PAPILLARY AND FOLLICULAR THYROID CARCINOMA

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PAPILLARY AND FOLLICULAR THYROID CARCINOMA

• 95/07/07
• The New England Journal of Medicine, January 29,
  1998
• ???

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Introduction

• Papillary and follicular (differentiated) thyroid
  carcinomas are among the most curable cancers.
• However, some patients are at high risk for
  recurrent disease or even death.
• Most of these patients can be identified at the
  time of diagnosis by using well-established
  prognostic indicators.
• The extent of the initial treatment and follow-up
  care should therefore be tailored to the level of
  risk.

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EPIDEMIOLOGY

• Although thyroid nodules are common,
  differentiated thyroid carcinomas are relatively
  rare.
• Clinically detectable thyroid carcinomas
  constitute less than 1 percent of all human
  cancers.
• The annual incidence rate in various parts of the
  world ranges from 0.5 to 10 cases per 100,000
  population.
• Papillary and follicular cancers are rare in
  children and adolescents, and their incidence
  increases with age in adults.

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• The median age at diagnosis is 45 to 50 years.
• Thyroid carcinomas are two to four times as
  frequent in women as in men.
• Thyroid microcarcinomas (diameter, 1 cm) are
  found in 5 to 36 percent of adults at autopsy but
  are rare in children.
• The reported increase in the incidence of these
  small carcinomas in recent years can be
  attributed to an improvement in pathological
  techniques.

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PATHOGENESIS

• Oncogenes
• Thyroid Irradiation
• Other Factors

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Oncogenes

• Recent advances in molecular biology have
  improved our understanding of the pathogenesis of
  thyroid carcinomas.
• Rearrangements of the tyrosine kinase domains of
  the RET and TRK genes with the amino-terminal
  sequence of an unlinked gene are found in some
  papillary carcinomas.
• Activating point mutations of the RAS genes are
  found with a similarly high frequency in thyroid
  adenomas and follicular carcinomas, suggesting
  that RAS mutations represent an early event in
  thyroid tumorigenesis.

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Thyroid Irradiation

• External irradiation to the neck during childhood
  increases the risk of papillary thyroid carcinoma
• The latency period between exposure and diagnosis
  is at least five years.
• The risk is maximal at about 20 years, remains
  high for about 20 years, and then decreases
  gradually.
• The risk is increased after a mean dose to the
  thyroid as low as 10 cGy.
• At higher doses (up to 1500 cGy), there is a
  linear relation between the dose and the risk of
  carcinoma.

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• At doses higher than 1500 cGy, the risk per gray
  decreases, probably because of cell killing.
• The risk of thyroid carcinoma is not increased in
  patients given iodine-131 for diagnostic or
  therapeutic purposes.

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Other Factors

• In countries where iodine intake is adequate,
  differentiated cancers account for more than 80
  percent of all thyroid carcinomas, with the
  papillary histologic type being the more frequent
  (accounting for 60 to 80 percent of cases).
• There is no increase in the incidence of thyroid
  carcinomas in countries where iodine intake is
  low, but there is a relative increase in
  follicular and anaplastic carcinomas.

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• A high incidence of papillary carcinomas has been
  reported in patients with adenomatous polyposis
  coli and Cowdens disease (the multiple hamartoma
  syndrome).
• About 3 percent of cases of papillary carcinoma
  are familial.

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PATHOLOGICAL FEATURES

• Papillary Carcinoma
• Follicular Carcinoma

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Papillary Carcinoma

• Papillary carcinoma is an unencapsulated tumor
  with papillary and follicular structures that is
  characterized by overlapping cell nuclei that
  have a groundglass appearance and longitudinal
  grooves, with invaginations of cytoplasm into the
  nuclei.
• Encapsulated, follicular, tall-cell,
  columnar-cell, clearcell, and diffuse sclerosing
  carcinomas are recognized histologic variants
  they are classified as papillary carcinomas
  because of their characteristic nuclear features.

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• The tumor is multicentric in 20 to 80 percent of
  patients (with the wide range attributable to
  variations in the care used to examine the
  thyroid) and bilateral in about one third.
• It spreads through the lymphatics within the
  thyroid to the regional lymph nodes and, less
  frequently, to the lungs.

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Follicular Carcinoma

• Follicular carcinoma is characterized by
  follicular differentiation but without the
  nuclear changes characteristic of papillary
  carcinoma.
• Follicular carcinomas are encapsulated, and
  invasion of the capsule and vessels is the key
  feature distinguishing follicular carcinomas from
  follicular adenomas.
• Two forms are recognized according to the pattern
  of invasion minimally invasive and widely
  invasive carcinomas.

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• The growth pattern may also vary, ranging from a
  well-differentiated pattern with macrofollicular
  structures to a poorly differentiated pattern
  with areas of solid growth and a high degree of
  atypia.
• Multicentricity and lymph-node involvement are
  less frequent than in papillary carcinoma, and
  metastases to the lungs and bones stem from
  hematologic spread.

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DIAGNOSIS

• Most differentiated thyroid carcinomas present as
  asymptomatic thyroid nodules, but the first sign
  of the disease is occasionally lymph-node
  metastases or in rare cases lung or bone
  metastases.
• Hoarseness, dysphagia, cough, and dyspnea suggest
  advanced disease.
• On physical examination, the carcinoma, usually
  single, is firm, moves freely during swallowing,
  and is not distinguishable from a benign nodule.

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• Among patients with thyroid nodules, the nodule
  is more likely to be a carcinoma in children and
  adolescents, patients older than 60 years, and
  men than in women 20 to 60 years old.
• Carcinoma should be suspected if a hard,
  irregular thyroid nodule is found, ipsilateral
  lymph nodes are enlarged or compressive symptoms
  are present, and there is a history of a
  progressive increase in the size of the nodule.
• Virtually all patients with thyroid carcinoma are
  clinically euthyroid and have normal serum
  thyrotropin concentrations.

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• Whatever the presentation, fine-needle aspiration
  cytology is the best test for distinguishing
  between benign and malignant thyroid nodules.
• Provided an adequate specimen is obtained, three
  cytologic results are possible benign,
  malignant, or indeterminate (or suspicious).
• False negative results, usually from sampling or
  interpretive errors, and false positive results
  are rare.
• Only about 20 percent of patients with
  indeterminate findings have malignant nodules,
  reflecting the difficulty of differentiating
  benign follicular adenomas from their malignant
  counterparts.

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• Thyroid ultrasonography is useful for assessing
  the size of the nodule, detecting other nodules,
  and guiding fine-needle biopsy in the case of a
  nodule that is small or difficult to palpate.

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PROGNOSTIC FACTORS

• The overall survival rate at 10 years for
  middle-aged adults with thyroid carcinomas is
  about 80 to 95 percent
• Five to 20 percent of patients have local or
  regional recurrences, and 10 to 15 percent have
  distant metastases.
• The prognostic indicators of recurrent disease
  and of death are the patients age at diagnosis
  and the histologic subtype and extent of the
  tumor.

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• Figure 2.
• Survival Rate among 1701 Patients with Papillary
  or Follicular Carcinoma and No Distant Metastases
  at the Time of Diagnosis.

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INITIAL TREATMENT

• Surgery
• Iodine-131 Therapy
• External Radiotherapy

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Surgery

• The goal of surgery is to remove all tumor tissue
  in the neck.
• Therefore, the thyroid gland and affected
  cervical lymph nodes should be resected.
• Although there is still some controversy about
  the extent of thyroid surgery, there are strong
  arguments in favor of a total or near-total
  thyroidectomy (leaving no more than 2 to 3 g of
  thyroid tissue) in all patients.

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• Total or near-total thyroidectomy results in a
  lower recurrence rate than more limited
  thyroidectomy because many papillary carcinomas
  are multifocal and bilateral.
• Furthermore, removal of most, if not all, of the
  thyroid gland facilitates total ablation with
  iodine-131.
• The argument against total thyroidectomy is that
  it increases the risk of surgical complications
  such as recurrent laryngeal-nerve injuries and
  hypoparathyroidism.
• Even with total thyroidectomy, often some thyroid
  tissue remains, as detected by postoperative
  scanning with iodine-131.

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Iodine-131 Therapy

• Iodine-131 therapy is given postoperatively for
  three reasons.
• First, it destroys any remaining normal thyroid
  tissue, thereby increasing the sensitivity of
  subsequent iodine-131 total-body scanning and the
  specificity of measurements of serum
  thyroglobulin for the detection of persistent or
  recurrent disease.
• Second, iodine-131 therapy may destroy occult
  microscopic carcinoma, thereby decreasing the
  longterm risk of recurrent disease.

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• Third, the use of a large amount of iodine-131
  for therapy permits postablative iodine-131
  total-body scanning, a sensitive test for
  detecting persistent carcinoma.
• Postoperative iodine-131 therapy should be used
  selectively.
• In low-risk patients, the longterm prognosis
  after surgery alone is so favorable that
  iodine-131 ablation is not usually recommended.
• However, all patients who are at high risk for
  recurrent disease should be treated with
  iodine-131, because it decreases both recurrence
  and death rates.

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• Iodine-131 scanning is performed four to six
  weeks after surgery, with no thyroid hormone
  treatment given in the interim.
• At our center, we use a dose of 2 mCi (74 MBq) of
  iodine-131 and obtain a total-body scan three
  days later.
• If any iodine-131 uptake is detected in the
  thyroid bed or elsewhere, a treatment dose is
  given.
• Another total-body scan is obtained four to seven
  days later, and thyroxine therapy is initiated.
• Total ablation is verified by performing
  iodine-131 total-body scanning 6 to 12 months
  later with 2 mCi.

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External Radiotherapy

• External radiotherapy to the neck and mediastinum
  is indicated only in patients in whom surgical
  excision is incomplete or impossible and the
  tumor tissue does not take up iodine-131.

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FOLLOW-UP

• The goals of follow-up after initial therapy are
  to maintain adequate thyroxine therapy and to
  detect persistent or recurrent thyroid carcinoma.
  
• Recurrences are usually detected during the early
  years of follow-up, but may be detected later.
• Therefore, follow-up is necessary throughout the
  patients life.

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Thyroxine Treatment

• The growth of thyroid-tumor cells is controlled
  by thyrotropin, and the inhibition of thyrotropin
  secretion with thyroxine improves the recurrence
  and survival rates.
• Therefore, thyroxine, in the form of
  levothyroxine sodium, should be given to all
  patients with thyroid carcinoma, whatever the
  extent of thyroid surgery and other treatment.
• The effective dose in adults is between 2.2 and
  2.8 ug per kilogram of body weight children
  require higher doses.

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• The adequacy of therapy is monitored by measuring
  serum thyrotropin three months after treatment is
  begun, the initial goal being a serum thyrotropin
  concentration of 0.1 u U per milliliter or less
  and a serum free triiodothyronine concentration
  within the normal range.

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Clinical and Ultrasonographic Examinations

• Palpation of the thyroid bed and lymph-node areas
  should be performed routinely.
• Ultrasonography is performed in patients at high
  risk for recurrent disease and in any patient
  with suspicious clinical findings.
• Palpable lymph nodes that are small, thin, or
  oval or that are reduced in size after an
  interval of three months are considered benign.

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• Serum thyroglobulin concentrations are
  undetectable in 20 percent of patients receiving
  thyroxine treatment who have isolated lymph-node
  metastases, and therefore, undetectable values do
  not rule out metastatic lymph-node disease.
• If there is a question of metastasis, an
  ultrasonographically guided lymph-node biopsy may
  be performed.

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Chest Radiography

• Chest radiography is no longer routinely
  performed in patients with undetectable serum
  thyroglobulin concentrations.
• The reason is that virtually all patients with
  abnormal radiographs have detectable serum
  thyroglobulin concentrations.

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Serum Thyroglobulin Measurements

• Thyroglobulin is a glycoprotein that is produced
  only by normal or neoplastic thyroid follicular
  cells.
• It should not be detectable in patients who have
  undergone total thyroid ablation, and its
  detection in such patients signifies the presence
  of persistent or recurrent disease.

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• The production of thyroglobulin by both normal
  and neoplastic thyroid tissue is in part
  dependent on thyrotropin.
• Thus, when interpreting the serum thyroglobulin
  value, one should take into account the serum
  thyrotropin value, as well as the presence or
  absence of thyroid remnants .
• If the serum thyroglobulin concentration is
  detectable during thyroxine treatment, it will
  increase after the treatment has been withdrawn.
• The serum thyroglobulin concentration is an
  excellent prognostic indicator.

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Iodine-131 Total-Body Scanning

• The results of iodine-131 total-body scanning
  depend on the ability of thyroid-cancer tissue to
  take up iodine-131 in the presence of high serum
  thyrotropin concentrations, which are achieved by
  withdrawing thyroxine for four to six weeks.

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CONCLUSIONS

• Most patients with papillary or follicular
  carcinomas can be cured.
• However, both the initial treatment and follow-up
  should be individualized according to prognostic
  indicators and any subsequent evidence of
  disease.

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The End

• Thank you for your attention.