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 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.
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 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.
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.
|Changes in the clinicopathological characteristics and genetic alterations of follicular thyroid cancer., Song YS,Lim JA,Min HS,Kim MJ,Choi H,Cho SW,Moon JH,Yi KH,Park DJ,Cho BY,Park YJ,, European journal of endocrinology, 2017 Sep 1 [PubMed PMID: 28864536]|
|Changes in standardized mortality rates from thyroid cancer in Korea between 1985 and 2015: Analysis of Korean national data., Choi YM,Kim WG,Kwon H,Jeon MJ,Han M,Kim TY,Shong YK,Hong SM,Hong EG,Kim WB,, Cancer, 2017 Aug 17 [PubMed PMID: 28817188]|
|Thyroid cancer incidence in Canada: a national cancer registry analysis., Topstad D,Dickinson JA,, CMAJ open, 2017 Aug 11 [PubMed PMID: 28807924]|
|Sex differences in cancer risk and survival: A Swedish cohort study., Radkiewicz C,Johansson ALV,Dickman PW,Lambe M,Edgren G,, European journal of cancer (Oxford, England : 1990), 2017 Aug 10 [PubMed PMID: 28802709]|
|Increases in Thyroid Cancer Incidence and Mortality., Davies L,Morris L,Hankey B,, JAMA, 2017 Jul 25 [PubMed PMID: 28742901]|
|The thyroid cancer epidemic, 2017 perspective., Roman BR,Morris LG,Davies L,, Current opinion in endocrinology, diabetes, and obesity, 2017 Oct [PubMed PMID: 28692457]|
|Key signaling pathways in thyroid cancer., Zaballos MA,Santisteban P,, The Journal of endocrinology, 2017 Nov [PubMed PMID: 28838947]|
|Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer., Son HY,Hwangbo Y,Yoo SK,Im SW,Yang SD,Kwak SJ,Park MS,Kwak SH,Cho SW,Ryu JS,Kim J,Jung YS,Kim TH,Kim SJ,Lee KE,Park DJ,Cho NH,Sung J,Seo JS,Lee EK,Park YJ,Kim JI,, Nature communications, 2017 Jul 13 [PubMed PMID: 28703219]|
|Papillary thyroid carcinoma: a cancer with an extremely diverse genetic background and prognosis., Lewiński A,Adamczewski Z,, Polish archives of internal medicine, 2017 Jun 30 [PubMed PMID: 28680025]|
|The Genetics of Papillary Microcarcinomas of the Thyroid: Diagnostic and Prognostic Implications., Rodrigues AC,Penna G,Rodrigues E,Castro P,Sobrinho-Simões M,Soares P,, Current genomics, 2017 Jun [PubMed PMID: 28659720]|
|Oncogenesis of Thyroid Cancer, Younis E,, Asian Pacific journal of cancer prevention : APJCP, 2017 May 1 [PubMed PMID: 28610401]|
|The Role of Central Neck Lymph Node Dissection in the Management of Papillary Thyroid Cancer., Shirley LA,Jones NB,Phay JE,, Frontiers in oncology, 2017 [PubMed PMID: 28674675]|
|[Clinical characteristics and prognosis of anaplastic thyroid carcinoma]., Wang JF,Zhu XH,Tan Z,Ge MH,, Zhonghua zhong liu za zhi [Chinese journal of oncology], 2017 Jun 23 [PubMed PMID: 28635233]|
|Primary Thyroid Carcinoma with Low-Risk Histology and Distant Metastases: Clinicopathologic and Molecular Characteristics., Xu B,Tuttle RM,Sabra MM,Ganly I,Ghossein R,, Thyroid : official journal of the American Thyroid Association, 2017 May [PubMed PMID: 28049366]|
|Clinical presentation, treatment and outcome of anaplastic thyroid carcinoma: results of a multicenter study in Germany., Wendler J,Kroiss M,Gast K,Kreissl MC,Allelein S,Lichtenauer U,Blaser R,Spitzweg C,Fassnacht M,Schott M,Führer D,Tiedje V,, European journal of endocrinology, 2016 Dec [PubMed PMID: 27926471]|
|Management of the Patient with Aggressive and Resistant Papillary Thyroid Carcinoma., Miftari R,Topçiu V,Nura A,Haxhibeqiri V,, Medical archives (Sarajevo, Bosnia and Herzegovina), 2016 Jul 27 [PubMed PMID: 27703298]|
|Patterns of metastasis in follicular thyroid carcinoma and the difference between early and delayed presentation., Parameswaran R,Shulin Hu J,Min En N,Tan WB,Yuan NK,, Annals of the Royal College of Surgeons of England, 2017 Feb [PubMed PMID: 27659362]|
|Epidemiology and Clinical Presentation of Medullary Thyroid Carcinoma., Raue F,Frank-Raue K,, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer, 2015 [PubMed PMID: 26494384]|
|Diagnostic accuracy of fine-needle aspiration cytology of thyroid gland lesions: A study of 200 cases in Himalayan belt., Sharma R,Verma N,Kaushal V,Sharma DR,Sharma D,, Journal of cancer research and therapeutics, 2017 Jul-Sep [PubMed PMID: 28862208]|
|Comparative analysis of diagnostic adequacy rate between aspiration and nonaspiration techniques of fine-needle cytology in patients with thyroid cancer and ultrasonographically suspicious cervical lymph nodes., Aydin C,Dellal FD,Tam AA,Ogmen B,Kilicarslan A,Topaloglu O,Ersoy R,Cakir B,, Diagnostic cytopathology, 2017 Aug 18 [PubMed PMID: 28834301]|
|Thyroid Cancer: Ultrasound Imaging and Fine-Needle Aspiration Biopsy., Melany M,Chen S,, Endocrinology and metabolism clinics of North America, 2017 Sep [PubMed PMID: 28760234]|
|Comparison of thyroid fine needle aspiration biopsy results before and after implementation of Bethesda classification., Ozdemir D,Bestepe N,Faki S,Kilicarslan A,Parlak O,Ersoy R,Cakir B,, Cytopathology : official journal of the British Society for Clinical Cytology, 2017 Jul 20 [PubMed PMID: 28727204]|
|Management of the lateral neck in well differentiated thyroid cancer., Cracchiolo JR,Wong RJ,, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology, 2017 Jun 22 [PubMed PMID: 28687430]|
|The Role of Central Neck Lymph Node Dissection in the Management of Papillary Thyroid Cancer., Shirley LA,Jones NB,Phay JE,, Frontiers in oncology, 2017 [PubMed PMID: 28674675]|
|Crucial parameters in thyroid carcinoma reporting - challenges, controversies, and clinical implications., Xu B,Ghossein R,, Histopathology, 2017 Aug 7 [PubMed PMID: 28782127]|
|Medullary Thyroid Cancer: Clinical Characteristics and New Insights into Therapeutic Strategies Targeting Tyrosine Kinases., Rajabi S,Hedayati M,, Molecular diagnosis & therapy, 2017 Jul 11 [PubMed PMID: 28698976]|
|Surgical management of medullary thyroid carcinoma., Konstantinidis A,Stang M,Roman SA,Sosa JA,, Updates in surgery, 2017 Jun [PubMed PMID: 28409442]|
|Minimal extrathyroidal extension does not affect survival of well-differentiated thyroid cancer., Al-Qurayshi Z,Shama MA,Randolph GW,Kandil E,, Endocrine-related cancer, 2017 May [PubMed PMID: 28249964]|
|Risk of malignancy in fine-needle aspiration biopsy in patients with thyroid nodules., Egset AV,Holm C,Larsen SR,Nielsen SH,Bach J,Helweg-Larsen JP,Larsen LV,Wanscher JH,Godballe C,, Danish medical journal, 2017 Feb [PubMed PMID: 28157060]|
|Application of the new American Thyroid Association guidelines leads to a substantial rate of completion total thyroidectomy to enable adjuvant radioactive iodine., Kluijfhout WP,Pasternak JD,Drake FT,Beninato T,Shen WT,Gosnell JE,Suh I,C L,Duh QY,, Surgery, 2017 Jan [PubMed PMID: 27855968]|
|Hürthle cell carcinoma: current perspectives., Ahmadi S,Stang M,Jiang XS,Sosa JA,, OncoTargets and therapy, 2016 [PubMed PMID: 27853381]|
|Advances and controversies in the management of medullary thyroid carcinoma., Maia AL,Wajner SM,Vargas CV,, Current opinion in oncology, 2017 Jan [PubMed PMID: 27792051]|
|The surgical approach to managing differentiated thyroid cancer., To K,Nixon IJ,, The Indian journal of medical research, 2016 Jun [PubMed PMID: 27748293]|
|Clinical significance of prophylactic central compartment neck dissection in the treatment of clinically node-negative papillary thyroid cancer patients., Gambardella C,Tartaglia E,Nunziata A,Izzo G,Siciliano G,Cavallo F,Mauriello C,Napolitano S,Thomas G,Testa D,Rossetti G,Sanguinetti A,Avenia N,Conzo G,, World journal of surgical oncology, 2016 Sep 19 [PubMed PMID: 27644091]|
|Therapeutic options in papillary thyroid carcinoma: current guidelines and future perspectives., Scott E,Learoyd D,Clifton-Bligh RJ,, Future oncology (London, England), 2016 Nov [PubMed PMID: 27387641]|
|Radioactive Iodine Treatment Is Associated with Improved Survival for Patients with Hürthle Cell Carcinoma., Jillard CL,Youngwirth L,Scheri RP,Roman S,Sosa JA,, Thyroid : official journal of the American Thyroid Association, 2016 Jul [PubMed PMID: 27150319]|
|Diagnosis and Management of Hereditary Thyroid Cancer., Bano G,Hodgson S,, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer, 2016 [PubMed PMID: 27075347]|