority of patients Tumor rapidly progresses despite repeated radioiodine administration

Pellegriti et al. CANCER November 15, 2002 / Vol 95 / No. 10

EXTERNAL BEAM RADIOTHERAPY

No studies have specifically evaluated the use of EBRT in PDTC. No improvement in overall survival has been documented

CHEMOTHERAPEUTIC AGENTS
The

use of chemotherapeutic agents for PDTC is still being investigated Chemotherapy is employed only in case of progressive metastatic Disease refractory to radioiodine treatment The response rate is low: 17-26% Benefits are often too poor to advocate its extensive use least in the early phases of the disease.
Santini et al. J Clin Endocrinol Metab, September 2002, 87(9):41604165

CONCLUSION
Rare association of thyroid cancer and hyperthyroidism Systematic evaluation of oncological risk in all hot thyroid nodes not recommended Cumbersome and not necessarily cost-effective. Further studies would be helpful to clarify this issue. Review of literature : Hyperthyroidism does not exclude thyroid malignancy Active surveillance and follow up is necessary