1. Endocrinology CPC

3. History/Findings: The patient is a 25 year old concert violinist from Drogheda who presented with a 5 cm x 4 cm x 3 cm mass in the left mid jugular area. Other small nodes were palpated in the remainder of the left neck, as well. There was a hard 2 cm in diameter mass located in the left lobe of the thyroid gland and the remainder of the gland was palpable and slightly firm.

4. Clinical History He underwent 5 fine needle aspirations, a CT scan, and a MRI at his local hospital. He was told he needed a thyroidectomy and radical neck dissection. (Please note a radical neck dissection would sacrifice the spinal accessory nerve which would paralyze the left trapezius muscle, a catastrophic deficit to a concert violinist.) The patient elected to come to SJH for additional consultation and treatment.

5. Lab/Imaging FNA #1 on 23-12-08 Left Neck – Apparent cyst with fragments of epithelium. FNA #2 on 16-01-09 Left thyroid – Atypical cellular fragments, suspicious for papillary carcinoma. FNA #3 on 24-01-03 Left thyroid – Consistent with colloid nodule. FNA #4 Left neck cyst – Histiocytes with epithelial cells. FNA #5 Solid neck mass – Consistent with papillary carcinoma.

6. FNA  FNA showing follicular cells.  The follicles are composed of small clusters of cells.  The colloid cannot be identified easily in this preparation.  The nuclei are monotonous without obvious atypia. http://pathweb.uchc.edu

7. MRI – Described the palpable masses and some calcification of the left thyroid lobe. CAT scan – Describes the palpable left neck mass but “no significant lymphadenopathy”; incidental note was made of a polyp in the left maxillary sinus. TFT’s within normal limits.

8. CT Scan This CT scan of the upper chest (thorax) shows a malignant thyroid tumour. The dark area around the trachea (marked by the white U-shaped tip of the respiratory tube) is an area where normal tissue has been eroded and died (necrosis) as a result of tumour growth.

9. Clinical Course: The patient was taken to the operating room where a total thyroidectomy in continuity with a left paratracheal and pretracheal lymph node dissection was performed along with a modified radical neck dissection. The jugular vein was sacrificed due to the surrounding lymphadenopathy, but the spinal accessory nerve was preserved. His post operative course was uneventful and he left the hospital after a brief inpatient stay. He and his family returned home. His TSH was 90 at 3 weeks post-op. He was given an ablative dose of 150 mc of radioactive iodine. A total body scan done at that time was negative. He will continue in follow-up, and his prognosis remains good.

13. Final Pathology: The final pathology report revealed the primary tumour to be papillary carcinoma, 2.5 cm to 3 cm in greatest dimension. The tumour was well differentiated. Additional foci of tumour were encountered in the isthmus of the gland. The right lobe was negative for tumour. Six out of seven paratracheal lymph nodes were found to be positive for metastatic papillary cancer and an additional 15 positive lymph nodes were encountered in the left neck dissection specimen. All in all, 32 lymph nodes were resected.

16. Lymph node with metastasis of papillary thyroid carcinoma (middle/bottom of image). The papillary thyroid carcinoma (thyroid cancer) shown here has the classically described appearance (papillary architecture -- papillae with fibrovascular cores). The diagnostic nuclear features for papillary thyroid carcinoma (nuclear inclusions, nuclear grooves, nuclear clearing, overlap of nuclear membranes/crowding) are present but not seen well at this magnification. The lymph node has several germinal centers (left, top/right of image). Adipose tissue (fat) is seen at the edge of the image (bottom and left).

17. Papillary tumours are the most common of all thyroid cancers (>70%). Papillary carcinoma typically arises as an irregular, solid or cystic mass that arises from otherwise normal thyroid tissue. This cancer has a high cure rate with ten year survival rates for all patients with papillary thyroid cancer estimated at 80-90%. Cervical metastasis (spread to lymph nodes in the neck) are present in 50% of small tumours and in over 75% of the larger thyroid cancers. The presence of lymph node metastasis in these cervical areas causes a higher recurrence rate but not a higher mortality rate. Distant metastasis (spread) is uncommon, but lung and bone are the most common sites. Tumours that invade or extend beyond the thyroid capsule have a worsened prognosis because of a high local recurrence rate.

18. Characteristics of Papillary Thyroid Cancer Peak onset ages 30 through 50 Females more common than males by 3 to 1 ratio Prognosis directly related to tumour size [less than 1.5 cm (1/2 inch) good prognosis] Accounts for 85% of thyroid cancers due to radiation exposure Spread to lymph nodes of the neck present in more than 50% of cases Distant spread (to lungs or bones) is very uncommon Overall cure rate very high (near 100% for small lesions in young patients)

19. Foundations of Molecular Diagnostics RNA protein DNA Cell

20. Pathological Pathways Follicular Epithelial Cell Papillary Thyroid Carcinoma Follicular Carcinoma

21. Oncogenes in thyroid carcinomas

22. RAS proto oncogenes commonly mutated in many different types of human cancers. three main RAS genes,  H-RAS (chromosome 11p15.5),  N-RAS (chromosome 1p13.2)  K-RAS (chromosome 12p12.1). Point mutations common  usually occur in the GTP-binding domain (codons 12 and 13), and in the  GTPase domain (codon 61), though other types of mutations, including amplifications and acquired polymorphisms have also been detected. N-RAS mutations may be more frequent than K-RAS and H-RAS point mutations. Hunt J. Expert Review of Molecular Diagnostics, Volume 5, Number 5, September 2005, pp. 725-734

23. BRAF located on chromosome 7q34. Point mutations in BRAF occur in multiple tumor types.  melanoma,  cholangiocarcinoma  papillary thyroid carcinoma. common point mutation is a T -A transversion at nucleotide 1796 in exon 15 (V599E). BRAF mutations have been reported in between 35% and 69% of papillary thyroid carcinomas. given its high prevalence and the high specificity for papillary thyroid carcinoma, it may be useful as a diagnostic marker, either in FNA specimens or in surgical specimens. Hunt J. Expert Review of Molecular Diagnostics, Volume 5, Number 5, September 2005, pp. 725-734

24. PAX 8-PPAR  Chromosomal translocation present in approximately 40% of follicular thyroid carcinomas. PAX8 - thyroid transcription factor critical for thyroid regulation of growth, differentiation and function. PPARγ (peroxisome proliferators- activated receptor γ)  nuclear receptor  ligand dependent transcription factor  highly expressed in adipose tissue. translocation may also be present in benign lesions, (follicular adenomas), Hunt J. Expert Review of Molecular Diagnostics, Volume 5, Number 5, September 2005, pp. 725-734

25. ret/PTC -1, -3 translocation is between the tyrosine kinase domain of the RET proto- oncogene on chromosome 10 and multiple different partner genes.  most common partner genes are ELE1 (PTC3) and  H4 (PTC1),  both located on chromosome 10. Both translocations are more frequently seen in radiation-induced tumours, ret-PTC3 translocation may be more common in solid variant of papillary carcinomas. ret/PTC rearrangements found in approximately 30-40% of papillary carcinomas. Hunt J. Expert Review of Molecular Diagnostics, Volume 5, Number 5, September 2005, pp. 725-734

26. Molecular markers in PTC  ret/PTC  To date 15 chimeric mRNAs involving 10 different genes have been described  Ret/PTC-1 and ret/PTC-3 are the most common types, accounting for 90%.  Morphological variants are likely to reflect variations in tumour biology which have yet to be fully defined.

27. ret/PTC and BRAF in an Irish PTC cohort

28. Sorafenib (Nexavar) Inhibits tumor cell proliferation and angiogenesis by targeting RAF KINASES and VEGF RECEPTORS; multikinase inhibitor that targets serine/threonine and receptor tyrosine kinases to decrease tumour growth and angiogenesis; FDA approved orphan drug indication for hepatocellular carcinoma in 2006.

29. Sunitinib Description: Inhibits VEGF-R2 and PDGF-R beta tyrosine kinase; has antineoplastic activity. Sunitinib is in a class of medications called multikinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps stop or slow the spread of cancer cells and may help shrink tumours.

30. Comments: A 25 year old male with a very hard left thyroid mass and massive left sided cervical lymphadenopathy has thyroid cancer until proven otherwise. We need to be prudent and selective in our employment of pre-operative testing. This will save a lot of money, avoid significant patient discomfort, and expedite the patient’s diagnosis and treatment.