Thyroid malignancies, after proper workup and diagnosis, can be separated into three rough categories:
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.
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).
The cytology and histopathology of papillary thyroid carcinoma 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 papillae. 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.
Follicular thyroid carcinoma, 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 diagnose FTC fully.
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.
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.
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 a small, 23 to 27 gauge, needles. In general, all moderate-to-high risk nodules greater than 1 cm should undergo biopsy, whereas a low-risk nodule may only require observation 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 the expectation 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 routine modalities 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 suspicious 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 necessary for therapeutic RAI ablation of thyroid malignancies.
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 0.5 to 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.
Staging for Thyroid Cancer most commonly uses the American Joint Committee on Cancer (AJCC) TNM (Tumor, Node, Metastasis) classification system, as endorsed by the American Thyroid Association, given their predictive values in prognosis and mortality. The system accounts for such factors such as the size of the tumor, presence, and extent of extra-thyroidal invasion, the number of nodal metastasis, and whether there is the presence of distal metastasis. As previously noted, age is a significant factor in predicting mortality in thyroid cancer patients, and its role is also significant in staging the disease. Patients under 55 years old at the time of diagnosis will receive a stage II diagnosis at the most.
Prognosis for thyroid cancer can vary greatly, depending on its type, size, patient's age, and amenability to resection. In general, the prognosis is good, with up to 95% 5-year survival rate for patients across all ages and races, with worse prognosis given to patient's based on the size of the tumor, the presence of extra-thyroidal extensions or metastasis, older age, or unfavorable tumor types such as undifferentiated cancer.
Left alone, thyroid cancer can be locally invasive, into the airway, esophagus, or other nearby neurovascular structures. Distant metastasis most commonly involves the lung, bone, and other soft tissue structures.
Both thyroid lobectomy and total thyroidectomy resections carry the potential for neurovascular injuries, with the most common involving the recurrent laryngeal nerve, leading to hoarseness of voice and potential respiratory failure with bilateral injuries.
There is no regular screening currently recommended for patients. Risk factors, such as prior radiation and family history as previously discussed, should heighten the provider's concern for malignancy, especially when in combination with the presence of rapidly enlarging nodule, nearby lymphadenopathy, or hoarseness.
Optimal outcome for the patient is contingent on an interprofessional, interprofessional team well with physicians and mid-level providers versed in endocrinology, surgery, radiology, and oncology. Nursing staff should assist in making sure the patient is involved in every step of their care, including pre-operative planning, to create a strategy that can accommodate the patient's current quality of life while promoting optimal prognosis. Therapies such as total thyroidectomy should be discussed in conjunction with the expectation for likely RAI therapy postoperatively, with continued lifelong surveillance and TSH monitoring.
|||Khatami F,Tavangar SM, A Review of Driver Genetic Alterations in Thyroid Cancers. Iranian journal of pathology. 2018 Spring [PubMed PMID: 30697281]|
|||Martínez JRW,Vargas-Salas S,Gamboa SU,Muñoz E,Domínguez JM,León A,Droppelmann N,Solar A,Zafereo M,Holsinger FC,González HE, The Combination of RET, BRAF and Demographic Data Identifies Subsets of Patients with Aggressive Papillary Thyroid Cancer. Hormones & cancer. 2019 Jun [PubMed PMID: 30903583]|
|||Zarkesh M,Zadeh-Vakili A,Akbarzadeh M,Nozhat Z,Fanaei SA,Hedayati M,Azizi F, BRAF V600E mutation and microRNAs are helpful in distinguishing papillary thyroid malignant lesions: Tissues and fine needle aspiration cytology cases. Life sciences. 2019 Apr 15 [PubMed PMID: 30890403]|
|||Pancer J,Mitmaker E,Ajise O,Tabah R,How J, A thyroid gland with over 30 foci of papillary thyroid carcinoma with activating BRAF V600E mutation. Endocrinology, diabetes & metabolism case reports. 2019 Mar 18 [PubMed PMID: 30884463]|
|||Echanique KA,Govindan A,Mohamed OM,Sylvester M,Baredes S,Yu-Lan Ying M,Kalyoussef E, Age-Related Trends of Patients Undergoing Thyroidectomy: Analysis of US Inpatient Data from 2005 to 2013. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2019 Mar [PubMed PMID: 30829140]|
|||Means C,Clayburgh DR,Maloney L,Sauer D,Taylor MH,Shindo ML,Coussens LM,Tsujikawa T, Tumor immune microenvironment characteristics of papillary thyroid carcinoma are associated with histopathological aggressiveness and BRAF mutation status. Head & neck. 2019 Aug [PubMed PMID: 30896061]|
|||[PubMed PMID: 30704165]|
|||[PubMed PMID: 30899725]|
|||[PubMed PMID: 30353424]|
|||[PubMed PMID: 30874735]|
|||[PubMed PMID: 29663333]|