Endocrine: Thyroid Cancer

Thyroid Cancer

Types of Thyroid Cancer

  • Differentiated Thyroid Carcinoma (DTC)
    • Papillary Thyroid Carcinoma (PTC)
    • Follicular Thyroid Carcinoma (FTC)
  • Anaplastic (Undifferentiated) Thyroid Carcinoma (ATC/UTC)
  • Medullary Thyroid Carcinoma (MTC)
  • Hürthle Cell Carcinoma
  • Lymphoma
  • Metastasis

Papillary Thyroid Carcinoma (PTC)

  • Most Common Thyroid Cancer (Overall, In Pediatrics & in a Thyroglossal Duct Cyst)
  • More Common After Childhood Neck Radiation Therapy
  • Mutations:
    • BRAF
    • RET (Not Associated with MEN II)
    • NTRK1
    • RAS – Less Common than FTC
    • *Mutations Tend to Cause Activation of MAPK (Mitogen-Activated Protein Kinase)
  • Least Aggressive
  • May Be Multifocal (20-30%) – More Common that FTC
  • Spread: Lymphatic
  • Most Common Site of Mets: Lung
  • Histology: Large Cells with Ground Glass Cytoplasm, Orphan Annie Nuclei & Psammoma Bodies Mn
    • Orphan Annie Nuclei – Large Washed Out Nuclei (Nuclear Clearing) with Powdery Chromatin & Nuclear Grooves
    • Psammoma Bodies – Calcified Clumps

Orphan Annie Nuclei 1

Psammoma Bodies (Arrow) 2

Follicular Thyroid Carcinoma (FTC)

  • Mutations:
    • PAX8/PPAR-Gamma-1
    • RAS – NRAS, HRAS & KRAS
    • *Mutations Tend to Cause Activation of AKT Pathway
  • Spread: Hematogenous Mn
    • Others Have Lymphatic Spread
  • Most Common Site of Mets: Bone
  • Histology: Crowded Microfollicles with Absent/Scant Colloid
    • More Suspicious if Cells Arranged in Clusters/Clumps with Absence of Follicle Formation
    • Unable to Differentiate Carcinoma from Benign Adenoma on FNA Alone – Requires Excision to Determine Capsule/Vascular Invasion
  • Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP)
    • No Risk for Metastatic Spread (Not Considered a Malignancy)
    • Indistinguishable on FNA & Requires Surgery to Differentiate

Follicular Thyroid Carcinoma 3

Anaplastic (Undifferentiated) Thyroid Carcinoma (ATC)

  • Undifferentiated Tumor of Thyroid Follicular Epithelium
    • Many Arise from Previously Differentiated (PTC/FTC) Thyroid Carcinoma
  • More Common in Elderly with History of Goiter
  • Mutations:
    • p53
    • PIK3CA
    • *May See any Mutation Associated with PTC/FTC
  • Most Aggressive – Most are Metastatic or Unresectable at Time of Diagnosis
    • 90% Have Regional or Distal Spread at Time of Diagnosis
    • 15-50% Have Distant Mets at Time of Diagnosis
  • Spread: Lymphatic
  • Most Common Site of Mets: Lung
  • Refractory to Radioactive Iodine (RAI) – Undifferentiated & Do Not Absorb Iodine
  • Histology: Marked Pleomorphism with Spindle Cells & Giant Cells

Anaplastic Thyroid Cancer, Pleomorphic Spindle Cells 4

Medullary Thyroid Carcinoma (MTC)

  • Neuroendocrine Tumor of Parafollicular C Cells
    • May Produce Calcitonin & CEA
  • Mutations: RET
  • Most (75%) are Sporadic but 25% are Hereditary (Associated with MEN IIA/IIB)
  • Hereditary MTC is Typically Bilateral & Multicentric
  • Most Have Already Metastasized at the Time of Diagnosis
    • 70% Have Clinically Detectable Cervical Lymph Nodes
    • 5-10% Have Distant Mets at Time of Diagnosis
  • Refractory to Radioactive Iodine (RAI)
  • Histology: Spindle-Shaped Pleomorphic Cells without Follicles, Stain for Calcitonin & Amyloid in Stroma

Medullary Thyroid Carcinoma; Pleomorphic Cells with Amyloid in Stroma (A), Stain Positive for Calcitonin (B) 5

Hürthle Cell Carcinoma

  • Previously Considered a Variant of FTC (Now Determined to be Distinct)
  • Poorer Prognosis Than FTC
    • Refractory to Radioactive Iodine (RAI)
  • Spread: Lymphatic (Opposed to FTC)
  • Histology: Eosinophilic Oxyphilic Cells (Oncocytes/Ashkenazy Cells) with Abundant Cytoplasm
    • Unable to Differentiate Carcinoma from Benign Adenoma on FNA Alone – Requires Excision to Determine Capsule/Vascular Invasion
  • Hürthle Cells are Commonly Seen on FNA – Nodules Containing Almost Entirely Hürthle Cells are More Concerning for Hürthle Cell Carcinoma

Hurthle Cell Carcinoma; Oncocytes with Abundant Granular Eosinophilic Cytoplasm and Prominent Nucleoli 6

Thyroid Lymphoma

  • Most (98%) are B Cell Lymphomas
  • Associated with Hashimoto’s Thyroiditis
    • Increases Risk 60x
  • Treatment: Chemotherapy & Radiotherapy

Metastases to the Thyroid

  • Primary Sources:
    • Renal Cell Carcinoma (Most Common)
    • GI Tract
    • Lung
    • Skin
    • Breast
  • Parathyroid Invades but Does Not Metastasize to the Thyroid

Diagnosis

Diagnosis

Indications for Preoperative Laryngoscopy

  • Hoarseness of Voice
  • Previous Neck Surgery
  • Extrathyroidal Invasion
  • Bulky Lymphadenopathy

Staging – AJCC

TNM Staging

T N M
1 < 2.0 cm N1a: Level VI or VII LN+
N1b: Level I-V LN+		 Mets
2 > 2.0 cm
3 3a: > 4.0 cm
3b: Invades Strap Muscles
4 4a: Invades Extensively Beyond the Thyroid
4b: Invades Toward Spine or into Large Blood Vessels

Differentiated (Papillary/Follicular) Thyroid Cancer

  • Most Important Prognostic Factor: Age
  • Stage (Age < 55 Years)
  T N M
I Any T Any N M0
II Any T Any N M1
  • Stage (Age ≥ 55 Years)
  T N M
I T1-2 N0 M0
II T1-2 N1 M0
T3 Any N M0
III T4a Any N M0
IV A T4b Any N M0
B Any T Any N M1

Anaplastic (Undifferentiated) Thyroid Cancer

  • All are Stage IV
  T N M
IV A T1-T3a N0 M0
B T1-T3a N1 M0
T3b-T4 Any N M0
C Any T Any N M1

Medullary Thyroid Cancer

  T N M
I T1 N0 M0
II T2-T3 N0 M0
III T1-3 N1a M0
IV A T4a Any N M0
T1-3 N1b M0
B T4b Any N M0
C Any T Any N M1

Treatment

Differentiated (PTC/FTC) Thyroid Carcinoma

  • Primary Surgery:
    • ≥ 4 cm or Extrathyroidal Invasion: Total Thyroidectomy
    • < 4 cm: Lobectomy vs. Total Thyroidectomy
      • Lobectomy Generally Preferred if Small (< 1 cm)
      • May Also Consider Serial Monitoring for Small (< 1 cm) PTC without Evidence of Invasive/Metastatic Features for Select Cases
      • Benefits of Total Thyroidectomy:
        • Removal of Potentially Multifocal Disease (Common in PTC)
        • Indication for Adjuvant RAI May Not Be Fully Known Until After Surgery
        • Able to Use Thyroglobulin for Postoperative Surveillance
      • Indications for Total Thyroidectomy:
        • Adjuvant RAI Indicated (Residual Thyroid Tissue Would Interfere with RAI)
        • Contralateral Disease
        • Contralateral Benign Nodularity
        • Concomitant Graves’ Disease or Hypothyroidism
        • History of Significant Radiation
        • Family History of Significant Thyroid Cancer
        • Comorbidities That Would Preclude Future Completion Thyroidectomy
        • Patient Preference
  • Node Management:
    • ≥ 4 cm, Extrathyroidal Invasion or Central Node Mets: Central Neck Dissection
    • Lateral Node Mets: Ipsilateral Lateral & Central Neck Dissections
      • If Lateral Lymph Nodes are Involved the Ipsilateral Central Lymph Nodes Usually are as Well
  • Adjuvant Radioactive Iodine (RAI/131I):
    • Indications:
      • > 4 cm
      • Extrathyroidal Invasion (Local/Lymphovascular Invasion, Cervical LN or Distant Mets)
      • Aggressive Histologic Findings
    • Administer 4-6 Weeks After Surgery (When TSH Highest)

Anaplastic (Undifferentiated) Thyroid Carcinoma

  • Primary Treatment: Total Thyroidectomy (If Able)
    • Requirements: No Local Invasion or Metastatic Disease
    • May Consider Lobectomy if There is No Evidence of Contralateral Nodularity (There is However Risk for Concomitant Foci of PTC)
  • Refractory to Radioactive Iodine (RAI)
  • Palliative Management:
    • Consider Thyroidectomy Only for Locally Invasive Disease with Impending Airway Compromise
    • Often Also Requires Placement of a Tracheostomy Tube

Hürthle Cell Carcinoma

  • If Hürthle Cells Seen on FNA: Thyroid Lobectomy First to Diagnose
  • If Diagnosed by Lobectomy or Evidence of Invasive Disease: Total Thyroidectomy
    • Modified Radical Neck Dissection Required for any Clinically Evident Lymph Node Involvement

Medullary Thyroid Carcinoma

  • Primary Treatment: Total Thyroidectomy & Node Dissection
  • Node Dissection:
    • No Lateral Neck Disease: Central Neck Dissection
    • Lateral Neck Disease: Central & Lateral Neck Dissections
  • Refractory to Radioactive Iodine (RAI)
  • Prophylactic Thyroidectomy in MEN II:

Monitor Recurrence

  • DTC (PTC/FTC): Thyroglobulin
    • Best After Total Thyroidectomy
  • MTC: Calcitonin & CEA

Mnemonics

Papillary Thyroid Carcinoma Histology

  • “Little Orphan Annie Wants a Momma & a Pappa”
    • Orphan Annie – Orphan Annie Nuclei
    • “s a Momma” – Psammoma Bodies
    • Pappa – Papillary Thyroid Carcinoma

Thyroid Cancer Route of Spread

  • “Pap”-ilary – Spreads to “Palp”able LN
  • “Foll”-icular – “Falls” & Spreads “Far” Away by Blood

References

  1. Punatar SB, Noronha V, Joshi A, Prabhash K. Thyroid cancer in Gardner’s syndrome: Case report and review of literature. South Asian J Cancer. 2012 Jul;1(1):43-7. (License: CC BY-NC-SA-3.0)
  2. Hassan MJ, Rana S, Khan S, Jairajpuri ZS, Monga S, Jain A, Jetley S. An Incidental Primary Papillary Carcinoma Arising in a Thyroglossal Duct Cyst: Report of a Rare Finding. J Lab Physicians. 2016 Jan-Jun;8(1):62-4. (License: CC BY-NC-SA-3.0)
  3. Kant S, Srivastava A, Kumar R, Verma AK, Mishra AK, Husain N. An intra-thoracic follicular carcinoma of thyroid: An uncommon presentation. Lung India. 2017 Mar-Apr;34(2):193-196. (License: CC BY-NC-SA-3.0)
  4. Kim SH, Kim HY, Jung KY, Choi DS, Kim SG. Anaplastic thyroid carcinoma following radioactive iodine therapy for graves’ disease. Endocrinol Metab (Seoul). 2013 Mar;28(1):61-4. (License: CC BY-NC-3.0)
  5. Somnay YR, Schneider D, Mazeh H. Thyroid: Medullary Carcinoma. Atlas Genet Cytogenet Oncol Haematol. 2013 Apr;17(4):291-296. (License: CC BY-2.0)
  6. Ahmadi S, Stang M, Jiang XS, Sosa JA. Hürthle cell carcinoma: current perspectives. Onco Targets Ther. 2016 Nov 7;9:6873-6884.(License: CC BY-NC-3.0)