Thyroid Neoplasms - المنصورة

• Thyroid neoplasms can be benign or malignant.

Classification

• Follicular adenoma is benign.
• Dunhill classification identifies malignant forms

Primary Carcinomas Based on Tissue Origin

• Follicular epithelium differentiates into papillary, follicular, papillofollicular and Hurthle cell carcinomas.
• Papillary thyroid carcinoma is the most common (60%).
• Follicular thyroid carcinoma accounts for 17%.
• Papillofollicular carcinoma behaves like papillary carcinoma.
• Hurthle cell carcinoma behaves like follicular carcinoma.
• Undifferentiated carcinomas include anaplastic thyroid carcinoma (13%).
• Parafollicular cells can develop into medullary carcinoma (6%).
• Lymphoid cells can give rise to malignant lymphoma (4%).
• Secondary thyroid cancers are rare and arise from metastasis or direct invasion.

Benign Tumors (Follicular Adenoma)

• Presents clinically as solitary nodules.
• Differential diagnosis requires histological examination to distinguish from follicular carcinoma.
  • Adenomas have absent capsule and pericapsular blood vessel invasion.
  • Follicular carcinomas have present capsule and pericapsular blood vessel invasion.
• Colloid is the commonest type with no microinvasion potential.
• Fetal (microfollicular) has microinvasion potential.
• Embryonal (atypical) has microinvasion potential.
• Hurthle cell has microinvasion potential.
• Hyalinising trabecular adenoma is also a type.
• Surgical treatment is by excision: hemithyroidectomy or lobectomy with isthmectomy.
• Follow-up is unnecessary after surgical treatment.

Malignant Tumors

• More common in females (3:1 ratio).

Etiology of thyroid malignancy:

• Radiation exposure is a predisposing factor for Papillary carcinoma.
• Pre-existing multinodular goiter is associated with Follicular carcinoma.
• Familial history is linked to Medullary carcinoma.
• Hashimoto's thyroiditis can lead to Non-Hodgkin's Lymphoma (NHL) or papillary carcinoma.
• Elevated TSH levels are associated with papillary carcinoma.
• Genetic factors can predispose to Cowden syndrome.

Cowden Syndrome

• Is an autosomal dominant condition.
• Mutation of the PTEN tumor suppressor gene causes it.
• Differentiated thyroid carcinoma can be a result.
• Oncogenes like C myc, C erb, C fos and Ras are associated with thyroid neoplasms.
• Carcinoma of the breast as well
• Multiple hamartomas appear as well.

Types of Malignant Tumors

• Differentiated Thyroid Carcinoma (DTC) originates from follicular cells.
  • Includes papillary, follicular, papillofollicular, and Hurthle cell carcinomas.
• Accounts for 90% of thyroid malignancies.
• Thyrotoxicosis occurs in 2% of DTC cases.
• Papillary carcinoma spreads through nodes, follicular spreads through blood.

Pathology of thyroid malignancy

• Penetration and invasion of the capsule happens.
• Presence of papillae, follicles, or both in differentiated types with irregular arrangement happens.
• Active irregular mitosis can be seen
• Rich vascularity is present.
• Psammoma bodies are pathognomonic of malignancy.
  • They are small areas of perivascular calcification in necrosed hyalinized cells.
• In X-rays, multiple small specks of granular calcification are seen.
  • Benign calcification appears as irregular blotchy areas and is larger in size.

Papillary Carcinoma:

• Incidence is 70-80%, the most common.
• Affects young adults aged 20-40 years.
• More common in females.
• Caused by radiation and iodine therapy.

Woolner Classification

• Occult (30%): primary tumor < 1 cm, presents with positive cervical lymph nodes.
• Intrathyroidal (50%): presents as solitary thyroid nodules (STN).
• Extrathyroidal (15%): presents as extracapsular spread of the tumor and multiple foci in the thyroid gland.
• Consistency can be soft, firm, hard or cystic.
• Solitary or multinodular.
• Contains brownish black fluid.

Follicular Carcinoma:

• Incidence is 10-15%.
• Occurs in middle age, 30-50 years.
• More common in females (2:1 ratio).
• Arises de novo or in a pre-existing multinodular goiter.

Woolner Classification:

• Minimally Invasive (50%): well encapsulated and presents as STN.
• Highly Invasive (50%): presents as multiple foci within the thyroid gland.

Anaplastic Carcinoma:

• Incidence is 1%.
• Occurs in older age, 50 and above.
• More common in females.
• Bulky mass invades the capsule.
• Encircles cervical structures and extends to the mediastinum.

Microscopic Features of tumors

• Papillary carcinoma shows well-defined unique features.
  • Cystic spaces are present.
  • Papillary projections form with psammoma bodies (50% of cases).
  • Malignant cells contain Orphan Annie eye nuclei, nuclear grooves and nuclear pseudo-inclusions
  • Commonly multicentric.
• Follicular carcinoma shows follicular cells with variable degrees of differentiation and solid sheets.
  • Diagnosis depends on finding capsular and vascular invasion, or metastasis.

Hurthle Cell Tumor:

• a variant of follicular neoplasm.
  • Oxiphil cells are predominant.
• Multicentricity is rare, except in Hurthle cell tumors. Lymph node spread occurs as well.

Spread

• Papillary Carcinoma spreads via lymphatics.
  • Usually, there is no blood spread and may cause extrathyroidal disease.
• Hurthle cell variant:
  • Spread via lymph node in Hurthle cell variant.
  • Blood is much more of a factor than in the other cancers.
  • Can spread into bones commonly (Skull, long bones, ribs), and lungs & liver.
• Lymphatics are of more concern than the blood vessels.
• Spread by direct invasion can cause multi-organ involvement.

Prognosis

• Papillary carcinoma is as slowly progressive, less aggressive, and one of the curable malignancies.
• Follicular is Aggressive tumor.
• Encapsulated in 97% & Invasive is in 70%.
• Anaplastic is Very poor tumor.
  • Very aggressive & most patients die within the first 2 years.

Medullary Carcinoma

• Represents an uncommon (5%) type of thyroid malignancy.

Types of Medullary Carcinoma:

• Sporadic occurs in the 5th/6th decade and more in females, usually solitary (70%) and unifocal.
  • Compression on the posterior part of the thyroid can happen with the tumor.
• Medullary Thyroid Carcinoma (MTC) with MEN II syndrome (more aggressive) affects a younger age group, often involves infants and children with marfanoid features.
  • Bilateral and multifocal/multicentric.
  • MTC with MEN type IIb (pheochromocytoma with hypertension) is more aggressive.
• Familial Non-MEN MTC (20%, least malignant) occurs in 4th/5th decades commonly multicentric.
  • Autosomal dominant in chromosome 10 (mutation of RET-Proto oncogene).

Characteristics of Medullary Carcinoma

• Gross Appearance: grey-white in color, well demarcated, non-encapsulated, and varying in size.
• Derived from parafollicular c-cells from the neural crest.
  • Characteristic Amyloid stroma.
• Immunohistochemistry reveals calcitonin in amyloid.
• Tumor produces calcitonin, a useful tumor marker, and also secretes 5-HT (serotonin), Prostaglandin, ACTH, and Vasoactive Intestinal Polypeptide (VIP).
• Spreads mainly to lymph nodes (60%).
• Not TSH dependent and does not take up radioactive iodine.

Clinical Picture of Thyroid Carcinoma

• Gland or nodule enlarges recently, not rapidly.
• Painful swelling.
  • Onset is insidious
  • Site is local in the mass, or referred to the ear (Arnold's nerve of the vagus).
• Solitary thyroid nodule is often present.
• Compression manifestation occurs as the lesion advances, with symptoms.
  • Dyspnea
  • Dysphagia.
  • Hoarseness

Clinical Presentation of Thyroid Carcinoma

• Carcinoma on pre-existing multinodular goiter (bilateral carcinoma).
  • Occurs in females, with a history of recent increase in goiter size, hoarseness of voice, persistent dry cough, occasional dysphagia, neck pain - local & referred.
  • May also report bony swelling/pathological fracture.

On examination:

• Excessive induration.
• Fixity to the surrounding structures.
• Enlarged cervical lymph nodes which are very suspicious to be a carcinoma.

Symptomless STN in the Healthy Gland of a Young Male Child (Carcinoma de Novo - Unilateral)

• A symptomless STN in a child or adolescent.
• Should be labeled as carcinoma, unless proven otherwise.
  • Like a breast lump in an elderly female
• Histologically, such minor is papillary carcinoma.
• Lump in the neck with occult primary tumors on the thyroid.
  • Occurs in a young or middle-aged male.
  • Reports for a unilateral lump in the neck.
  • Without a history of sore throat, tuberculosis, or buccal ulcer.
  • The thyroid is not enlarged.
  • Enlarged LNs are found to be matted and firm with no tenderness.
• A biopsy of the lymph nodes shows thyroid tissue with papillary carcinoma.

Rapidly Increasing Swelling of the Thyroid with Hoarseness of Voice, Dyspnea

• Diffuse or Bilateral Carcinoma de Novo presents with:
  • Rapid swelling of the neck, difficulty in breathing.
  • Hoarseness of voice with no prior thyroid swelling noticed.
• Thyroid.
  • Swelling.
  • Firm consistency with a diffuse margin.
• Cervical LNs may be found:. -Irregular, enlarged, firm and hard with no tenderness
• Histopathologically, It shows anaplastic carcinoma of the thyroid.

Malignant Change on a Preexisting STN

• A thyroid nodule turning into carcinoma is uncertain, but cancer risk is overstated.
• A benign tumor rarely turns malignant.
• Complications of malignant tumors of the thyroid gland include spread, pressure, fungation,ulceration, hemorrhage & infection.

Spread of Thyroid Carcinoma

• Local spread: Affects the whole gland, then spreads to other areas.
  • Trachea.
  • Esophagus.
  • Neighboring tissues.
  • Recurrent Laryngeal Nerve.
• Lymphatic spread: important especially in papillary type (occult carcinoma).
  • Where 2ry malignant LNs may be discovered before the 1ry tumor which is small.
• Invade lymphatics accompany the vessels & may give enlargement (invasion) in the following LNs.
  • Pretracheal LNs.
  • Internal jugular LNs (deep cervical).
  • LN along the RLN.
  • Supraclavicular LNs in posterior triangle.
  • Upper mediastinal LNs.
• In advanced cases when lymphatics are blocked by malignant cells result to retrograde lymphatic spread that may involve:
  • Base of the skull.
  • Cervical spine or clavicle
  • Hilar glands & medial part of lung parenchyma.

Blood spread:

• It is more common in follicular than in papillary carcinoma.
• Affected organs are the lung and bone.
• In occult carcinoma, secondary deposits may appear before the primary tumor.
  • Removal of the primary tumor may lead to regression of the metastasis.
• Due to local infiltration, includes Dyspnea, Dysphagia, and Hoarseness.
• Dyspnea occurs in the trachea.
• Dysphagia occurs in the esophagus.
• Hoarseness of voice occurs in the recurrent laryngeal nerve.

Investigation

• Thyroid function tests include TSH, Free T3 & Free T4.
• Thyroid antibody titer will be raised in carcinoma.
• Tumor markers are tested.
  • Serum thyroglobulin is a marker.
  • S-calcitonin is a marker for Medullary Carcinoma.
• Ultrasound (Neck US).
  • Good anatomical images of the thyroid and surrounding structures.
  • Identifies nodules (number, size, vascularity, echogenicity).
  • USG-guided FNAC.
  • Detects recurrent cases, solid or cystic nature, single or multiple nodules & benign lesion VS malignant lesion.

Ultrasound features differentiate between benign and malignant lesions

• Benign lesions have hyperechoic or cystic masses, well-defined margins, peripheral eggshell calcification and sonolucent rim (halo).
• Malignant lesions have hypoechoic masses, poorly defined margins, micro-calcification and high vascularity.
• Plain X-ray on neck can show stippling calcification and also pulmonary metastases.

Isotope scan

• Scan is done for a solid nodule in US.
• Malignant lesions usually appear as cold areas in the scan.
• Benign lesions appear also cold on the ultrasound scan and include: Cysts, Hemorrhage in a cyst & Degenerative nodule

FNAC (Fine Needle Aspiration and Cytology)

• FNA is the investigation of choice.
• FNA is useful and helps diagnose.
  • Papillary carcinoma.
  • Anaplastic carcinoma.
  • Colloid nodules.
  • Medullary carcinoma.
  • Lymphomas.
  • Thyroiditis. Suspicious solitary/multiple nodules/dominant nodules should be tested. Diagnostic accuracy of FNAC includes a Sensitivity of 95% & Specificity of 85%. Thy 1 is non-diagnostic.
• Thy 2 is non-neoplastic.
• Thy 3 is follicular.
• Thy 4 is suspicious of malignancy.
• Thy 5 is malignancy.
• FNA is less reliable in a cyst,
• FNA is also not reliable at present in follicular carcinoma of the thyroid because capsular & vascular invasions cannot be found for differentiation
• FNA is more reliable using some types, Benign cases have: Polyploidy and Monoclonal attributes, whereas malignant has: Aneuploidy and Polyclonal
• MR spectroscopy and thyroid-immunoperoxidase helps differentiate

Assessment of Metastases

• Direct & indirect laryngoscopy for visualization of vocal cords is used.
• Bone survey can be performed
• Abdominal US can assess spread.
• BA swallow can check for infiltration of the esophagus.
• Venography can check for obstruction in SVC.

TNM staging for DTCs

• T refers to the size and extent of the primary tumor.
  • T0 - No evidence of primary tumor.
  • T1 - Tumor < 2 cm, subdivides into T1a (<1 cm) and T1b (1-2 cm).
  • T2 - Tumor 2-4 cm.
  • T3 - Tumor > 4 cm limited to the thyroid or only minimally Extrathyroid extension.
  • T4 divided into T4a (Invasion to Subcutaneous tissue, Larynx, Trachea & Esophagus) T4b -Invasion to Prevertebral fascia Carotid encasement, mediastinal vessels.
• N refers to regional lymph node involvement.
  • Nx - Regional lymph nodes cannot be assessed.
  • N0 - No regional lymph node involvement.
  • N1 - Regional lymph node involvement.
    • Divided into N1a.
    • Divided into N1b
• M refers to distant metastasis.
  • Mx - Metastasis cannot be assessed.
  • M0- No distant spread.
  • M1 - Distant metastasis is present.

Prognosis

• Age is included in staging as an important factor.
• Low-risk group: Men ≤ 40, women ≤ 50, no distant metastases or Small 5cm
• or less intra-thyroid papillary or follicular carcinoma, etc.
• High-risk group: All patients with distant metastases.
• All older patients with extra-thyroid papillary or follicular carcinoma with major capsular Involvement and tumors of 5 cm or more the the extent of disease.

European consensus report defines three risk categories for DTC

• Very low-risk: small tumor with classical tissue build-up

Prognostic systems include

• AMES
• AGES
• MACIS scoring

Treatment of Papillary and Follicular Carcinoma (Differentiated)

• Total thyroidectomy is the gold standard. Hemithyroidectomy may be suitable if the tumor is <1 cm, unifocal, and node-negative.
• Lymph node management includes modified block neck dissection if positive, or observation if negative.
• TSH suppression therapy involves thyroxine given daily postoperatively to keep TSH below 0.01, as the tumor is hormone-dependent.
• Radioactive iodine therapy (RAIT) to the neck is indicated for tumors >1 cm, high-risk groups, extracapsular extension and unfavorable histology to eliminate any recurrence Medical therapy involves targeted therapy for advanced DTC using agents.
• Metastatic disease options include total thyroidectomy, RAIT, external radiation therapy, or surgical excision of isolated bone secondaries.

Medullary Carcinoma Treatment

• Total thyroidectomy to also include Central neck block dissection. Then evaluate what can be seen in the LN.
• Derived from parafollicular cells so tumor not TSH dependent doesn't uptake radioactive iodine. Exclusion if other components of MEN II are present

Anaplastic Carcinoma Treatment

• This cancer is inoperable, as there is local infiltration to the trachea or carotid sheath. Surgery isn't done unless to relieve tracheal compression. Thus, Palliative postoperative irradiation & chemotherapy.

• Malignant Lymphoma

• part of systemic lymphoma primary

• thyroid lymphoma More common rare

• Chemotherapy

Summary of Malignant Tumors of Thyroid Gland

• Papillary is the most common, affects young adults, spreads via lymph nodes, has Orphan Annie eye nuclei, and has -is an excellent one and depends on age to influence. Then there are the medullary, follicular and anaplastic tumors which are all uncommon.