IN THE NAME OF GOD

THYROID CASE PRESENTATION

By: Maghsoomi.Z.MD

Case 1

A 54 years old female with susceptible lymph node

6 years ago (91.12.29) because of MNG she underwent surgery and

pathology results were Normal MNG.

She took Levothyroxine after surgery

US 92.05.02(after 6 month of surgery)

Multiple LN size 3cm

After 4 years because of hypothyroidism came to

endocrinologist office and reevaluated because of last US

US 97.03.21

Review pathology 97.03.29

Review pathology 97.04.14

Lab data Date Lab Data

97.04.09 (m after TX)

97.08.12 ( m after TX)

Calcitonin (pg/ml) 1966 (up to5) 213 (up to11.5)

CEA (ng/ml) 41.42(up to5) Ca (mg/dl) 9.4 P (mg/dl) 2.94 PTH (pg/ml) 66.5 (14.5_87.1)

Urine Metanephrine & Normetanephrine &Epinephrine

Be checked with normal result

Candidate for surgery and performed in Imam

Khomeini Hospital (Lt Lateral neck dissection)

97.07.17

Pathology Results

Total LN involvement 5

Spiral neck , chest & abdominal CT scan (97.07.25) (1 week after surgery)

4 LN with coarse calcification & size 27*20 in base of left neck

(upper mediastinum)

6 mm calcification region in 7th segment of liver

Date Lab Data

97.04.09 (6 y after first surgery)

97.08.12 (1 m after second surgery)

Calcitonin (pg/ml) 1966 (up to 5) 213 (up to11.5)

CEA (ng/ml) ---- 41.42(up to5) Ca (mg/dl) 9.4 ---- P (mg/dl) 2.94 ---- PTH (pg/ml) 66.5 (14.5_87.1) ----

Urine Metanephrine & Normetanephrine &Epinephrine

Be checked with normal result

----

97.08.13 Octerotide Scan 97.08.28

Octerotide Scan 97.08.28

Octerotide Scan 97.08.28

Octerotide Scan 97.08.28

Last US 97.09.06

Summery

A 54 years old female HX of MTC and total thyroidectomy (91.12.29) Lateral LN dissection (97.07.17) Supra mediastinal LN on left side 27*20 confirmed by octerotide scan Neck US 4.5*7 & 3.4*4.7 mm LN Lt neck Last calcitonin: 213

Imaging MTC with Persistent Elevated Ctn

The Journal of Clinical Endocrinology & Metabolism 2007, 92(11):4185–4190

Imaging MTC with Persistent Elevated Ctn

• Using these imaging modalities detect 98% of neck recurrences; 100%

of mediastinal lymph nodes, lungs, and liver metastases; and 94% of

bone metastases.

• FDG PET has no place in routine imaging

The Journal of Clinical Endocrinology & Metabolism 2007, 92(11):4185–4190 22

ATA Managment Guideline 2015

Small volume & asymptomatic

• Small-volume residual outside of cervical lymph nodes (thyroid bed or

soft tissue metastases)

gross extra thyroidal extension into major structures in the neck: EBRT as

adjuvant therapy

early soft tissue recurrence of MTC: surgical resection, usually followed by

EBRT

• Small-volume lymph node OR distant metastases: usually followed with

observation (imaging at 6_12 month interval)

2018,Medullary thyroid cancer: Surgical treatment and prognosis

Large volume or symptomatic ●Macroscopic residual in the thyroid bed or cervical soft tissue metastases : If unresectable EBRT, preference to

use systemic therapy

●Symptomatic or large-volume loco regional lymph node disease – Resection of large-volume locoregional

lymph node

if the basal serum calcitonin >1000 pg/mL or if more than five metastatic lymph nodes be removed with a

previous surgery for asymptomatic large-volume lymph node metastases :observation or systemic therapies

(tyrosine kinase inhibitors)

●Symptomatic or large-volume distant metastasis

locally directed therapies such as surgical resection, EBRT, embolization, or radiofrequency ablation.

cannot locally directed therapies, systemic treatment (ie, tyrosine kinase inhibitors) 2018,Medullary thyroid cancer: Surgical treatment and prognosis

Large volume or symptomatic ●Macroscopic residual in the thyroid bed or cervical soft tissue metastases : If unresectable EBRT, systemic therapy

preference to use EBRT

●Symptomatic or large-volume loco regional lymph node disease – Resection of large-volume locoregional lymph node

if the basal serum calcitonin >1000 pg/mL or if more than five metastatic lymph nodes be removed with a previous

surgery for asymptomatic large-volume lymph node metastases :observation or systemic therapies (tyrosine kinase

inhibitors)

●Symptomatic or large-volume distant metastasis –

locally directed therapies such as surgical resection, EBRT, embolization, or radiofrequency ablation.

cannot locally directed therapies, systemic treatment (ie, tyrosine kinase inhibitors)

2018,Medullary thyroid cancer: Surgical treatment and prognosis

• EBRT for very select patients with extensive preoperative gross extrathyroidal

extension or large-volume, multicompartment macroscopic lymph node

involvement

• In high risk patients (residual disease, extrathyroidal extension, or nodal

involvement), locoregional recurrence free rate was 86% at 10 years with

postoperative external beam radiation therapy (EBRT) as compared to 52% in

those without adjuvant EBRT ,However, radiation may not confer survival

advantage

2018,Medullary thyroid cancer: Surgical treatment and prognosis

Rationale for Targeted Therapy in MTC: When

• Clinical Indications

Targeted therapy should be considered where local treatments have been

exhausted

impending compression of specific sites such as the central nervous system or the

airway, where a smaller disease volume may be critical, considered sooner

TKIs also help in palliation of distressing secretory symptoms such as diarrhea and

Cushing’s syndrome

Priya SR, Targeted Therapy for Medullary Thyroid Cancer: A Review. Front Oncol. 2017

Priya SR, Targeted Therapy for Medullary Thyroid Cancer: A Review. Front Oncol. 2017

Priya SR, Targeted Therapy for Medullary Thyroid Cancer: A Review. Front Oncol. 2017

Targeted Radionuclide Therapy or Peptide Receptor

Radionuclide Therapy (PRRT)

• over expression of somatostatin type 2 receptors (SSTR)

• PRRT with 90Y or 177Lu-DOTATATE (DOTA-Tyr-octreotate)

• Salavati et al. treated over a period of 8 years, a cohort of 28 patients with recurrent and metastatic MTC.

• All patients previous surgery, radiotherapy, conventional chemotherapy, and local palliative measures

17 patients (60.7%) SD, 5 of 28 (17.7%) PR and 6 (21.4%) disease progression.

The median survival of patients with SD: 36 months, that of patients with PR : 72 months, and the median survival for patients with PD : 24 months

Priya SR, Targeted Therapy for Medullary Thyroid Cancer: A Review. Front Oncol. 2017

Disease Outcome • tumors confined to the gland, the 10-year survival rate was 95.6%

• regional stage disease had an overall survival (OS) rate of 75.5% (4).

• presenting with DM at diagnosis had a 10-year survival of approximately 20%

• calcitonin levels of over 150 pg/ml were associated with DM and extrathyroidal extension

• Preoperative calcitonin levels of 500 pg/ml, nodal metastasis, and preoperative status best predicted failure

to achieve biochemical cure

• In high risk patients (residual disease, extrathyroidal extension, or nodal involvement), locoregional

recurrence free rate was 86% at 10 years with postoperative external beam radiation therapy (EBRT) as

compared to 52% in those without adjuvant EBRT ,However, radiation may not confer survival advantage

Priya SR, Targeted Therapy for Medullary Thyroid Cancer: A Review. Front Oncol. 2017

Disease Outcome • Tumors confined to the gland, the 10-year survival rate was 95.6%

• Regional stage disease had an overall survival (OS) rate of 75.5% (4).

• presenting with DM at diagnosis had a 10-year survival of approximately 20%

• calcitonin levels of over 150 pg/ml were associated with DM and extrathyroidal

extension

• Preoperative calcitonin levels of 500 pg/ml, nodal metastasis, and preoperative

status best predicted failure to achieve biochemical cure

Priya SR, Targeted Therapy for Medullary Thyroid Cancer: A Review. Front Oncol. 2017

PROGNOSIS

• age, vascular invasion, and TNM (tumor, node, metastasis)

• Calcitonin and carcinoembryonic antigen (CEA) doubling times sensitive markers

for progression and aggressiveness of metastatic MTC

Calcitonin doubling times less than 6 to 12 months with poor survival while

doubling times >24 months with a very favorable prognosis

• Specific germline mutations in RET predict the aggressiveness of the tumor

Case 2

A 48 years old female with HX of poorly

differentiated PTC was admitted for workup

of pulmonary mass

Because of thyroid nodule FNA was done 89.05.19

Surgery in Isfahan 89.6.6

Thyroid Pathology 89.6.6

Thyroid Pathology 89.6.6

WHOLE BODY BONE SCAN 89.07.10 (1 month after surgery)

96.09.02 (7 y after surgery)

96.06.08 93.02.14 91.06.09 (2 y after surgery)

DATE

LAB DATA

>1000 96.07(70) 2.02 0.3 Tg

11.5 13.89 19.34 Anti Tg

.8 7.04 0.005 0.004 TSH

She take levothyroxine and lab data

US 96.09.02

US guided FNA of pretracheal lesion96.09.04

PATHOLOGY REPORT 96.09.04

2 times RF were done 96.10.05 & 96.11.03

POST RF US 97.02.04 (before size 23*16*10)

Lab data

97.02.11 (5m after RF)

96.09.02 (before RF)

96.06.08 93.02.14 91.06.09 (2 y after surgery)

DATE

LAB DATA

532 >1000 96.07(70) 2.02 0.3 Tg

12 11.5 13.89 19.34 Anti Tg

0.11 .8 7.04 0.005 0.004 TSH

Admit in Imam Khomeini Hospital

97.03.20

WHOLE BODY BONE SCAN with SPECT 97.03.21

WHOLE BODY BONE SCAN with SPECT 97.03.21

US 97.03.22

SPIRAL NECK & CHEST CT Scan 97.03.24

97.05.23 200 mci I131

Whole body Scan 1 week after I therapy

Hemoptysis occurred 97.07.14 and bronchoscopy

was done

Bronchoscopy 97.07.14

Large vegetative endobronchial

lesion occulted the lumen in RT

intermediate bronchus

BRONCHIAL PATHOLOGY 97.07.14

Pathology Result 97.07.14

Predominantly granulation tissue with small pieces of bronchial mucosa

with mild mixed inflammation

Admit in Firoozgar hospital 97.09.11

Octerotide Scan 97.09.14

Octerotide Scan 97.09.14

Spiral chest CT scan was done 97.09.19

FNA GUIDED US 97.09.17

Pathology & IHC review

Summery

A 48 years old female with poorly differentiated PTC Thyroidectomy: 89.06.06 RF neck mass: 96.10.05,96.11.03 RAI 200mci Bronchopulmonary Metastases with Octerotide scan positive Last Tg: 1996 ng/ml

• Definition / general

Malignant follicular cell neoplasm with limited evidence of follicular

cell differentiation

Intermediate clinical behavior between well differentiated (papillary

and follicular carcinoma) and anaplastic carcinoma

(Am J Surg Pathol 2007;31:1256, Surg Pathol Clin 2014;7:475, Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017)

• Terminology

Insular / trabecular carcinoma

Primordial cell carcinoma

Poorly differentiated follicular carcinoma

Poorly differentiated papillary carcinoma

Solid type follicular carcinoma

High risk thyroid carcinoma of follicular cell origin

Cherkaoui GS, Poorly differentiated thyroid carcinoma: a retrospective clinicopathological study. Pan Afr Med J. 2015;21:137. Published 2015 Jun 22. doi:10.11604/pamj.2015.21.137.6720

poorly differentiated thyroid cancer: (PDTC)

• aggressive thyroid cancer

• high tendency to extrathyroidal extension regional node

• distant metastases

• patients’ overall five years survival range between 50 - 89%

Positive stains

Keratin, thyroglobulin (decreased expression), TTF1, Ki67: 10 - 30% (Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017

Molecular / cytogenetics description

Alteration of early event of thyroid carcinogenesis: RAS family and BRAF mutation

(Surg Pathol Clin 2014;7:475)

Alteration associated with dedifferentiation: mutation of p53, TERT, CTNNB1 and AKT1

(Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017)

DD:

• Anaplastic thyroid carcinoma: completely lacks follicular differentiation, prominent nuclear pleomorphism and necrosis; generally thyroglobulin- TTF1- (Surg Pathol Clin 2014;7:475)

• Hürthle cell tumors: poorly differentiated thyroid carcinoma can be predominantly composed of oncocytic cells (often with a small cell component) but also has necrosis and ≥ 3 mitoses/10 HPF

,Shuanzeng Wei, M.D., Ph.D.Revised: 31 July 2018, last major update November 2017,Poorly differentiated thyroid carcinoma

• Has nodal and hematogenous metastases and 3 year survival of 38%

• Extends to perithyroidal soft tissue in 60 - 70% cases

• Vascular invasion in 60 - 90% cases

• Regional lymph node metastasis in 15 - 65%

• Distant metastasis in 40 - 70%

Treatment remains the same than WDT

• neck dissection whenever feasible followed by RIT if the tumor is

radioavid.

• A close monitoring is required to improve its outcome

• Adjuvant therapy such as RIT, External beam radiotherapy (EBRT) and

chemotherapy remain poorly established

• Even though poorly differentiated cells have the ability to trap radioiodine in more than 80% of cases including distant metastasis at the time of diagnosis .

• 15% of cases has a decreased iodine uptake, and consequently a limited RIT value

• One-third of all patients with PDTC develop recurrent disease, and only 30% of patients with distant metastases may achieve complete remission with radioiodine therapy

Cherkaoui GS, Poorly differentiated thyroid carcinoma: a retrospective clinicopathological study. Pan Afr Med J. 2015;21:137. Published 2015 Jun 22. doi:10.11604/pamj.2015.21.137.6720 Duo LJ, Transient partial response of poorly-differentiated thyroid carcinoma to sunitinib treatment: Oncol Lett. 2015;10(1):492-496.

External beam radiotherapy (EBRT)

• questionable

• indicated depending on locoregional recurrence risk, especially

patients with positive margins, gross residual disease and regional

lymph node metastasis with no distant metastasis

• palliative treatment in bony metastases

Cherkaoui GS, Poorly differentiated thyroid carcinoma: a retrospective clinicopathological study. Pan Afr Med J. 2015;21:137. Published 2015 Jun 22. doi:10.11604/pamj.2015.21.137.6720

Chemotherapy

• for inoperable cases.

• It contributes theoretically to loco regional control by improving

respectability or by reducing disease progression

Cherkaoui GS, Poorly differentiated thyroid carcinoma: a retrospective clinicopathological study. Pan Afr Med J. 2015;21:137. Published 2015 Jun 22. doi:10.11604/pamj.2015.21.137.6720

• new therapeutic options such as kinase inhibitors (KIs)

• These targeted therapies, which has been approved for poorly

differentiated thyroid and medullary thyroid carcinomas, increased

disease-free survival, although not curative and reserved to patients

with progressive or symptomatic disease

Gianì F, (2016) Resistance to Kinase Inhibitors in Poorly Differentiated and Anaplastic Thyroid Cancer: Preclinical In vitro Evidences. Endocrinol Metab Syndr 5:251.

Although several small-molecule Ki have been explored for the treatment of advanced, progressive, and radioiodine refractory (RAIR) thyroid tumours, and some of them have been approved for use in clinical practice (sorafenib and lenvatinib for DTC and PDTC)

Drugs Tumour Phase Patients

(N) PR (%) CR (%)

SD>6 months

(%) PD (%)

References/Clinical

trials* Sorafenib PDTC II 2 NE NE NE NE Kloos

ATC; PDTC II 2 0 0 0 2 (100%) Gupta-Abramson

Lenvatinib PDTC II 28 NE NE NE NE Schlumberger et al.

*Estimated study completion date; Abbreviation: PR (partial response), CR (complete response), SD (stable disease), PD (progressive disease), PFS (progression-free survival), OS (overall survival), NE (not evaluable)

Gianì F, (2016) Resistance to Kinase Inhibitors in Poorly Differentiated and Anaplastic Thyroid Cancer: Preclinical In vitro Evidences. Endocrinol Metab Syndr 5:251.

• EGFR Inhibitors: Overexpression of the EGFR is frequently detected in

poorly differentiated and ATC, although there is no evidence that

EGFR is a primary driver of these tumors.

• However, a case report of a 79 year old male patient with metastatic

PDTC harbouring EGFR mutation showed a PFS of more than 11

months when treated with the selective EGFR TKI erlotinib (OSI-774).

PDTCs with minimal/low I-131 avidity and low serum Tg level but with macroscopic disease clinical

signs and symptoms of disease progression

need close monitoring

other diagnostic modalities including FDG/68Ga-DOTATATE PET-CT and USG,. Certain other

unresolved questions that needs future research direction are: (a) Questionable role of Re-

differentiation agents: in one study by Fortunati et al., valproic acid induced the expression of NIS

Thyroglobulin “nonsecretor” metastatic poorly differentiated thyroid carcinoma with noniodine concentrating disease and aggressive clinical course,Kalshetty Ashwini .2018 : 33 ,3 ,218-223

• Undetectable serum Tg was defined as an unstimulated Tg \1 ng/ml measured at least 5 weeks

after total thyroidectomy and at least 3 months (3–11 months; median 6 months) after adjuvant

RAI.

• This is most likely due to tumor heterogeneity and the presence of a less differentiated tumor

component.

Ann Surg Oncol. 2015 Dec;22(13):4193-7. doi: 10.1245/s10434-015-4567-3. Epub 2015 Apr 17

• Detectable Tg levels after surgery and RAI in a subset of PDTC patients appear to predict a higher

rate of death and recurrence

Eur Thyroid J 2018;7:313–318

• age, the high TNM stage, extrathyroidal extension, positive margins

and distant metastasis as factors associated with unfavourable

outcome

Cherkaoui GS, Poorly differentiated thyroid carcinoma: a retrospective clinicopathological study. Pan Afr Med J. 2015;21:137. Published 2015 Jun 22. doi:10.11604/pamj.2015.21.137.6720