thyroid carcinoma

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    • Neoplasms of the Thyroid
      • Solitary thyroid nodule
        • palpably discrete swelling within an otherwise apparently normal thyroid gland.
        • majority are localized, non-neoplastic conditions
          • a dominant nodule in multinodular goiter
          • simple cysts
          • foci of thyroiditis
          • benign neoplasms such as follicular adenomas.
        • benign neoplasms outnumber thyroid carcinomas by a ratio of nearly 10 : 1.(MCQ)
        •  Clinical criteria for benignancy of a given thyroid nodule:
          • Solitary nodules are more likely to be malignant than multiple nodules. (MCQ)
          • Nodules in younger patients – more likely to be malignant (MCQ)
          • Nodules in males – more likely to be malignant (MCQ)
          • A history of radiation treatment to the head and neck region – more likely to be malignant (MCQ)
          • Functional nodules that take up radioactive iodine in imaging studies (hot nodules) – more likely to be benign  (MCQ)
    • Adenomas of the thyroid
      • typically discrete, solitary masses
      • derived from follicular epithelium
      • also known as follicular adenomas.
      • follicular adenomas are not forerunners to carcinomas (MCQ)
      • vast majority of adenomas are nonfunctional
      • “Toxic adenomas”
        • Hormone production in functional adenomas (“toxic adenomas”) is independent of TSH stimulation
        • Somatic mutations of TSH receptor signaling pathway
          • found in
            • toxic adenomas,
            • toxic multinodular goiter
          • they are Gain-of-function mutations (MCQ)
          • occur most often TSHR itself or the α-subunit of Gs (GNAS)
          • mutations cause  “thyroid autonomy” allowing follicular cells to secrete thyroid hormone independent of TSH stimulation
        • This causes symptoms of hyperthyroidism and produces a “hot” thyroid nodule on imaging. (MCQ)
      • Features that are important in making the distinction of solitary nodule from multinodular goiters (MCQ)
        • In freshly resected specimens the adenoma bulges from the cut surface and compresses the adjacent thyroid
        • The color ranges from gray-white to red-brown, depending on the cellularity of the adenoma and its colloid content.
        • The neoplastic cells are demarcated from the adjacent parenchyma by a well-defined, intact capsule.
      • Hürthle cell adenoma
        • neoplastic cells acquire brightly eosinophilic granular cytoplasm (oxyphil or Hürthle cell change)
        • clinical presentation and behavior of a follicular adenoma with oxyphilia  is no different from that of a conventional adenoma. (MCQ)
      • The hallmark of all follicular adenomas is the presence of an intact, well-formed capsule encircling the tumor. (MCQ)
        • Careful evaluation of the integrity of the capsule is therefore critical in distinguishing follicular adenomas from follicular carcinomas, which demonstrate capsular and/or vascular invasion
      • As many as 10% of cold nodules eventually prove to be malignant on histologic analysis (MCQ)
      • Malignancy is rare in hot nodules (toxic adenomas). (MCQ)
      • Because of the need for evaluating capsular integrity, the definitive diagnosis of adenomas can be made only after careful histologic examination of the resected specimen.
      • Follicular adenomas have an excellent prognosis (MCQ)
      • They do not recur or metastasize.
    • Carcinomas of the thyroid
      • a female predominance is shown in the early and middle adult years
      • cases presenting in childhood and late adult life are distributed equally among males and females
      • Major subtypes of thyroid carcinoma
        • Papillary carcinoma (>85% of cases) (MCQ)
        • Follicular carcinoma (5% to 15% of cases)
        • Anaplastic (undifferentiated) carcinoma (<5% of cases)
        • Medullary carcinoma (5% of cases)
      • All ,except medullary carcinomas ,arise from the follicular epithelium (MCQ)
      • two oncogenic pathways involved in the three follicular cell–derived malignancies
        • mitogen-activated protein (MAP) kinase pathway
        • phosphatidylinositol-3-kinase (PI-3K)/AKT pathway
      • Molecular genetic of Thyroid cancer
        • Papillary Carcinomas.
          • Activation of the MAP kinase pathway is a feature of most papillary carcinomas (MCQ)
          • 2 Mechanisms causing activation of the MAP kinase pathway (MCQ)
            • rearrangements of RET or NTRK1 (neurotrophic tyrosine kinase receptor 1)
              • they encode transmembrane receptor tyrosine kinases
            • activating point mutations in BRAF
              • BRAF product is an intermediate signaling component in the MAP kinase pathway
          • RET gene
            • located on chromosome 10q11 (MCQ)
            • receptor tyrosine kinase it encodes is normally not expressed in thyroid follicular cells
            • The frequency of RET/PTC rearrangements is significantly higher in papillary cancers arising in the backdrop of radiation exposure
            • presence of a RET/PTC fusion protein leads to constitutive expression of the tyrosine kinase in thyroid follicular cells, with resultant activation of the MAP kinase pathway. (MCQ)
            • presence of BRAF mutations in papillary carcinomas correlates with adverse prognostic factors like metastatic disease and extra-thyroidal extension.
      • Follicular Carcinomas.
        • one third to one half of follicular thyroid carcinomas harbor mutations in the PI-3K/AKT signaling pathway, resulting in constitutive activation of this oncogenic pathway. (MCQ)
        • A unique (2;3)(q13;p25) translocation has been described in one third to one half of follicular carcinomas. (MCQ)
        • This translocation creates a fusion gene composed of
          • portions of PAX8, a paired homeobox gene that is important in thyroid development
          • peroxisome proliferator-activated receptor gene (PPARG), whose gene product is a nuclear hormone receptor implicated in terminal differentiation of cells.
      • Medullary Thyroid Carcinomas.
        • Familial medullary thyroid carcinomas
          • occur in multiple endocrine neoplasia type 2 (MEN-2,) (MCQ)
          • associated with germline RET proto-oncogene mutations that lead to constitutive activation of the receptor. (MCQ)
        • RET mutations are also seen in approximately one half of nonfamilial (sporadic) medullary thyroid cancers.
    • Risk factors for Thyroid carcinoma
      • exposure to ionizing radiation in childhood  is risk factor to papillary (MCQ)
      • Deficiency of dietary iodine (and by extension, an association with goiter) is linked with a higher frequency of follicular carcinomas. (MCQ)
    • Papillary Carcinoma
      • most common form of thyroid cancer
      • occur most often between the ages of 25 and 50,
      • account for the majority of thyroid carcinomas associated with previous exposure to ionizing radiation. (MCQ)
      • They are are solitary or multifocal lesions.
      • lesions may contain areas of fibrosis and calcification and are often cystic. microscopic hallmarks of papillary neoplasms
      • contain branching papillae having a fibrovascular stalk covered by a single to multiple layers of cuboidal epithelial cells(MCQ)
      • ground-glass or Orphan Annie eye nuclei(MCQ)
        • the nuclei cells contain finely dispersed chromatin, which imparts an optically clear or empty appearance,
      • “pseudo-inclusions” or intranuclear grooves(MCQ)
        • invaginations of the cytoplasm may in cross-sections give the appearance of intranuclear inclusions (“pseudo-inclusions”) or intranuclear grooves.
        • diagnosis of papillary carcinoma is made based on these nuclear features, even in the absence of papillary architecture. (MCQ)
      • Psammoma bodies(MCQ)
        • Concentrically calcified structures
        • When present in fine-needle aspiration material, they are a strong indication that the lesion is a papillary carcinoma. (MCQ)
      • Foci of lymphatic invasion by tumor are often present
      • involvement of blood vessels is relatively uncommon, particularly in smaller lesions.
      • Metastases to adjacent cervical lymph nodes are estimated to occur in up to half the cases.
      • Histologic variants of papillary carcinoma
        • follicular variant (MCQ)
          • most common variant
          • most liable to misdiagnosis,
          • shows higher frequency of RAS mutations
          • more frequently encapsulated
          • has a lower incidence of lymph node metastases and extra-thyroidal extension
          • have a favorable prognosis
      • tall-cell variant
        • occur in older individuals
        • have higher frequencies of vascular invasion, extra-thyroidal extension
      • diffuse sclerosing variant
    • What is papillary microcarcinoma(MCQ)
      • conventional papillary carcinoma
      • less than 1 cm in size
      • usually confined to the thyroid gland
      • observed as an incidental finding upon surgery.
      • precursors of the usual papillary cancers.
    • Clinical Course.
      • present as asymptomatic thyroid nodules
      • first manifestation may be a mass in a cervical lymph node.
      • presence of isolated cervical nodal metastases does not seem to have a significant influence on the generally good prognosis of these lesions.
      • It is usually a single nodule, moves freely during swallowing and is not distinguishable from a benign nodule.
      • Rarely hematogenous metastases most commonly in the lung.
      • cold masses on scintiscans(MCQ)
    • Prognosis
      • have an excellent prognosis(MCQ)
      • prognosis is less favorable among
        • patients older than 40 years
        • presence of extra-thyroidal extension
        • presence of distant metastases (stage)
      • Follicular Carcinoma
        • more common in women (3 : 1)
        • present at an older age than do papillary carcinomas,
        • peak incidence between 40 and 60 years of age
        • more frequent in areas with dietary iodine deficiency (25% to 40% of thyroid cancers (MCQ)
        • Morphology
          • composed of fairly uniform cells forming small follicles containing colloid, quite reminiscent of normal thyroid
          • Hürthle cell or oncocytic variant of follicular carcinoma
            • tumors are dominated by cells with abundant granular, eosinophilic cytoplasm (MCQ)
          • Follicular lesions in which the nuclear features are typical of papillary carcinomas should be treated as papillary cancers(MCQ)
        • Clinical Course and treatment
          • present as slowly enlarging painless nodules
          • Most frequently they are cold nodules on scintigrams
          • vascular (hematogenous) dissemination is common
          • Prognosis  is largely dependent on the extent of invasion and stage at presentation.
          • Why most follicular carcinomas are treated with total thyroidectomy followed by the administration of radioactive iodine ? (MCQ)
            • Metastases are likely to take up the radioactive element, which can be used to identify and ablate such lesions.
          • Why patients are usually treated with thyroid hormone after surgery to suppress endogenous TSH.? (MCQ)
            • any residual follicular carcinoma may respond to TSH stimulation
          • Serum thyroglobulin levels are used for monitoring tumor recurrence(MCQ)
      • Anaplastic (Undifferentiated) Carcinoma
        • They are aggressive
        • mortality rate approach 100%.
        • mean age of 65 years
        • neoplastic cells express epithelial markers like cytokeratin (MCQ)
        • neoplastic cells are usually negative for markers of thyroid differentiation, like thyroglobulin. (MCQ)
        • usually present as a rapidly enlarging bulky neck mass.
        • Symptoms related to compression and invasion-  dyspnea, dysphagia, hoarseness, and cough, are common.
      • Medullary Carcinoma
      • neuroendocrine neoplasms
      • derived from the parafollicular cells, or C cells, of the thyroid
      • secrete calcitonin(MCQ)
        • calcitonin measurement plays an important role in the diagnosis and postoperative follow-up of patients.
      • About 70% of tumors arise sporadically.
      • The remainder occurs in the setting of
        • MEN syndrome 2A or 2B
        • familial medullary thyroid carcinoma, or FMTC
      • activating point mutations in the RET protooncogene play an important role in the development of both familial and sporadic medullary carcinomas. (MCQ)
      • Cases associated with MEN types 2A or 2B
        • occur in younger patients,
        • even arise during the first decade of life.
      • sporadic ,FMTC  show a peak incidence in the 40s and 50s.
      • Sporadic cases present as a solitary nodule
      • bilaterality and multicentricity are common in familial cases.
      • composed of polygonal to spindle-shaped cells, which may form nests, trabeculae, and even follicles. (MCQ)
      • Acellular amyloid deposits, derived from altered calcitonin polypeptides, are present in the adjacent stroma (MCQ)
      • As with all neuroendocrine tumors, electron microscopy reveals variable numbers of membrane-bound electron-dense granules within the cytoplasm of the neoplastic cells (MCQ)
      • Peculiar feature of familial medullary cancers is the presence of multicentric C-cell hyperplasia in the surrounding thyroid parenchyma, a feature that is usually absent in sporadic lesions.
      • Patients present with  paraneoplastic syndrome,
        • diarrhea due to the secretion of VIP
        • Cushing syndrome due to ACTH
      • Notably, hypocalcemia is not a prominent feature, despite the presence of raised calcitonin levels. (MCQ)
      • useful biomarkers  for presurgical assessment of tumor load
        • circulating calcitonin (MCQ)
        • secretion of carcinoembryonic antigen (MCQ)
      • Medullary carcinomas arising in the context of MEN-2B are generally more aggressive and metastasize more frequently (MCQ)
        • all asymptomatic MEN-2 kindred carrying germline RET mutations are offered prophylactic thyroidectomy as early as possible to protect against the inevitable development of medullary carcinomas, the major risk factor for poor outcome in these families. (MCQ)


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