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In part 2, we address risk assessment and staging, findings that suggest the presence of aggressive tumors, recurrent/metastatic disease, and treatment with chemotherapy and external-beam radiotherapy. Experimental treatments utilizing molecular targets, redifferentiation agents, and gene therapy are covered briefly as well.
Most thyroid cancers are slow-growing, easily treatable tumors with an excellent prognosis after surgical resection and targeted medical therapy. Unfortunately, 10% to 15% of thyroid cancers exhibit aggressive behavior and do not follow an indolent course. Approximately one-third of patients with differentiated thyroid cancers will have tumor recurrences. Distant metastases are present in about 20% of patients with recurrent cancer. Approximately half of patients with distant metastases die within 5 years. The loss of the ability to concentrate radioiodine and produce thyroglobulin is a sign of dedifferentiation, which occurs in about 30% of patients with persistent or recurrent thyroid cancer. Dedifferentiation is associated with poorer responses to conventional therapy and difficulty monitoring tumor burden. Clinicians must identify tumors with more aggressive biology and treat them accordingly with more aggressive regimens. Part 1 of this two-part article, which appeared in March, described in detail the distinct types of thyroid cancer, as well as risk factors, outcomes, treatment, and prognostic factors, with a focus on thyroid cancers of follicular cell origin. Part 2 covers risk assessment and staging, findings that suggest the presence of aggressive tumors, recurrent/metastatic disease, and treatment with chemotherapy and external-beam radiotherapy. Experimental treatments utilizing molecular targets, redifferentiation agents, and gene therapy are covered briefly as well.
As we noted in the March issue of ONCOLOGY, most thyroid cancers are slow-growing, easily treatable tumors with an excellent prognosis after surgical resection and targeted medical therapy. Unfortunately, 10% to 15% of thyroid cancers exhibit aggressive behavior and do not follow an indolent course. Clinicians must identify tumors with more aggressive biology and treat them accordingly with more aggressive regimens. Part 1 of this review explored the distinct types of thyroid cancer, as well as risk factors, outcomes, treatment, and prognostic factors, with a focus on thyroid cancers of follicular cell origin. In part 2, we address risk assessment and staging, findings that suggest the presence of aggressive tumors, recurrent/metastatic disease, and treatment with chemotherapy and external-beam radiotherapy. Experimental treatments utilizing molecular targets, redifferentiation agents, and gene therapy are covered briefly as well.
Patients can be staged or stratified into high- and low-risk groups based on several systems for assessing clinical risk. A comprehensive review of all the clinical staging systems for thyroid cancer is beyond the scope of this article, yet they will be briefly described.
The most widely used staging system is the TNM system found in the 6th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. Age, tumor size, nodal status, and presence of distant metastases are the four components of this system.
In the AJCC system, tumors smaller than or equal to 2 cm in greatest dimension are classified as T1. Tumors greater than 2 cm but less than or equal to 4 cm in size are classified as T2. Tumors larger than 4 cm or with minimal extrathyroidal extension are classified as T3. Any tumor that extends beyond the thyroid capsule to invade local structures such as the larynx, trachea, esophagus, recurrent nerve, or the subcutaneous soft tissues is classified as T4a. Tumors that invade the prevertebral fascia or encase the carotid or mediastinal vessels are classified as T4b. Regional nodal metastases are described as either N1a or N1b. The 1a designation signifies the presence of central neck (level VI) metastases only. N1b signifies nodal metastases to the lateral neck (levels II, III, IV, or V) or mediastinum (level VII). The presence or absence of distant metastases is classified as either M1 or M0, respectively.
There are three different stage groupings based on the type of thyroid cancer: PTC, FTC, and HCC are considered together and have the same staging; but MTC and ATC have distinct staging systems. For PTC, FTC, and HCC, persons less than 45 years old are staged based only on the presence (stage II) or absence (stage I) of metastases. This is reflective of the more favorable prognosis for younger patients. Patients 45 years or older with PTC, FTC, or HCC, and patients of any age with MTC are staged the same, based on tumor size, nodal status, and presence of metastases. All ATCs are automatically considered T4 and stage IV tumors.
Thyroid cancer patients can be separated into high- and low-risk groups based on any of several postoperative risk classification systems. In the late 1980s, two widely used postoperative clinical risk classification systems for thyroid cancer were introduced: AGES and AMES. Patient age, tumor grade, extent, and tumor size are the components of the AGES system developed by investigators at the Mayo Clinic. Age, metastases, extent, and tumor size are the components of the AMES system developed by investigators at the Lahey Clinic. Distant metastases, patient age, completeness of resection, local invasion, and tumor size are the components of the MACIS system. The MACIS system evolved from the AGES system, in part because of the interobserver variability associated with thyroid tumor grading and the importance of completeness of resection. The European Organisation for Research and Treatment of Cancer classification system takes into account gender, histology, extrathyroidal invasion, and metastases.
Most systems have a scoring formula that assigns points to the different variables, and patients are then stratified into risk groups. Regardless of the risk classification system used, the risk of death is about 5% in low-risk patients and about 40% in high-risk patients. Each of the staging strategies places about 70% to 85% of patients into low-risk groups.[5,6]
Although FNA biopsy is highly sensitive and specific for PTC, the various histologic subtypes of papillary thyroid cancer are probably not discernable by FNA. A diagnosis of follicular carcinoma cannot reliably be made by cytologic features alone because demonstration of vascular or capsular invasion is required. Therefore, FNA alone cannot be used to distinguish benign follicular or Hrthle cell neoplasms from follicular cancers. These lesions require surgical resection in order to make the diagnosis of cancer. Poorly differentiated or insular carcinomas are distinguished from anaplastic cancers by their cytologic features of a highly cellular aspirate with monomorphic cells. Insular carcinoma frequently resembles medullary thyroid cancer on FNA, but unlike medullary carcinoma, staining is negative for calcitonin and positive for thyroglobulin. Findings in anaplastic or undifferentiated cancers usually show the FNA specimen to be very cellular with necrosis, inflammation, and cellular pleomorphism revealing bizarre, giant, or multinucleated cells.
During thyroidectomy, findings of local invasion or regional nodal metastases warrant a more aggressive resection. Primary tumors adherent to the overlying strap muscles or underlying trachea may necessitate segmental resection of these structures. Under no circumstances, however, should the recurrent laryngeal nerve be segmentally resected. Blood supply to the parathyroid glands must be preserved. Any devascularized parathyroid glands must be reimplanted. The need for extended resection of adjacent structures should be tempered by the requirement to provide tumor clearance without significant morbidity.
The finding of nodal metastases in the central or lateral neck mandates appropriate nodal clearance in these compartments. We recommend close inspection of the central compartment and lateral compartment nodes with excisional biopsy of suspicious nodes for frozen section. If frozen section confirms metastatic disease, then a formal compartmental dissection should be performed.
Central neck dissection requires removal of all nodal tissue between the trachea and carotid sheath and from the thoracic inlet to the hyoid bone. The recurrent laryngeal nerve and blood supply to the parathyroid glands are preserved. The superior mediastinum is cleared by removing nodes down to the innominate vein, usually in conjunction with cervical thymectomy. Pretracheal nodal tissue is also removed from the midline.
Radical neck dissection, which may be used for other head and neck malignancies, should not be performed for thyroid cancer. During radical neck dissection the sternocleidomastoid muscle, spinal accessory nerve, and internal jugular vein are resected. Although tumor clearance is excellent, this operation is associated with a poor cosmetic and functional result. Furthermore, radical neck dissection for thyroid cancer is unnecessary because the nodal metastases from thyroid cancers do not usually invade these adjacent structures. Local disease control and cure are no better with radical neck dissection than that seen with the less morbid "functional" or modified radical neck dissection.[8-10] In functional neck dissection an en bloc resection of the fibrofatty tissue and lymphatic network of the lateral neck is performed. The sternocleidomastoid muscle and spinal accessory nerve are preserved. In the absence of direct invasion, the internal jugular vein can be preserved. When directly involved, one jugular vein may be sacrificed without concern.
Anaplastic cancers do not respect the normal cervical tissue planes like other thyroid cancers. If during thyroidectomy the tumor is found to have extensive invasion into or through the normal tissue planes of the central or lateral neck, a diagnosis of anaplastic cancer should be entertained and frozen section biopsy should be performed. In most cases, complete surgical resection of ATC is not possible, in which case airway preservation should be the primary goal.
During the postoperative period the clinician should be cognizant of the signs that herald more aggressive tumor biology. Metastases found on physical exam, radiologic exam, or radioiodine scan usually upstage the cancer, and portend a worse prognosis. Furthermore, persistently elevated thyroglobulin after surgery and/or radioiodine suggests residual tumor burden or residual functioning thyroid tissue. When thyroglobulin is elevated due to tumor burden, it may be due to residual primary tumor, locoregional disease, or nodal or distant metastases. It should be noted that thyroglobulin is reliable as a tumor marker only in the absence of circulating antithyroglobulin antibodies, and is not a sensitive tumor marker when functioning (nonablated) thyroid tissue is left in situ. Poorly differentiated tumors may not concentrate radioiodine despite low iodine stores and elevated TSH. Alternative strategies must be employed for surveillance and treatment when radioiodine avidity is lost or when thyroglobulin is not a valid tumor marker.
The methods of long-term follow-up include surveillance with physical exam, measurement of thyroglobulin as a tumor marker, and radiographic surveillance with ultrasound and/or radioiodine scanning. When any of these surveillance measures identifies a suspicious lesion, further measures are taken to thoroughly examine for local recurrence or metastases. For example, when lymphadenopathy is identified on physical exam, it should be evaluated by a complete ultrasound of the neck and FNA of suspicious lesions (eg, masses in the thyroid bed or abnormal lymph nodes). Based on a recent consensus statement a TSH-stimulated serum thyroglobulin ≥ 2 µg/L is sensitive in screening for recurrence of low-risk patients with PTC. When thyroglobulin is found to be elevated, sites of metastatic disease are searched for. Ultrasonography or radioiodine scanning should be able to identify the majority of significant disease. The loss of radioiodine avidity may be associated with a poorer prognosis-when there is a palpable recurrence, for example, or when thyroglobulin is elevated but there does not appear to be uptake on a low-dose radioiodine scan. These thyroglobulin-positive but radioiodine-negative tumors may be evaluated with fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) scanning as described below. Finally, progression of disease to distant metastases is a poor prognostic sign.
Imaging with FDG-PET has been used extensively in the diagnostic work-up for malignancy, including thyroid cancer. Compared to benign lesions, a greater percentage of thyroid cancers have been shown to be FDG-PET-avid.[12-20] Incidentally discovered FDG-PET-avid thyroid tumors were found to have a 47% chance of being malignant in one study. In other studies, the sensitivity for detecting thyroid cancer with PET has been 75% to 90%, with a specificity of 90%.[19,21] It is a promising development that some poorly differentiated metastatic thyroid cancers have been found to be FDG-PET-avid when radioiodine uptake scanning was negative[19,22-24]; PET scanning may therefore be a good alternative method of surveillance for those select patients. In fact, in April 2003 the Centers for Medicare and Medicaid Services (CMS) began recommending coverage for FDG-PET scanning in patients with thyroid cancer of follicular cell origin previously treated by thyroidectomy and radioactive iodine ablation who have serum thyroglobulin levels > 10 ng/mL. Due to the added expense, lack of availability, and poor anatomic detail, FDG-PET is not feasible for routine use in differentiating benign from malignant thyroid nodules, but it appears to be useful in the imaging of recurrent poorly differentiated radioiodine-negative thyroid cancers.
Approximately one-third of patients with differentiated thyroid cancer will have tumor recurrences; most will be diagnosed within the first 10 years after treatment. Locoregional recurrences may arise in the central or lateral neck, thyroid remnant, mediastinum, or rarely in the trachea or muscle overlying the thyroid bed. Distant metastases are present in about 20% of those who recur. The most common sites of metastases are lung, bone, and brain. Overall, approximately 10% of patients with PTC, 25% of patients with FTC, and 35% of patient with HCC develop distant metastases. As age at diagnosis increases, the likelihood of developing distant metastasis increases as well. The prognosis is better for patients with small radioiodine-avid lung metastases and worse for those with skeletal metastases or non-radioiodine-avid metastases.[28,29] Overall, about 50% of those patients with distant metastases die within 5 years.
For locally recurrent thyroid cancer the diagnosis should be confirmed with FNA biopsy. Bulky disease identified in the lymph nodes of the central or lateral compartments should be resected surgically. In most cases, radioiodine ablation is performed following reoperation. Revisional surgery should not be conducted without preoperative cytologic evidence of the presence of cancer because of the risks of reopening the central neck and the need to define an end point to the surgery (ie, resection of the known recurrent or residual cancer). Revisional surgery in the central neck in particular is fraught with danger, with a higher incidence of nerve injury and permanent hypoparathyroidism. Reoperation should be undertaken only by those individuals experienced in the technique. The authors have found that monitoring the integrity of the recurrent laryngeal nerve with a nerve-monitoring or nerve-stimulating device may be beneficial in this setting.
It is prudent to avoid repeated doses of radioiodine, especially when resectable disease is identified. In rare cases of recalcitrant and aggressive thyroid cancer external-beam radiotherapy can be considered, but should probably be used as a last resort only as it often complicates or obviates subsequent reoperation due to the fibrotic scarring that occurs following treatment.
Distant thyroid cancer metastases can be found in the lung, bone, and brain. When identified, surgical resection should be considered for isolated large metastases. Radioiodine should be used for nonresectable or miliary type metastases, or following surgical resection. Chemotherapy can be considered, but there are no effective chemotherapeutic regimens. In some experimental settings protocols utilizing redifferentiation agents followed by radioiodine are being used.
There is no effective chemotherapeutic regimen for thyroid cancer. As mentioned earlier, chemotherapy is an established component of the multimodality therapy for ATC, but there appears to be no role for monotherapy. In contrast to ATC, chemotherapy has no role in the treatment of MTC or differentiated follicular cell-derived cancers, and no regimen has shown a promising response rate. Doxorubicin has been used as monotherapy, but response is poor. A combined chemotherapeutic regimen consisting of doxorubicin plus cisplatin showed a combined complete plus partial response rate of 26% in one study. Another study evaluated the response of a regimen of doxorubicin, cisplatin, and vindesine, but found minor responses only in three of eight patients. Some clinicians have attempted to use chemotherapy in the setting of poorly differentiated non-radioiodine-avid tumors, but promising results are lacking thus far.
External-beam radiotherapy (EBRT) can be considered for those patients with inoperable, locally invasive, or recurrent thyroid cancers. It is also worth considering for those patients with poorly differentiated or undifferentiated (anaplastic) cancers. External-beam radiotherapy is usually employed only when other modalities have failed or are ineffective. In these rare cases EBRT can be considered, but should probably be used as a last resort only since its use often complicates or obviates subsequent reoperation due to the development of fibrotic scarring after radiation treatment. An example of when EBRT may be beneficial is when there is known residual or recurrent disease that cannot be resected, and radioiodine uptake scanning is negative. External-beam radiotherapy is also commonly part of neoadjuvant therapy for patients with anaplastic cancer.
• Novel Targets-Despite the many modalities available for the treatment of thyroid cancer, overall survival for this malignancy has not seen an improvement in the past 20 years. For this reason there is interest in novel targeted therapies for thyroid cancer, including gene therapy and redifferentiation therapy. The therapeutic targets described below have shown some promise in preclinical trials or experimental models, but are not being used routinely in the clinical setting.
The past decade has seen a surge of research on targeted therapies aimed at protooncogenes, signal transduction pathways, or oncoproteins that are specific to cancer, but do not affect normal cells. Radioiodine ablation is an example of targeted therapy. Since the sodium-iodine symporter (NIS) is expressed almost exclusively on thyroid cells, only those tissues that are capable of concentrating radioiodine (normal thyroid and thyroid cancer) are exposed to lethal doses of radiation. Some thyroid cancers of follicular cell origin and all medullary thyroid cancers have no ability to concentrate radioiodine, making radioiodine ablation ineffective for these tumors. Therapy targeted toward novel pathways may be particularly important in the treatment of these radioiodine-negative, poorly differentiated or dedifferentiated thyroid cancers.
Pathways sought for targeted therapy are usually those related to the early events in oncogenesis. Cancers of follicular cell origin are believed to develop from multiple genetic alterations as opposed to a single gene mutation. Activating mutations in genes encoding tyrosine kinases are believed to be common early events in thyroid oncogenesis. Pathways germane to the early events in papillary thyroid oncogenesis include the RET/PTC rearrangement, which results in constitutive activation of the RET tyrosine kinase; mutations in H, K, and N-RAS, which lead to constitutive G protein activation; and BRAF mutations affecting the mitogen-activated protein kinase (MAPK) pathway.
The RET protooncogene has been shown to play a role in the pathogenesis of both papillary and medullary thyroid cancer. Several specific rearrangements of RET through either inversion or translocation have been observed; this occurs in about one-third of PTC cases. In PTCs arising following exposure to ionizing radiation, RET/PTC1 or RET/PTC3 rearrangements are more common.[33,34] MEN 2 and familial MTC are caused by germline point mutations in the RET protooncogene.[35-37] Sporadic MTC has also been linked to somatic RET mutations.
Mutations in H, K, and N-RAS are oncogenic when they lead to constitutive activation of the G proteins to which RAS binds. RAS mutations are thought to be early events in the oncogenesis of follicular, papillary, and Hrthle cell cancers. The prevalence of the RAS oncogene is believed to be highest in follicular cancers.
The translocation of PAX-8 (a thyroid transcription factor) to peroxisome proliferator-activated receptor (PPAR) Î³1 (a nuclear hormone receptor) has been implicated in the oncogenesis of follicular cancers. These PAX-8/PPARÎ³ rearrangements have been found in many follicular carcinomas, but only rarely in follicular adenomas.[39,40]
BRAF is a serine/threonine kinase thought to play a role in proliferation, differentiation, and apoptosis through its effects on the MAPK pathway. A high prevalence of BRAF mutations (36% to 69%) has been identified in papillary thyroid cancers.[41-44] The tall cell variant of PTC has a high prevalence of BRAF mutations as do poorly differentiated or anaplastic cancers arising from PTC.
Epidermal growth factor receptor (EGFR/ErbB1) and HER2/neu (ErbB2) are commonly overexpressed in PTC.[45-47] Because of this, treatment with humanized monoclonal anti-ErbB2 (trastuzumab [Herceptin]) and anti-ErbB1 (cetuximab [Erbitux]) is being explored.
• Redifferentiation-As discussed above, about 2% to 5% of all thyroid cancers dedifferentiate over time. In those patients with persistent or recurrent thyroid cancer, dedifferentiation occurs at a more alarming rate of about 30%. During dedifferentiation the thyroid cancer loses the ability to express thyroid-specific genes such as NIS, TSH-R, and thyroglobulin. This loss of NIS makes the use of radioiodine ineffective. Loss of TSH-R makes TSH suppression ineffective, and the loss of thyroglobulin expression prevents its use as a tumor marker. Redifferentiation therapy targets these thyroid-specific genes in order to restore expression and thereby allow the use of conventional treatments such as radioiodine and TSH suppression. Retinoids, aromatic fatty acids, PPARÎ¥ agonists, histone deacetylase inhibitors, and HMG-CoA reductase inhibitors have been used in preclinical studies.
Retinoic acids are biologically active derivatives of vitamin A that have been shown to regulate cellular differentiation and growth in many human cancers. In some studies retinoic acids have been shown to increase NIS mRNA expression and radioiodine uptake in vitro.[50-52] Other studies have been less promising. In one clinical trial retinoic acid induced iodine uptake in 50% of subjects. Unfortunately, these effects have not been durable in most reports, and have not led to dramatic clinical responses.
The aromatic fatty acids phenylacetate and phenylbutyrate have been shown to induce growth inhibition and redifferentiation in several human cancers including thyroid cancer. In vitro studies have shown that phenylacetate induces growth inhibition and decreased VEGF secretion in thyroid cancer cell lines. Phenylacetate has also been shown to enhance the antiproliferative effect of retinoic acid in FTC cell lines.
PPARÎ³ agonists have been shown to inhibit cellular proliferation and induce apoptosis. The PPARÎ³ agonists that have received the most attention are the antidiabetic drugs which are derivatives of thiazolidinedione: rosiglitazone (Avandia), pioglitazone (Actos), ciglitazone, and troglitazone. Thiazolidinedione derivatives have antiproliferative effects in many human cancers, including thyroid cancer. Troglitazone has had antiproliferative effects in PTC, FTC, HCC, and ATC cell lines.[58-61] The mechanism of action for PPARÎ¥ agonists has not yet been elucidated.
Histone deacetylase (HDAC) inhibitors modulate the acetylation of histones and other intracellular molecular targets pertinent to cell growth and division. Examples of HDAC inhibitors under investigation include depsipeptide, trichostatin A, and suberoylanilide hydroxamic acid. Histone deacetylase inhibition can induce differentiation and apoptosis in thyroid cancer cell lines. NIS mRNA expression has also been shown to be upregulated by depsipeptide and trichostatin A in vitro.[62,63] If HDAC inhibition leads to significantly increased uptake of iodine, their use could lead to improved effectiveness of RAI in poorly differentiated tumors.
The HMG-CoA reductase inhibitors are popular cholesterol-lowering drugs commonly known as statins. HMG-CoA reductase inhibitors have been shown to have antiproliferative effects and promote differentiation in several human cancer cell lines. Lovastatin has been shown to inhibit cell proliferation and induce apoptosis in thyroid cancer cells.[64,65] In one study lovastatin was shown to induce redifferentiation of ATC in vitro in low doses.
• Gene Therapy-Gene therapy is the offspring of translational research into the molecular mechanisms of oncogenesis. Gene therapy may be expedient in thyroid cancer because of the expression of thyroid specific genes. The sodium iodide symporter, TSH receptor, thyroglobulin, thyroid peroxidase, TTF-1, and TTF-2 are examples of thyroid-specific genes. Gene therapy can be broken down into three broad approaches: corrective, cytoreductive, and immunomodulatory.
The goal of corrective gene therapy is to replace a defective gene, restore a deleted gene, or abrogate the effect of an oncogene. Perhaps the most obvious example of a target for corrective gene therapy is the RET protooncogene in MTC. The p53 tumor suppressor gene, tyrosine phosphatase Î· , and Gadd45Î¥ have all been implicated in ATC and have been used as targets for corrective gene therapy as well.[68-73]
The goal of cytoreductive gene therapy is to deliver a gene that leads to cell death or makes the cell susceptible to cytotoxic drugs. The most common strategy is suicide gene therapy by the introduction of viral thymidine kinase followed by the administration of ganciclovir, which leads to selective killing of cells that express the viral thymidine kinase. This strategy has been effective in ATC cell lines and in nude mice.[74-76]
Perhaps one of the most promising new strategies is the reintroduction of a functioning NIS gene in NIS-deficient thyroid cancers in order to restore iodine concentrating capacity. Medullary thyroid cancer does not express NIS and poorly differentiated and anaplastic cancers often have lost the cell surface expression of NIS, rendering radioiodine scanning and ablation ineffective for these tumors. The reintroduction of a functional NIS gene might make radioiodine treatment effective in these cancers. In experimental models the NIS gene has been transfected into NIS-defective thyroid cancer cells, and has resulted in restoration of the ability to accumulate iodine both in vitro and in vivo.[77-79] Successful NIS gene transfer has been demonstrated in both follicular cell-derived and medullary cancers.
The goal of immunomodulatory gene therapy is the introduction of genes that will enhance the immune system's response to the tumor and increase the immunogenicity of the tumor. The expression of cytokines with antitumor activity such as interleukin (IL)-2 (Proleukin) and IL-12 has been the main focus of immunomodulatory gene therapy thus far. IL-2 and IL-12 have been used alone or in conjunction with suicide gene therapy or tissue-specific promoters and have shown promise in vitro and in vivo for both follicular cell-derived and medullary cancers.[80-83]
The majority of thyroid cancers are slow-growing and easily treatable, with an excellent prognosis after appropriate surgical and medical therapy. Despite this, there has been no improvement in overall survival for thyroid cancer in the past 20 years. Unfortunately, 10% to 15% of thyroid cancers do not follow an indolent course, and exhibit aggressive behavior. Approximately one-third of patients with differentiated thyroid cancers will have tumor recurrences, and most will be diagnosed within the first 10 years after treatment. Dedifferentiation occurs in about 30% of patients with persistent or recurrent thyroid cancer leading to poorer responses to conventional therapy and difficulty monitoring tumor burden. Distant metastases are present in about 20% of those who recur. Overall, about 50% of patients with distant metastases die within 5 years.
Clinicians need to be able to identify tumors with more aggressive biology and treat them accordingly with more aggressive regimens. Novel therapies utilizing molecular targets, redifferentiation agents, and gene therapy are exciting potential therapeutic options on the horizon.
Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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