Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

My name is Rodrigo Arrangoiz I am a breast surgeon/ thyroid surgeon / parathyroid surgeon / head and neck surgeon / surgical oncologist that works at Center for Advanced Surgical Oncology in Miami, Florida. I was trained as a surgeon at Michigan State University from (2005 to 2010) where I was a chief resident in 2010. My surgical oncology and head and neck training was performed at the Fox Chase Cancer Center in Philadelphia from 2010 to 2012. At the same time I underwent a masters in science (Clinical research for health professionals) at the University of Drexel. Through the International Federation of Head and Neck Societies / Memorial Sloan Kettering Cancer Center I performed a two year head and neck surgery and oncology / endocrine fellowship that ended in 2016. Mi nombre es Rodrigo Arrangoiz, soy cirujano oncólogo / cirujano de tumores de cabeza y cuello / cirujano endocrino que trabaja Center for Advanced Surgical Oncology en Miami, Florida. Fui entrenado como cirujano en Michigan State University (2005 a 2010 ) donde fui jefe de residentes en 2010. Mi formación en oncología quirúrgica y e n tumores de cabeza y cuello se realizó en el Fox Chase Cancer Center en Filadelfia de 2010 a 2012. Al mismo tiempo, me sometí a una maestría en ciencias (investigación clínica para profesionales de la salud) en la Universidad de Drexel. A través de la Federación Internacional de Sociedades de Cabeza y Cuello / Memorial Sloan Kettering Cancer Center realicé una sub especialidad en cirugía de cabeza y cuello / cirugia endocrina de dos años que terminó en 2016.

Molecular Genetics of Thyroid Cancer Part 3

March 10, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

The second most common type of thyroid cancer:
- Is follicular thyroid carcinoma (FTC):
  - 4.6% of the cases based on the SEER database between 2010 and 2014
Fundamentally all follicular carcinomas are:
- RAS-like tumors:
  - There profile is different from classic PTC because they do not have BRAF mutations:
    - Most of them have RAS and RAS-like mutations
- Yoo S.K et al, from Korea showed that the genetic profile of follicular carcinomas:
  - Is very similar to follicular adenomas (FA) because they are related tumors:
    - Most FTC originate from a FA and eventually break through the capsule and become carcinomas
- Encapsulated follicular variant of PTC:
  - Their molecular profile is much closer to a FA and FTC than to classic PTC
- Infiltrative follicular variant of PTC has a molecular profile:
  - That is more like classic PTC than FTC
- The biologic difference between
  follicular pattern RAS-like tumors and classic PTC:
  - Is the infiltrative growth pattern (Figure)
- The difference between these tumors is not only phenotypically based on gross pattern, but also based on biological and clinical differences:
  - Because follicular pattern RAS-like tumors:
    - Retain avidity to radioactive iodine
  - BRAF-like tumors (classic PTC and infiltrative follicular variant of PTC) have the classic features of PTC:
    - They are infiltrative, they spread to lymph nodes first and later to distant sites, and they lose the expression of genes associated with thyroid differentiation
  - RAS-like tumors (FA, FTC, NIFTP, and invasive encapsulated follicular variant of PTC):
    - May or may not have nuclear features of PTC, they are encapsulated, they spread to distant sites (rarely to lymph nodes), and they retain expression of genes associated with thyroid differentiation
The RAS genes (HRAS, KRAS and NRAS):
- Encode for the interconnected G-proteins:
  - That play a critical role in the intracellular transduction of signals arising from cell membrane receptors
RAS protein in its inactive state:
- Is bound to guanosine diphosphate (GDP):
  - Upon activation, it releases GDP and binds guanosine triphosphate (GTP):
    - Thus activating the MAPK and other signaling pathways, such as PI3K/AKT
- Typically, the activated RAS / GTP protein becomes promptly inactive:
  - Due to its intrinsic GTPase activity and the action of cytoplasmic GTPase-activating proteins:
    - Point mutations in the domains of the RAS gene either increase its affinity for GTP (mutations in codons 12 and 13) or inactivate its autocatalytic GTPase activity (mutation in codon 61):
      - The consequence of this is that the mutant protein becomes permanently switched in the active position and continuously activates its downstream targets
- Mutations in the RAS genes are believed play
  an early role in the cellular transformation and may predispose to the progression benign tumors to malignant tumors
- Point mutations involving the specific sites (codons 12, 13 and 61) of the NRAS, HRAS or KRAS genes:
  - Are identified in roughly 10% to 20% of PTC:
    - PTC holding RAS mutation invariably have follicular subtype histology:
      - This mutation also correlates with significantly less prominent nuclear features of PTC, more common
        thyroid encapsulation, and a lower rate of lymph node metastases
    - A few studies have linked RAS
      mutations with PTC:
      - That have a more aggressive behavior, such as a higher frequency of distant metastases
    - Mutations in the RAS gene are not limited to PTC and also found in other benign and malignant thyroid neoplasms, as well as in tumors from other tissues
    - RAS gene mutations are identified in approximately:
      - 20% to 40% of follicular thyroid adenomas (FTA)
      - 40% to 50% of FTC
      - 20% to 40% of anaplastic thyroid carcinoma (ATC)
  - When a FNA cytology is indetermined and the molecular profile identifies a RAS mutation:
    - The risk of malignancy varies
      between the type of mutation:
      - HRAS = 71%
      - NRAS = 63%
      - KRAS = 33%
The concept of progression from benign to malignant tumors is supported by the molecular profile shared by these different tumors:
- More evidence supporting this concept of cancer progression is the similar morphology that these lesions have, along with experimental mouse data showing very similar results
Pathologist observing thyroid nodules have detected this step wise progression
The nodule in Figure developed from a single cell driven by the RAS mutation, it continued to grow and grow, it eventually forms a capsule, looking microscopically like a benign adenoma (goiter), then it continues to progress, it accumulates more genetic alterations (micro mRNA, and it involves other molecular pathways), it becomes a tumor, it eventually breaks through the capsule, and it will give you invasive encapsulated follicular variant of PTC:
- If an FNA is performed of area A it would come back as Bethesda II, in area B it would come back as a Bethesda IV, and in area C as Bethesda V:
  - This has changed the practice of cytopathology with molecular
    testing helping us understand better the biological nature of these tumors

Figure: Molecular Changes Precede Histological Changes. The tumor measures 2.5 cm, it has a thin
capsule (black arrows) and shows an area of flat epithelial cells lining the follicles representing a benign thyroid
goiter (tumor area A). Microfollicular areas with well-developed nuclear features of PTC are seen in tumor area
B representing a probable NFTP. Tumor area C has separation artifact with the formation of papillary structures
with nuclear features of PTC. Molecular studies of each section will show NRAS mutation.

Etiology / Pathogenesis of Medullary Thyroid Cancer

March 9, 2025March 3, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Medullary thyroid cancer (MTC):Accounts for approximately 1% to 2% of thyroid cancers in the United States.
These tumors originate from:The neural crest derived parafollicular C-cells of the thyroid gland:Which produce calcitonin:Other secretory products made by the C-cells include:Carcinoembryonic antigen (CEA)
Most MTCs occur sporadically (75%):But they are also found in hereditary syndromes (25% of the cases) such as:Multiple endocrine neoplasia (MEN) 2A
- - Multiple endocrine neoplasia (MEN) 2B
  - Familial MTC (FMTC).
MEN2A accounts for 95% of MEN2 cases:Is characterized by: MTC
- - Primary hyperparathyroidism (PHPT)
  - Peochromocytoma
- There are four variants of the MEN2A syndrome: Classical MEN2A,
The familial forms are characterized by:Germline mutations in the RET proto-oncogene:Located on chromosome 10q 11.2:It encodes a single pass transmembrane receptor of the tyrosine kinase family
- - RET is typically expressed in the cells of:The neural crest
    - The branchial arches,
    - The urogenital system.
  - Approximately 50% of sporadic MTCs harbor somatic RET mutations
  - 18% to 80% of sporadic MTC lacking somatic RET mutations have:Somatic mutations of:HRAS, KRAS, or rarely NRAS.
  - More than 100 mutations, duplications, insertions, or deletions associated with hereditary MTC have been described and are:Associated with varying levels of tumor aggressiveness and genotype-phenotype correlations with other tumors such as pheochromocytomas, PHPT, and CLA
  - The American Thyroid Association (ATA) classifies hereditary MTC into several risk categories:The highest risk (HST) category includes patients with: MEN2B and the RET codon M918T mutation
    - The high risk (H) category includes patients with:RET codons C634 and A883F mutations
    - All remaining mutations are grouped in the:Moderate risk (MOD) category

Relationship of Common RET Mutations to Risk of Aggressive MTC

cropped-18403652_10206829497335208_5004404657991480104_n1.jpg

What is Head and Neck Surgery?:
- It is a surgical sub-specialty that deals mainly with benign and malignant tumors of the head and neck region, including:
  - The scalp, facial region, eyes, ears, nose, nasal fossae, paranasal sinuses, oral cavity, pharynx (nasopharynx, oropharynx, hypopharynx), larynx (supraglotic larynx, glottis larynx, subglotic larynx), thyroid gland, parathyroid gland, salivary glands (parotid glands, submandibular glands, sublingual glands, minor salivary glands), soft tissues of the neck, skin of the head and neck region.
    - The head and neck surgeon’s work area:Does not cover tumors or diseases of the brain and other areas of the central nervous system or those of the cervical spine:This is the neurosurgeon field.
- Among the diagnostic procedures performed by the head and neck surgeon, are the following:
  - Nasopharyngolaryngoscopy:
    - Performed to examine, evaluate and, possibly perform a biopsy, of oral cavity, pharyngeal and laryngeal lesions.
- The surgeries most commonly performed by the head and neck surgeon are:
  - Total or near total thyroidectomies
  - Hemithryoidectomies (lobectomies)
  - Comprehensive neck dissections
  - Selective neck dissections
  - Maxillectomies:
    - Total maxillectomy
    - Subtotal maxillectomy
    - Infrastructure maxillectomy
    - Suprastructure maxillectomy
    - Medial maxillectomy
  - Mandibulectomy:
    - Segmental
    - Marginal
  - Tracheostomy
  - Salivary gland surgeries:
    - Parotid gland operations:
      - Limited superficial parotidectomy with identification and preservation of the facial nerve
      - Superficial parotidectomy with identification and preservation of the facial nerve
      - Near total parotidectomy with identification and preservation of the facial nerve
      - Total parotidectomy
    - Submandibular gland resection
    - Sublingual gland resection
  - Resection of tumors of the oral cavity:
    - Glossectomy
    - Resection of the floor of the mouth tumors
  - Resection of tumors of the pharynx
  - Resection of tumors of the larynx
  - Split-thickness skin grafts
  - Full-thickness skin grafts
  - Sentinel lymph node mapping and sentinel lymph node biopsy
  - Resection of malignant skin tumors (BCC, SCC, melanoma) of the head and neck region
The formation of the head and neck surgeon includes mastering the following subjects:
- Surgical Anatomy
- History and Basic Principles of Head and Neck Surgery
- Epidemiology, Etiology, and Pathology of Head and Neck Diseases
- Diagnostic Radiology of the Head and Neck Region
- Tumors of the Scalp, Skin and Melanoma
- Eyelids and Orbit
- Nasal Cavity and Paranasal Sinuses
- Skull Base and Temporal Bone
- Lips and Oral Cavity
- Pharynx and Esophagus
- Larynx and Trachea
- Cervical Lymph Nodes
- Thyroid and Parathyroid Glands
- Salivary Glands
- Neurogenic Tumors and Paragangliomas
- Soft Tissue Tumors
- Bone Tumors and Odontogenic Lesions
- Reconstructive Surgery
- Oncologic Dentistry and Maxillofacial Prosthetics
- Principles of Radiation Oncology
- Principles of Chemotherapy
- Molecular Oncology, Genomics and Immunology
- Nutrition
- Biostatistic

Rodrigo Arrangoiz MS, MD, FACS a head and neck surgeon / endocrine surgeon / surgical oncologist and is a member of Sociedad Quirúrgica S.C at the America British Cowdray Medical Center in Mexico City:

prof_739_20190417135234

Rodrigo Arrangoiz MS, MD, FACS:
- Is a member of the American Head and Neck Society

- He is a member of the American Thyroid Association:

Unknown

Training:

• General surgery:

• Michigan State University:

• 2004 al 2010

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• Fox Chase Cancer Center (Filadelfia):

• 2010 al 2012

• Masters in Science (Clinical research for health professionals):

• Drexel University (Filadelfia):

• 2010 al 2012

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• IFHNOS / Memorial Sloan Kettering Cancer Center:

• 2014 al 2016

#Arrangoiz

#Teacher

#Surgeon

#Cirujano

#ThyroidExpert

#ThyroidSurgeon

#CirujanodeTiroides

#ExpertoenTiroides

#ExpertoenParatiroides

#Paratiroides

#Hiperparatiroidismo

#CancerdeTiroides

#ThyroidCancer

#PapillaryThyroidCancer

#SurgicalOncologist

#CirujanoOncologo

#CancerSurgeon

#CirujanodeCancer

#HeadandNeckSurgeon

#CirugiaEndocrina

#CirujanodeTumoresdeCabezayCuello

#OralCavityCancer

#Melanoma

Medullary Thyroid Cancer Awareness Month

March 8, 2025March 3, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

👉Two articles published by a Rodrigo Arrangoiz on medullary thyroid cancer

http://www.remedypublications.com/american-journal-of-otolaryngology-and-head-and-neck-surgery-abstract.php?aid=218

https://s3.amazonaws.com/academia.edu.documents/57472024/final_published_paper.pdf?response-content-disposition=attachment%3B%20filename%3DMedullary_Thyroid_Carcinoma_Literature_R.pdf&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIAIWOWYYGZ2Y53UL3A%2F20200302%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Date=20200302T210556Z&X-Amz-Expires=3600&X-Amz-SignedHeaders=host&X-Amz-Signature=d78d7b605c8a3e8c49d59b7d9545a3f645b1aa4ff1cbda4f57fb4e274bb30849

#Arrangoiz #ThyroidSurgeon

#ThyroidExpert

Molecular Genetics of Thyroid Cancer Part 2

March 8, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Papillary thyroid carcinoma (PTC):
- Is one of the best molecularly understood cancers:
  - With more that 97% of the driver mutations identified
One of the main goals of the cancer genome atlas research network study (TCGA) thyroid project:
- Was to detect cancer-initiating mutations, i.e., driver mutations:
  - In those cases that lacked the well-known PTC driver mutations (BRAF V600E, point mutations of RAS genes, and gene fusions involving RET and NTRK):
    - These cases are referred to by computational biologists as “dark matter” cases
- These very important studies under the umbrella of NCI and NIH analyzed 496 PTCs that permitted several analyses:
  - That showed that approximately 75% of all PTC:
    - Developed through the molecular mechanism of point mutation:
    - The most common been the:
      - BRAF V600E mutation
    - The second most common the:
      - RAS mutation
    - The thyroid most common the:
      - TERT mutation – That constituted a small percentage of tumors but was found to be a marker of aggressive disease
  - Roughly 15% of PTC develop through the mechanism of gene fusions:
    - The most common been RET / PTC,
      NTRK 1/3, ALK, BRAF, PAX8 / PPARG
    - The RET / PTC, NTRK 1/3, ALK have very important therapeutic implications for advanced thyroid cancer:
      - Because of the availability of targeted inhibitors with low toxicity and
        high efficacy for the management of these tumors
  - Roughly 7% of PTC develop exclusively from the molecular mechanism of copy number alterations (CNA) (Figure)

Roughly 45% to 75% of PTC (29% to 83%) have a mutation in the BRAF gene:
- Making it the most frequently known genetic
  alteration in PTC
- Practically all mutations involve:
  - Nucleotide 1799 and result in a valine-to-glutamate substitution at residue 600 (V600E):
    - This point mutation leads to constitutive activation of BRAF kinase:
      - Resulting in a constant phosphorylation of MEK and downstream effectors of the MAPK pathway (Figure)
  - Other mechanisms of BRAF activation in PTC include:
    - K601E point mutation:
      - Small in-frame insertions or deletions surrounding codon 600
    - AKAP9-BRAF rearrangement:
      - Which is more common in PTC associated with radiation exposure
BRAF V600E mutation:
- Is the prevailing mutation in PTC:
  - With classical histology and in the tall cell subtype:
    - But is rare in follicular subtypes tumors
- In multiple studies, the existence of the BRAF mutation:
  - Has been linked with aggressive tumor biology such as:
    - Advanced stage at presentation
    - Extrathyroidal extension (infiltrative)
    - Recurrence
    - Lymph node or distant metastases
- BRAF V600E mutation:
  - Is an independent predictor of tumor recurrence:
    - Even in patients with stage I to stage II disease
- The ability of thyroid cancers to trap
  radioiodine:
  - Has been identified to be decreased in tumors with the BRAF V600E mutations and this may lead to treatment failures of the recurrent disease:
    - Which is due to the dysregulation of the function of sodium iodide
      symporter (NIS) and other genes metabolizing iodide in the thyroid follicular cells
- In thyroid nodules, the V600E BRAF mutation is limited to PTC, poorly differentiated and ATC arising from PTC:
  - Consequently, the identification of the BRAF V600E mutation in FNA cytology of thyroid nodules:
    - Practically confirms the diagnosis of PTC
  - Testing for the BRAF mutation is very useful diagnostically in thyroid FNA samples with indeterminate results:
    - As it can help to determine the diagnosis of PTC in a important portion of these biopsies
Pathologically PTC is one disease and biologically at a minimum PTC has two significantly different groups:
- Based on multiple type of analysis like gene expression alterations, microRNA alterations, DNA methylation, transcriptomics (Figure)
The Cancer Genome Atlas (TCGA) study on PTC highlighted that PTC can be grouped into:
- BRAFV600E-like and RAS-like tumors:
  - BRAFV600E-like tumors:
    - Also harbor RET fusions
  - RAS-like tumors:
    - Show RAS mutations, the BRAFK601E, and PPARG and THADA fusions
- The V600E BRAF–like PTC:
  - Are usually classic PTC and tall cell subtype of PTC
- Clinically when we look at the differentiation score:
  - Which is the expression of genes involved in iodine metabolism and synthesis:
    - BRAF tumors:
      - Loose expression of thyroid differentiation markers
    - RAS-like tumors retain them:
      - Almost at the level of a normal thyroid cell
      - This is important therapeutically because one of the most efficient management options in thyroid cancer is iodine therapy
    - RAS-like tumors:
      - Are usually follicular variant PTC
  - Usually all BRAF mutations are BRAF-like and all RAS mutations are RAS-like:
    - But all other type of molecular alterations can be hidden in either BRAF-like and RAS-like:
      - For example, BRAF K601E mutations are found in RAS-like tumors

Molecular Subtypes of Papillary Thyroid Carcinomas

Graph exemplifying the difference between follicular pattern RAS-like tumors and classic PTC,
which is the infiltrative growth pattern.

Calcitonin

March 7, 2025January 24, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Calcitonin:
- Is produced by the:
  - Parafollicular cells / C-cells of the thyroid gland:
    - Works to oppose the actions of PTH
- It helps lower ionized calcium levels:
  - Primarily in two ways:
    - First, it inhibits osteoclast-mediated bone resorption
    - Second, it inhibits resorption of calcium and phosphate by the kidney
Calcitonin:
- Has no direct effects on:
  - Intestinal absorption
  - Osteoblast-mediated bone formation
It is also used in the treatment of hypercalcemic crisis:
- 4 IU/kg subcutaneously / intramuscularly
It acts quickly (24 to 48 hours):
- Is more effective when used in combination with glucocorticoids
Finally, calcitonin is a useful marker:
- With regard to surveillance in medullary thyroid carcinoma

#Arrangoiz #Calcitonin #ParathyroidSurgeon #ParathyroidExpert #CalciumHemostasis #Teacher #Surgeon #HeadandNeckSurgeon #CancerSurgeon #MSMC #MountSinaiMedicalCenter #Miami #Mexico

Diagnosis of Medullary Thyroid Carcinoma (MTC)

March 7, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

The diagnosis of medullary thyroid cancer (MTC):
- Is usually made after fine-needle aspiration (FNA) biopsy in a patient who has a solitary thyroid nodule (or a dominant nodule within a multinodular goiter):
  - The sensitivity of FNA is 50% to 80%:
    - Although higher sensitivity can be obtained by the addition of immunohistochemical staining for calcitonin
If the clinical suspicion for MTC is high:
- Patient with diarrhea, flushing, and a thyroid nodule:
  - Calcitonin can be measured in the washout of the FNA biopsy needle:
    - Although this may not be readily available in many commercial laboratories
In some cases:
- The diagnosis of MTC is made after thyroid lobectomy for a suspicious or indeterminate FNA biopsy:
  - Surgical specimens from patients with MTC show:
    - Spindle-shaped and frequently pleomorphic cells without follicle development:
      - Because these cells originate from the calcitonin-producing parafollicular C cells of the thyroid
  - The use of serum calcitonin screening to complement ultrasound and FNA in the routine diagnosis of thyroid nodules is controversial in the United States:
    - Measurement of serum calcitonin has not been a part of the routine evaluation of patients with thyroid nodules in the United States:
      - The high frequency of falsely elevated serum calcitonin values, the inability to confirm the high calcitonin by pentagastrin stimulation in the United States, and the accuracy of FNA biopsy: would argue against a change in this recommendation
    - Further, occasional patients with locoregional metastases or locally invasive MTC will have normal unstimulated serum calcitonin concentrations
In some countries (eg, European countries) where pentagastrin is available, however, serum basal and stimulated calcitonin levels are routinely used in the evaluation of thyroid nodules to facilitate the preoperative diagnosis of MTC
Differential Diagnosis:
- The differential diagnosis in a patient presenting with a neck mass:
  - Is extensive and varies with the age of the patient at presentation
- The majority of these masses represent benign thyroid nodules and cysts
- Neck masses that are not of thyroidal origin may be from:
  - Congenital
  - Vascular anomaly
  - Inflammatory:
    - Lymph node enlargement
  - Other neoplastic:
    - Primary or metastatic disease disorders
In addition to medullary thyroid cancer (MTC):
- Elevated calcitonin results may also be seen in patients with:
  - Hypercalcemia
  - Hypergastrinemia
  - Neuroendocrine tumors
  - Renal insufficiency
  - Papillary and follicular thyroid carcinomas
  - Goiter
  - Chronic autoimmune thyroiditis
  - Prolonged treatment with:
    - Omeprazole (greater than two to four months)
    - Beta blockers
    - Glucocorticoids:
      - Has been associated with hypercalcitoninemia
In addition, the presence of heterophilic antibodies to calcitonin:
- Can falsely elevate serum calcitonin levels
Elevated carcinoembryonic antigen (CEA) levels can also occur in patients with:
- Heterophilic antibodies
- Gastrointestinal tract inflammatory disease
- Benign lung disease
- Non-thyroid malignancies
- Cigarette smoking
Evaluation:
- For patients diagnosed with medullary thyroid cancer (MTC) on the basis of cytologic evaluation of a thyroid nodule:
  - Evaluation should include:
    - Measurement of serum calcitonin, carcinoembryonic antigen (CEA), ultrasonography of the neck (if not already performed), genetic testing for germline RET mutations, and biochemical evaluation for coexisting tumors, especially pheochromocytoma
    - Serum calcitonin and CEA:
      - The serum calcitonin and carcinoembryonic antigen (CEA) concentrations should be measured in patients diagnosed with MTC on the basis of cytologic evaluation of a thyroid nodule
      - These tests can establish that the tumor is capable of hypersecreting the hormones and, if so, the values can be compared with postoperative values
  - Postoperatively:
    - Results may provide a prognostic factor or indicate biochemical cure
In a study of 226 patients with MTC:
- Preoperative serum calcitonin concentrations:
  - Where significantly correlated with tumor size in both the sporadic and familial cases
- In addition, among 45 patients who had a preoperative serum calcitonin concentration of 50 pg/mL or less:
  - 44 had normal concentrations after surgery:
- In contrast, only 50 of 120 patients with preoperative serum calcitonin concentrations higher than 50 pg/mL had normal concentrations after surgery
In a second study of 224 patients with MTC:
- 62% of patients without nodal metastases had normal calcitonin postoperatively:
  - 10% of node positive patients had normal postoperative calcitonin levels
Assessment of calcitonin and CEA doubling times postoperatively:
- Provides sensitive markers for progression and aggressiveness of metastatic MTC:
  - Postoperative calcitonin doubling time was a prognostic factor for survival in a study of 65 patients followed for 3 to 30 years:
    - Ten-year survival was: 8%, 37%, and 100% for doubling times:
      - Under six months, between six months and 24 months, and greater than 24 months, respectively
Radiologic evaluation:
- MTC can spread by:
  - Local invasion or metastasis:
    - Within the neck or distantly
- When MTC is diagnosed by fine-needle aspiration (FNA) biopsy:
  - Ultrasonography of the neck is indicated to look for cervical lymph node involvement
- For patients with local lymph node metastases on ultrasound or with preoperative serum basal calcitonin > 500 pg/mL (indicating high risk of local or distant metastatic disease):
  - Additional imaging is required to assess for metastatic disease:
    - In this setting, based con literature review I suggest cross-sectional imaging including:
      - Chest computed tomography (CT)
      - Neck CT with IV contast
    - Three-phase contrast-enhanced liver CT or contrast-enhanced liver magnetic resonance imaging (MRI)
    - Axial MRI, and bone scintigraphy:
      - In patients suspected of having skeletal metastases
      - MRI may be superior to other imaging modalities
- I do not recommend 18-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) imaging or somatostatin receptor imaging:
  - For routine initial screening for metastatic disease:
    - The sensitivity of FDG-PET scanning for detecting metastatic disease is variable:
      - But improves with higher calcitonin levels
      - Sensitivity 78% versus 20% for basal calcitonin value greater than or less than 1000 pg/mL, respectively
  - The use of radionuclide imaging with 111-In-octreotide or 99m-Tc-DMSA:
    - Is not currently recommended for routine initial screening for metastatic disease
    - However, three patients have been described who had regional and distant metastases of MTC detected by somatostatin receptor scintigraphy but not by CT scan
  - How to select patients with a negative CT scan to undergo somatostatin receptor scintigraphy is not clear:
    - Scanning may be more useful in localizing residual or recurrent disease after primary therapy
Genetic screening in sporadic MTC:
- Germline RET testing:
  - In all patients with newly diagnosed C cell hyperplasia or apparently sporadic MTC:
    - Initial germline testing in patients with C cell hyperplasia or apparently sporadic MTC should include:
      - Sequencing of exons 10, 11, and 13 through 16 of the RET gene
    - Sequencing of the remaining exons in the RET gene should be considered in patients with:
      - Clinical features or family history highly suggestive of hereditary medullary syndromes who demonstrate no mutations in exons 10, 11, or 13 through 16
While it is possible for clinicians to directly order genetic testing from reference laboratories:
- It is strongly encourage to have a consultation with genetic counselors who are familiar with both the ethical issues and legal informed consent requirements (which can vary significantly in different regions) that are involved in germline testing
When the index patient is positive for a germline mutation:
- Family members should be offered genetic counseling and genetic screening
An important question is what proportion of patients with apparently sporadic MTC have unsuspected germline mutations in the RET proto-oncogene (the underlying defect in MEN2) and, therefore, have heritable disease:
- Studies of unselected patients with MTC have found, on average:
  - That approximately 6% to 7% (range 1.5% to 24%) have germline RET mutations
- In one report, 35 of 482 patients (7.3%) with apparently sporadic MTC had mutations, and in 18 of these 35:
  - Gene carriers were identified in relatives
75% of the familial medullary cases:
- Had no prior family history:
  - A much higher percentage (approximately 60%) of patients with sporadic MTC have somatic (acquired) mutations in the RET gene within the tumor cells:
    - These mutations are present only in the tumor cells and are not detected by standard genetic testing (ie, using leukocyte DNA)
- The presence of somatic RET mutations correlate with:
  - Lymph node metastases
  - Persistent disease
  - Lower survival
- However, in one study:
  - Only mutations in exons 15 and 16 of the RET gene were associated with the worse prognosis:
    - While those in other exons had a more indolent course
Since it is unclear how knowledge of a specific somatic (acquired) RET mutation should impact clinical management:
- I do not routinely test tumor samples
Testing for coexisting tumors:
- Most patients require biochemical evaluation for coexisting tumors (particularly pheochromocytoma and hyperparathyroidism) prior to thyroidectomy:
  - Even when genetic screening is performed preoperatively:
    - The results are rarely known prior to surgery
- For patients with unknown RET mutational status and for patients who have a germline RET mutation:
  - Serum calcium:
    - To rule out hyperparathyroidism requiring concomitant surgical intervention
  - Plasma fractionated metanephrines:
    - As the initial screen for pheochromocytoma):
      - Normal plasma fractionated metanephrines values exclude a symptomatic catecholamine-secreting neoplasm
      - Mildly elevated values of normetanephrine could be falsely positive in which case additional evaluations including 24-hour urinary fractionated metanephrines, catecholamines, and adrenal imaging may be required to effectively rule in or rule out pheochromocytoma prior to surgery
      - Adrenal imaging should not be performed unless there is biochemical evidence suggesting a possible pheochromocytoma
In a patient with negative RET proto-oncogene testing and no family history of MEN2 syndrome:
- Biochemical testing for coexisting tumors is typically not required
What is Head and Neck Surgery?:
- It is a surgical sub-specialty that deals mainly with benign and malignant tumors of the head and neck region, including:
  - The scalp, facial region, eyes, ears, nose, nasal fossae, paranasal sinuses, oral cavity, pharynx (nasopharynx, oropharynx, hypopharynx), larynx (supraglotic larynx, glottis larynx, subglotic larynx), thyroid gland, parathyroid gland, salivary glands (parotid glands, submandibular glands, sublingual glands, minor salivary glands), soft tissues of the neck, skin of the head and neck region. The head and neck surgeon’s work area:Does not cover tumors or diseases of the brain and other areas of the central nervous system or those of the cervical spine:
    - This is the neurosurgeon field
Among the diagnostic procedures performed by the head and neck surgeon, are the following: Nasopharyngolaryngoscopy:
- Performed to examine, evaluate and, possibly perform a biopsy, of oral cavity, pharyngeal and laryngeal lesions.
The surgeries most commonly performed by the head and neck surgeon are: Total or near total thyroidectomies
Hemithryoidectomies (lobectomies)
Comprehensive neck dissections
Selective neck dissections
Maxillectomies: Total maxillectomy
Subtotal maxillectomy
Infrastructure maxillectomy
Suprastructure maxillectomy
Medial maxillectomy
Mandibulectomy: Segmental
Marginal
Tracheostomy
Salivary gland surgeries: Parotid gland operations: Limited superficial parotidectomy with identification and preservation of the facial nerve
Superficial parotidectomy with identification and preservation of the facial nerve
Near total parotidectomy with identification and preservation of the facial nerve
Total parotidectomy
Submandibular gland resection
Sublingual gland resection
Resection of tumors of the oral cavity: Glossectomy
Resection of the floor of the mouth tumors
Resection of tumors of the pharynx
Resection of tumors of the larynx
Split-thickness skin grafts
Full-thickness skin grafts
Sentinel lymph node mapping and sentinel lymph node biopsy
Resection of malignant skin tumors (BCC, SCC, melanoma) of the head and neck region
The formation of the head and neck surgeon includes mastering the following subjects: Surgical Anatomy
History and Basic Principles of Head and Neck Surgery
Epidemiology, Etiology, and Pathology of Head and Neck Diseases
Diagnostic Radiology of the Head and Neck Region
Tumors of the Scalp, Skin and Melanoma
Eyelids and Orbit
Nasal Cavity and Paranasal Sinuses
Skull Base and Temporal Bone
Lips and Oral Cavity
Pharynx and Esophagus
Larynx and Trachea
Cervical Lymph Nodes
Thyroid and Parathyroid Glands
Salivary Glands
Neurogenic Tumors and Paragangliomas
Soft Tissue Tumors
Bone Tumors and Odontogenic Lesions
Reconstructive Surgery
Oncologic Dentistry and Maxillofacial Prosthetics
Principles of Radiation Oncology
Principles of Chemotherapy
Molecular Oncology, Genomics and Immunology
Nutrition
Biostatistic
Rodrigo Arrangoiz MS, MD, FACS a head and neck surgeon / endocrine surgeon / complex surgical oncologist and is a member of Mount Sinai Medical Center, in Miami Beach, Florida
Rodrigo Arrangoiz MS, MD, FACS:
- Is a member of the American Head and Neck Society
- He is a member of the American Thyroid Association
Training:
- General surgery:
  - Michigan State University:
  - 2004 al 2010
Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:
- Fox Chase Cancer Center (Filadelfia):
  - 2010 al 2012
Masters in Science (Clinical research for health professionals):
- Drexel University (Filadelfia):
- 2010 al 2012
Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:
- IFHNOS / Memorial Sloan Kettering Cancer Center:
  - 2014 al 2016

Molecular Genetics of Thyroid Cancer Part 1

March 7, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Most of the data that has been gathered is associated with somatic mutations:
- Many of which occur early in the
  transformation process and are crucial for cancer development
In thyroid cancer, vital genes are commonly mutated via two separate molecular mechanisms:
- Point mutations
- Chromosomal rearrangements
Point mutations:
- Are the result of a single nucleotide change within the DNA chain:
  - Which activates or inactivates a
    protein
Chromosomal rearrangements:
- Represent a large-scale genetic abnormality with breakage and fusion of parts of the same chromosome or different chromosomes
The molecular pathogenesis of thyroid cancer:
- Is relatively simple with two molecular pathways:
  - The mitogen‑activated protein kinase (MAPK) pathway
  - The phosphatidylinositol 3 – kinase – protein kinase B (PI3K-AKT) pathway (Figure)
These pathways are activated in most thyroid cancers:
- Via distinct molecular mechanisms mentioned previously, like:
  - Point mutations (single nucleotide variant):
    - Where a single nucleotide is
      changed:
      - Which activates or inactivates a protein
  - Gene fusions:
    - Were parts of two different genes located in the same or different chromosome are fused to each other:
      - That results in the generation of chimeric protein
  - Copy number alterations (CNA):
    - That have been recently accepted as a driver mutation for oncocytic cell tumors
Activation of the MAPK pathway:
- Is a critical step for tumor initiation
- The mutated genes that impact
  these pathways encode:
  - The cell-membrane receptor tyrosine kinases:
    - RET and NTRK1
  - Intracellular signal transducers:
    - RAS and BRAF
- These mutually exclusive mutations:
  - They do not overlap with each other because they activate the same pathway and only one event is sufficient to activate the process for cancer development:
    - Occur in roughly 70% to 75% of patients with PTC and are associated with specific clinical, pathologic, and biological tumor characteristics (Table)
- In follicular thyroid cancer (FTC), in addition to mutations of RAS:
  - Another common event is PAX8 / PPARG rearrangement
Thyroid cancer progression and dedifferentiation involves a number of additional mutations:
- That affects the PI3K-AKT pathway and other cell signaling pathways