Cancer, Thyroid


Article Author:
Kenny Lee


Article Editor:
Sebastiano Cassaro


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
12/22/2018 10:18:27 AM

Introduction

Thyroid malignancies, after proper workup and diagnosis, can be separated into three rough categories:

  1. Differentiated thyroid carcinoma, including papillary, follicular, and Hürthle cell cancers, arises from follicular cells of the thyroid and accounts for 90-95% of all thyroid malignancies.
  2. Medullary thyroid carcinoma, arises from parafollicular cells and accounts for another 6%.
  3. Anaplastic thyroid carcinoma accounts for less than 1% of thyroid malignancies.

Etiology

As with other tumors, the role of oncogenes and tumor-suppressor genes in thyroid cancer cannot be overstated, and transformation of a proto-oncogene to an oncogene or loss of a tumor suppressor gene is often the key step toward the initial malignant transformation. A point mutation in the BRAF gene is associated with up to 40% of cases of papillary thyroid cancer and often associated with anaplastic thyroid cancer. RET, another proto-oncogene, was activated in nearly 60% to 70% of papillary thyroid cancer occurring after irradiation. Inactivating mutation of the p53 tumor suppressor gene is common in patients with anaplastic thyroid carcinoma.

Thyroid cancer, as compared with other types of malignancies, is more closely associated with irradiation. Patients exposed during childhood have a much higher risk of developing thyroid carcinoma, and this risk is further compounded by higher dosages of radiation, up to 1500 cGy due to thyroid cell killing at even higher dosages.

Epidemiology

Thyroid cancer remains a rare malignancy, representing 1% to 4% of all malignancies in the United States. Chances of diagnosis have risen over the past several decades due to improved diagnostic modality and increased use of thyroid ultrasound, and death rates have remained stable. It is the fifth most common malignancy for females, with females having a 2 to 3 times greater chance of being diagnosed with thyroid cancer compared with males. As was mentioned earlier, most thyroid cancers are derived from the follicular epithelium, with cases of papillary thyroid carcinoma(PTC) and follicular thyroid carcinoma (FTC) far more common than anaplastic thyroid cancer (ATC).

Histopathology

The cytology and histopathology of PTC are unique in their roles in the diagnosis of the malignancy. Well-recognized cellular histomorphology of PTC include ample papillar projections and the so-called psammoma bodies, which are calcified clumps of cells likely derived from necrosed papillas. Also paramount to a diagnosis is findings of intranuclear inclusion bodies and nuclear grooving in individual cells, with the nuclei often described as large, clear, ground glass, or "Orphan Annie"-eyed.

FTC, as another member of follicular cell malignancies, can represent a much wider range of morphologic variability. Diagnosis of FTC is dependent on abnormal positioning and spread of thyroid follicles, including extracapsular and vascular invasions. Nuclear atypia itself may or may not be present, although it does indicate a worse prognosis when present. Given that individual cellular morphology is insufficient for FTC diagnosis, a fine-needle aspiration (FNA) biopsy cannot be used to fully diagnose FTC. 

Medullary thyroid carcinoma (MTC) originates from the parafollicular C cells. Given its origin, its histologic diagnosis and later prognosis can be demonstrated by the presence of amyloid deposition and calcitonin immunoreactivity in the sample.

ATC can be differentiated from the others because of its extremely poor prognosis, including a poorly differentiated histology portending a more grim outcome. Often, multinucleated giant cells with intranuclear invagination can be observed microscopically.

History and Physical

Most commonly, patients first present with a neck mass, which may represent a primary tumor or metastatic lymphadenopathy. Other times, the mass may be nonpalpable and found incidentally on neck imaging. For patients with a family history of thyroid malignancies, the RET oncogene or MEN2 elective early thyroidectomy may result in findings of early malignancies that are only observable through the microscope.

A thorough history and physical, unfortunately, is rarely sufficient for the diagnosis of thyroid malignancy, and its diagnosis is contingent on cytologic or histologic findings on biopsy. Nevertheless, findings in the history and physical can help guide the skilled physician toward later necessary workups.  Features such as childhood radiation to the head and neck, iodine deficiency in endemic areas, and a well-documented family history of thyroid malignancies should spark immediate concerns. Evolution of symptoms such as rapid growth of a thyroid nodule over weeks and months, development and worsening of dysphagia and breathing, and systemic symptoms such as weight loss and fatigue should be queried. Physical examination should include a thorough study of the neck and regional nodes for possible firmness, irregularities, and adherence to the underlying tissue of the dominant nodule.

Evaluation

A thyroid function test for patients presenting for possible malignancies is appropriate, as a hyperthyroid state often correlates with a lower risk of malignancy. 

Evaluation of the thyroid nodule for malignancy should begin with a diagnostic ultrasound, which has become popular both in the clinic and in the operating room due to its ease-of-use, portability, and cost-effectiveness. A diagnostic ultrasound should begin by identifying features suspicious for malignancy, such as microcalcifications, hypoechoic interiors, an ill-defined margin, nodularity, greater height than width, or vascular flows that are often chaotically arranged. On the other spectrum, a purely cystic nodule usually can be safely classified as benign. Taking into account the risk of malignancy in addition to the size of the nodule, the physician may proceed with an FNA biopsy of the nodule using small, 23-27 gauge, needles. In general, all moderate-to-high risk nodules greater than 1 cm should be biopsied, whereas a low-risk nodule may be safely observed until it is 2cm or larger.

It is relevant that, although a diagnostic ultrasound can be used to assess the anatomic characteristic of a nodule, a radioisotope scan can be used to assess the functional characteristic of a thyroid nodule, when the patient has previously suppressed TSH. As with thyroid function tests, a hyperfunctioning "hot" nodule demonstrating avid uptake of radioisotope is rarely associated with malignancy, whereas malignancy may be expected in 15% to 20% of "cold" nodules.  

An FNA biopsy may be performed with or without ultrasound guidance, although non-palpable or posteriorly-placed lesions should be biopsied under guidance to increase the diagnostic accuracy of the sample. The FNA biopsy result is then reported by on the Bethesda Criteria for Reporting Thyroid Cytology, which stratifies the result of the biopsy based on cytology and recommended course of action. It cannot be overemphasized that FNA allows for analysis of individual cellular feature and not the overall architecture of the nodule. As such, while FNA is excellent for diagnosis of PTC, the most common thyroid malignancy, it cannot detect capsular or vascular invasions by FTC with discrete cytologic characteristics. As a result, while FNA can categorize certain findings as suspicious for FTC, a diagnosis of FTC cannot be made until the final pathology is confirmed. 

While CT and MRI are not routinely used in the evaluation of thyroid nodules for malignancies, their use may be appropriate in assessing for local spread in more advanced diseases or those with enlarged cervical nodes in association with a suspcious mass. For patients with thyroid mass with extension into the substernal region confirmed by ultrasound or plain radiographs, a CT would be advised. Also of concern regarding CT with iodinated contrast is its use on hyperthyroid patients, which has the potential to trigger an uncontrolled life-threatening thyroid storm. Note the use of iodinated contrast for patients scheduled to undergo future radioactive iodine (RAI) ablation as sufficient depletion of iodine is required for therapeutic RAI ablation of thyroid malignancies. 

Treatment / Management

Surgical resection of differentiated thyroid cancer, including both PTC and FTC, remains the mainstay of treatment in association with RAI ablation and TSH suppression. Radiation and systemic chemotherapy seldom play a significant role in treatment, although they may be used in advanced cases refractory to conventional methods. The decision to use any one or all three modalities is one that should involve the physician and the patient regarding the goal of care, future prognosis, risks of recurrences, ease of surveillance, and the relative costs and morbidities involved with each method. 

Appropriate surgical resection of thyroid malignancies can range from hemithyroidectomy/thyroid lobectomy to total thyroidectomy, with or without lymph node dissection. For indeterminate nodules or smaller unilateral thyroid cancers without evidence of metastasis, sometimes a lobectomy may suffice, with the advantages of preservation of viable thyroid tissues and contralateral parathyroids and nerves. However, there is the potential for subsequent completion thyroidectomy, which is a decision the physician should explore with the patient. Traditional guidelines favor total thyroidectomy for lesions greater than 1cm, because of the multiple foci often present in PTC and also to facilitate RAI ablation and future surveillance with Tg marker. However, the current trend has been toward more careful patient selection in total thyroidectomy as more recent studies have called into question the mortality benefits associated with total thyroidectomy. Some well-supported indications for total thyroidectomy include DTC larger than 4cm, those with extrathyroidal extensions, and those with local or distant metastasis. For DTCs smaller than 1cm, there is no clear surgical indication for resection unless there exist significant cervical lymph nodes, extrathyroidal extensions, or a notable family history of thyroid CA or clinical history of irradiation.

The decision for lymph node dissection should be made on a patient-by-patient basis, and there remain controversies about the proven survival benefit for prophylactic node dissection. Regardless, all patients with proven or suspected PTC should undergo a thorough examination of both the central and lateral neck for possible nodal metastasis. While the lateral neck can be easily accessible via ultrasound pre-operatively, the central neck and its compartment nodes are more difficult to assess as they lie in a more anatomically challenging position. As such, careful inspection and palpation of the central neck should be performed at the time of surgery, with subsequent compartmental neck dissection should abnormal nodes be found. Again, the role of prophylactic neck dissection in the absence of nodal metastasis is uncertain, and while proponents of routine prophylactic central compartment dissection will point to lower recurrence risk in their patient, other studies show higher risk of nerve injuries and hypocalcemia without an improvement in survival benefits. The lateral neck compartments, as they are not routinely entered in thyroidectomy, should be assessed pre-operatively with ultrasound and subsequent FNA biopsy if there is a concern for abnormal nodes. If pathologic nodes are confirmed, an ipsilateral neck dissection should be carried out, with a formal clearance of defined lymph node compartments as opposed to isolated "berry-picking" of diseased nodes.

Radioactive Iodine(RAI) therapy, as a mainstay of treatment, functions to ablate remaining thyroid tissues for improved future surveillance of recurrence and as adjuvant therapy for detected or occult metastasis. As mentioned, RAI should be a routine recommendation for patients with grossly extrathyroidal spread or distant metastasis with clear benefits toward survival benefits and recurrence risks. Patients with high-risk malignancies, including those with larger than 4cm PTCs, microscopic extrathyroidal extension, or nodal metastasis, should also be offered RAI therapy. PTCs smaller than 4cm or without evidence of nodal, local, or regional metastasis are not routinely given RAI therapy. Patients who are candidates for RAI therapy should maintain a low iodine diet for 1 to 2 weeks to ensure iodine depletion of the cells and be cautioned against large iodine administrations such as through iodinated contrast or amiodarone to improve the avidity to iodine uptakes of the cells. Equally important is the association iodine uptake has with high TSH level, with a goal of 30mIU/liter.  This level of TSH can be achieved either through withdrawal of thyroid hormones or administration of exogenous recombinant human TSH.  

TSH suppression, as the last element in general treatment of DTCs, is successful because TSH receptors continue to be expressed in DTCs, and TSH has been found to be growth factors in DTCs. A high dosage of exogenous thyroid hormone usually is given, although there must exist a careful balance between the risk of malignancy versus the multiple adverse effects caused by hyperthyroidism, including possible atrial fibrillation. In patients with high-risk malignancies, the goal TSH should be no more than .1mIU/liter, and in patients with intermediate risks, the goal TSH should be between .1-.5mIU/liter. Those with low risk may have TSH in the lower reference range, between .5-2.0mIU/liter. 

With regards to the treatment of MTC, genetic testing for germline RET mutation is also recommended prior to treatment. When there is a concern for MTC, serum calcitonin, carcinoembryonic antigen, and biochemical testing for the presence of coexisting hyperparathyroidism and pheochromocytoma are all standard facets of treatment. Serum catecholamine especially must be obtained, as the presence of pheochromocytoma must be confirmed or excluded before treatment of the MTC.  

In general, total thyroidectomy is the standard of care for patients with MTC with resection of local and regional metastases. A PTC should be performed prior to the age of 1 in patients with confirmed MEN2B RET mutation, and patients with other RET germline mutation should receive PTC before the age of 5. In patients with confirmed MTC, prophylactic level VI nodal dissection should be performed at the time of the total thyroidectomy, with bilateral level VI dissection if there is confirmed central neck metastases. Patients with confirmed lateral zone nodal metastases should receive lateral compartment dissection, central neck dissection, and total thyroidectomy. Patients with confirmed distant metastases, however, may be advised to undergo a less aggressive approach due to the extensive risk of morbidity involved in surgery, and mostly palliative surgical options should be considered if there is concomitant neck pain or dysphagia. Of note, as MTC is not of follicular origin, there is no role for radioactive iodine ablation or TSH suppression in the management of MTCs.

There is little to no role for surgery in the treatment of ATC.  Distant metastases are common in patients with initial diagnosis due to its rapidly progressive course, and local invasion into the trachea or vasculature commonly makes the malignancy unresectable. Mortality approaches near 100% for ATCs. A conservative surgical approach for palliation should be considered in these patients. 


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Cancer, Thyroid - Questions

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A 35-year-old female presented to her primary care provider regarding results of a fine-needle aspiration she received two weeks before for a neck nodule. She was informed the pathology reveals the most common type of thyroid cancer. Which of the following is a hallmark of the pathology for this cancer?



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A 45-year-old female underwent total thyroidectomy for follicular thyroid carcinoma and was admitted for observation. The same night patient endorsed tingling and fasciculation of her jaws. What is the complication as a result of her surgery?



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Fine needle aspiration was performed on a 42-year-old female with an isolated hard thyroid nodule. Pathology was able to confirm the diagnosis. Which is true?



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A patient was found to have irregular, necrotic appearing lesion of the thyroid that acutely appeared in the last 3 months. Fine needle aspiration confirmed the likely diagnosis. What are the treatment options available for this patient?



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A 43-year-old patient undergoes fine needle aspiration (FNA) of an incidentally found thyroid nodule. What is true regarding the pathology obtained via the fine needle aspiration?



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An investigator is planning to use a commercially available complementary DNA (cDNA) microarray to investigate the expression of known differentiation markers in thyroid cancer. Surgical biopsy specimens of cancer are obtained, messenger RNA (mRNA) is extracted, and cDNA is generated, fluorescently labeled, and hybridized to the microarray. Subsequently, the microarray is scanned, intensity values are measured, and statistical analysis is performed. What must the investigator do in order to make sense of this data?



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A patient presents with a gradually enlarging throat lump and back pain. The patient subsequently found to have lesions of the bone, likely metastasis, related to a thyroid malignancy found during workup. What is the likely malignancy, and what is the 5-year survival rate for this patient?



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A patient presented after total thyroidectomy for follicular thyroid carcinoma. What is a postoperative medical treatment for and what is a potential side-effect of this treatment?



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What is the most common type of thyroid malignancy?



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Fine needle aspiration was unable to fully establish the diagnosis for a thyroid nodule found on examination. Thyroid lobectomy is to be performed. What is the most likely thyroid malignancy should the pathology comes back positive for cancer and what is the next step?



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A 40-year-old African male with a history of smoking presented with a neck mass. Subsequent fine-needle aspiration was positive for papillary thyroid carcinoma. What is the leading risk factor for the development of this tumor?



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An adolescent is diagnosed with papillary thyroid carcinoma. How does the cancer spread, and where is the most likely location of distant metastasis?



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A 36-year old female presents with a 2-month history of a right-sided neck mass. She initially thought that this was related to her respiratory tract infection and thought nothing of it. She says she is now worried, as the mass has not disappeared. She has no other symptoms. On exam, there is a 4 cm mass on the right side of the neck just below the thyroid cartilage. The nodule appears fixed to the surrounding tissues and appears to move with the act of swallowing. She denies a family history of cancer. The nuclear scan reveals a cold nodule and the fine needle aspiration reveals atypical cells. Which of the following statements is true regarding this lesion?



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A 28-year-old female presents with a 3-month history of a right-sided neck mass. On exam, there is a 3 cm mass on the right side of the neck just below the thyroid cartilage. The nodule appears fixed to the surrounding tissues and appears to move with the act of swallowing. A fine-needle aspiration reveals atypical cells with remnants of dead papillae. The nuclear scan suggests a cold nodule. What is one factor that has shown to decrease the risk of this lesion?



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A patient presents with nodular swelling of the neck. Fine needle aspiration was performed of the nodule, and pathology returned showing "psammoma bodies" and intranuclear bodies which the pathologist described as "Orphan Annie"-eyed. Given this pathology and resultant diagnosis, the patient was most likely exposed to which of the following risk factor at a young age?



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An 18-year-old male presents with the sudden appearance of a neck mass in the last several months. Two months ago his primary care provider prescribed hydrochlorothiazide and amlodipine for resistant hypertension. His blood pressure today is 150/90 mmHg despite being compliant on the medication. He also reports symptoms including diaphoresis, palpitations, itching of the skin, and diarrhea. The patient has a family history of neck tumors. From what cell does the neck mass most likely originate?



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A 45-year-old woman was taken to the operating theater for a total thyroidectomy. In the process of dissection, a nerve coursing inferolateral to the thyroid, before diving down to the thyroid, was inadvertently transected. What nerve was injured, and what are the expected deficits for the patient?



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A patient came in after she noticed a new lump in her neck. The patient was unaware of the lump until just a few days ago. After physically examining the patient, the provider decided to further investigate the lump using ultrasound. Which of the following characteristic findings would most incentivize the provider to do a fine-needle aspiration of the lesion?



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A patient presenting days prior with complaints of neck pain and trouble swallowing was found to have a large 5 cm thyroid mass localized mostly to the right thyroid lobe on computed tomography scan. There appeared to be palpable nodes in the left neck as well. Which of the following is the most appropriate treatment for this patient?



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Cancer, Thyroid - References

References

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