TITLE: Medullary Thyroid Cancer<=
br>
SOURCE: Grand Rounds Presentation, UTMB, Dept. of Otolaryngology
DATE: October 27, 2010
RESIDENT PHYSICIAN: David M. Gleinser, MD
FACULTY PHYSICIAN: Susan Mc=
Cammon,
MD
SERIES EDITOR: Francis B. Quinn, Jr., MD
ARCHIVIST: Melinda Stoner Quinn, M=
SICS
&q=
uot;This
material was prepared by resident physicians in partial fulfillment of
educational requirements established for the Postgraduate Training Program =
of
the UTMB Department of Otolaryngology/Head and Neck Surgery and was not int=
ended
for clinical use in its present form. It was prepared for the purpose of
stimulating group discussion in a conference setting. No warranties, either
express or implied, are made with respect to its accuracy, completeness, or
timeliness. The material does not necessarily reflect the current or past
opinions of members of the UTMB faculty and should not be used for purposes=
of
diagnosis or treatment without consulting appropriate literature sources and
informed professional opinion."
Medullary thyroid cancer (MTC) is a cancer of th= e parafollicular C-cells of the thyroid, and is considered a neuroendocrine tumor since the C-cells are derived from neural crest cells. MTC is the 3rd most common thyroid cancer after papillary= and follicular carcinoma, and is a secretory tumor known to secrete calcitonin,= carcinoembryonic antigen (CEA), adrenocorticotropin hormone (ACTH), substance P, and gastrin. MTC has two forms, sporad= ic and familial.
Forms:
The Sporadic form of MTC represents roughly 75% = of MTC cases, and typically carries a worse prognosis. Tumors of this type tend to be unifocal and unilateral. The typical age at presentation is arou= nd the 5th-6th decades, and there is usually no family histo= ry of MTC.
The familial form represents the other 25% of ca=
ses
seen. These tumors are multifocal =
and
bilateral at presentation, but tend to carry a better prognosis overall.
Presentation:
MTC typically presents as a slow growing neck ma= ss. Nodal disease is common, with 50-60% of= cases presenting with nodal metastasis at the time of presentation. Patients may also complain of compressi= ve symptoms (dysphagia and/or dyspnea) and hoarseness (recurrent laryngeal ner= ve involvement). Diarrhea is another symptom that is commonly noted. Th= is is because calcitonin, typically present in high amounts in MTC, causes an increased excretion of electrolytes into the intestine. Water then follows these electrolytes i= nto the lumen, thus leading to the diarrhea
Syndromes:
As stated previously, MTC is associated with AD = syndromes. The most common of these is MEN IIA, or Sipple Syndrome. The triad of feat= ures associated with this syndrome includes MTC, pheochromocytoma, and parathyro= id hyperplasia. The RET mutations associated with Sipple syndrome typically involve codons 609, 611, 618, 620, and most commonly, 634. The 634 mu= tation is also responsible for cutaneous amyloidosis (Lichen amyloidosis) sometime= s seen in this syndrome. Familial MTC is another AD disease associated with MTC. It is thought to be a subclass of MEN IIA as it shares similar mutat= ions in the RET proto-oncogene (609, 611, 618, and 620). However, unlike MEN IIA, there is no hi= story of pheochromocytoma or parathyroid hyperplasia. In addition, the 634 mutation is rarely seen in familial MTC. To officially make a diagnosis of famil= ial MTC, there must be at least 2 or more family generations of MTC without any sign of pheochromocytoma or parathyroid hyperplasia. MEN IIB is another AD syndrome associa= ted with MTC. The major features noted= in this syndrome include MTC, pheochromocytoma, musculoskeletal manifestations= (marfanoid habitus, pes cavus, pectus excavatum, proximal muscle weakness), mucosal neuromas, urinary and intestinal malformations. The MTC seen in this syndrome tends to be much more aggressive than = in the other syndromes. Luckily, MEN = IIB is very rare. The mutation involving = codon 918 is the most notable mutation involving MEN IIB.
As the RET proto-oncogene mutation is strongly
associated with MTC, the American Thyroid Association (ATA) has made multip=
le
recommendations as to who should be screened for this mutation. Any patient with a diagnosis of MTC sho=
uld be
screened. In addition, any patient=
who
has signs/features of MEN IIA, IIB, and familial MTC should be screened.
When RET mutations are found, action must be tak= en to help prevent morbidity and mortality. First, all family members should be screened. Various recommendations as to the type = of treatment that should be performed have been proposed by the ATA. The treatment typically involves perfor= ming a total thyroidectomy at minimum. Th= e age at which to perform the thyroidectomy depends on the mutation involved. It has been discovered that some mutati= ons are associated with a much more aggressive form of disease than others. For this reason, the ATA has grouped th= ese mutations into four categories, A-D. D represents the most aggressive forms, while A is the least aggressive. The A category involves mutations in co= dons 768, 790, 791, 804, and 891. Categ= ory B has the 609, 611, 620, and 630 mutations while category C has the 634 mutation. Category D has the 918 a= nd 883 mutations.
Given that category D represents the most aggres= sive forms of the disease, the ATA recommends that patients with these mutations undergo total thyroidectomy prior to 1 year of age. Prior to removal, these patients should undergo ultrasound examination of their thyroid, central neck compartment, lateral neck compartments, and superior mediastinum. Serum calcitonin levels should be order= ed as well, but it is much less reliable in this age group. Patients with category C mutations are recommended to undergo total thyroidectomy prior to age 5, but should have = an ultrasound and serum calcitonin levels by age 3. Patients in categories A and B could potentially wait to have a thyroidectomy until after 5 years, thus helping = to prevent complications as these children have been allowed to develop more.<= span style=3D'mso-spacerun:yes'> However, these children should be screen= ed with ultrasound and serum calcitonin by age 3. In all cases, if the ultrasound reveals a thyroid nodule > 5mm or= there is a serum calcitonin level > 40 pg/mL, the patient should undergo a thy= roidectomy at the time of the discovery since these findings have been shown to be associated with a higher risk of MTC and metastasis. Neck dissections do not offer improved outcomes in the asymptomatic population and thus have not been recommended except in the cases where gross disease is noted.
In addition to the screening and treatment for M= TC, patients with RET mutations must also undergo screening for pheochromocytoma and parathyroid hyperplasia. In pa= tients who are noted to have mutations involving the 918 or 634 codons, it is recommended that they undergo screening for pheochromocytoma by the age of = 10 and yearly thereafter with either a serum or 24 hour urine metanephrine/normetanephrine. With= all other mutations, screening can occur at the age of 20 and annually thereaft= er. In patients noted to have mutations rel= ated to MEN IIA, they should undergo screening for hyperplastic parathyroid glan= ds as well. If the mutation involves the= 630 or 634 codon, screening should begin around age 8 and then annually thereaf= ter with a serum calcium and intact parathyroid hormone (PTH). For all other mutations, patients can b= egin screening at age 20 and yearly thereafter.
In the event that an older patient is found to h= ave mutations in the RET proto-oncogene (age > 1 in MEN IIB and age > 5 in MEN IIA and Familial MTC), it is recommended that these patients undergo immediate ultrasound examination and have a serum calcitonin checked. If the calcitonin level is less than 40 pg/mL, or any thyroid nodules are less than 5mm, total thyroidectomy is recommended. If the calcitonin is greater than 40 pg/mL or thyroid nodules are greater than 5mm, a total thyroidectomy along with a central neck dissection are recommended. If nodal disease is discovered in the l= ateral neck, then a formal neck dissection (levels IIa-V) is warranted. If during dissection, parathyroid gland= s are removed. These should be placed in= to the forearm and marked, especially if the patient has or may have MEN IIA. The reason for this is that these patie= nts may require further neck treatments, thus the previously removed parathyroid glands could be injured in the neck upon re-operation leading to hypoparath= yroidism and its complications.
In the symptomatic patient, once MTC is suspecte= d, there are two primary tests that should be obtained; a serum calcitonin and a fine-needle aspiration (FNA) of the suspected nodule. Chang et al reviewed the pathology slides of 34 patients with known MTC. They found that 82% of the pa= tients were correctly diagnosed by FNA alone. Three patients were diagnosed with follicular neoplasms, 1 with a desmoid tumor, and 2 others were suspicious for MTC. Overall, however, every patient underwe= nt surgery and was correctly diagnosed. Pappavaskova et al reported that of the cases they reviewed with patients undergoing FNA biopsy in diagnosing MTC, 89% were diagnosed correc= tly by FNA alone. However, 99% of the patients underwent surgery, and were diagnosed correctly. Although FNA is considered a reliable t= est when it comes to diagnosing MTC, it typically discovers the disease in its later stages. Serum calcitonin levels are thought to be much better at detecting disease earlier, thus improving outcomes. Of all thyroid nodules, = it is estimated that 0.3-1.4% are MTC. T= he controversy involves whether it is appropriate to order serum calcitonin le= vels on every patient with thyroid nodules, as cost may become an issue. Elisei et al examined 10,864 patients w= ith thyroid nodules who had been screened by calcitonin levels and/or FNA biopsy. They found that 0.4% had MTC. Of the patients who were scre= ened with serum calcitonin levels, the MTC was discovered earlier, and thus trea= ted in an earlier stage. These patient= s had much better outcomes than those who were diagnosed by FNA alone; 59% comple= te remission rate versus 2.7% for patients who did not have MTC initially suspected by serum calcitonin. The= next question to be asked is: what calcitonin level corresponds to likely disease? Costante et al reported t= hat the positive predictive value of serum calcitonin in the detection of MTC w= as 8.3% for levels 20-50 pg/mL, 25% for 51-100 pg/mL, and 100% for levels grea= ter than 100 pg/mL.
The next step in the process of diagnosing and treating MTC involves further laboratory studies. If a serum calcitonin has not yet been ordered, it should be done so now. In addition, the presence of a RET mutation must be known. A serum calcium is also important in th= is situation to assess for possible MEN IIA. Following the additional laboratory studies, an ultrasound of the thyroid, central neck compartment, lateral necks, and the super mediastinum should be performed. If a RET muta= tion discovered, the family members should be screened and treated as discussed above. In addition, the patient should undergo screening for pheochromocytoma. If= any lymph nodes are detected on ultrasound, or if the serum calcitonin is great= er than 400 pg/mL, the patient should undergo a CT scan of the neck and thorax= as well as a triple phase CT scan of the liver to assess for metastatic disease. Machens et al found that distant metastasis began to appear when the measured calcitonin levels were= 400 pg/mL of greater. They also found = that when the serum calcitonin level was 15,000 pg/mL, or if there was a nodule = that was 5cm in size, the metastatic rate was 50%. When the serum calcitonin level was 100,000 pg/mL or if a 6cm or lar= ger nodule was discovered, the rate of metastasis was 100%.
Treatment Options:
The extent of treatment for MTC depends on the e= xtent of the disease. Once MTC has metastasized, the chance for cure is very low. The first thing to consider if surgery is warranted is whether the patient has a pheochromocytoma. Treatment of the pheochromocytoma takes precedence as operating on a patient with an active pheochromocytoma could prove fatal. In many cases, the extent of the MTC w= ill be limited, and surgical cure still remains a possibility. If the disease is confined to the thyro= id or has spread to lymph nodes within the central neck compartment, the treatmen= t involves a total thyroidectomy and central compartment neck dissection. If any lateral neck nodal disease is discovered, neck dissections involving levels IIa through V should be perfo= rmed in addition to the above. When the= MTC is deemed advanced (distant metastasis, invasion of the trachea, esophagus, or= larynx) the treatment is palliative with the goal to maintain speech, swallowing and parathyroid function. Multiple stu= dies have shown that the extent of surgery has no effect on patients with advanc= ed MTC.
One question that arises when dealing with any t= hyroid malignancy is what to do with the recurrent laryngeal nerve if the tumor is encasing or invading it. The first assessment must be to determine whether the nerve is functional. For this reason, all patients should un= dergo flexible laryngoscopy prior to the operative procedure to properly document= the functional status of the cords. If= the nerve is out, and it is involved in tumor, the never should be taken with t= he tumor. If it is working, then the = extent of the disease dictates what should be done. If the patient has limited disease, the nerve should be taken in an attempt to obtain proper oncological resection. If the patient has advanced disease, the nerve is not resected in or= der to preserve speech.
Postoperative Care:
In the post-operative period, it is important to assess whether all disease has been removed. The most commonly used post-operative screening test is the serum calcitonin. Following resection, i= t typically takes 1-2 months before the serum calcitonin levels normalize, if all disea= se has been removed. For this reason,= it is recommended that the first post-operative calcitonin be drawn 2-3 months af= ter resection. If it is undetectable, = the patient should only be observed on a routine basis as the risk of recurrenc= e is roughly 3% in this situation. Modi= gliani et al showed that when the post-operative calcitonin was undetectable, the = 10 year survival rate was 97%. If the calcitonin level is detectable, but less than 150 pg/mL, persistent disease should be considered. In this scen= ario, a neck ultrasound should be ordered to assess for disease. Work-up for distant metastasis is to be considered, however, the likelihood of finding metastatic disease when the calcitonin is less than 150 pg/mL is very low. If the calcitonin level is greater than 150 pg/mL, then a full metastatic work-up should be performed, as the likelihood of finding distant disease is higher. This work-up sh= ould include a CT of the neck and thorax as well as a triple phase contrasted CT= of the liver, along with a bone scan. The calcitonin doubling time can also be determined post-operatively, and will = aid in two aspects. First, it should b= e used to help guide how often a patient should be re-evaluated, and second, it can predict future outcomes. For insta= nce, if the calcitonin doubling time is < 6 months, these patients have 5 and= 10 year survival rates of 25% and 8%, respectively, and thus these patients wi= ll need to be followed and monitored much more closely for disease recurrence = than those with longer doubling times. = If the doubling time is 6-24 months, the survival improves to 92% and 37%, respectively. If it is over 24 mon= ths, then the 10 year survival is close to 100%.
If during the work-up, nodal disease greater tha=
n 1cm
in size or other gross disease is discovered in the neck, the consensus is =
that
formal resection should be performed in an attempt to remove the disease.
If the work-up for local and/or distant metastas= is comes back negative with a detectable calcitonin, then observation is recommended. In the past, extensiv= e neck dissections and mediastinal lymph node removal was performed in an attempt = to locate and remove disease in this scenario. However, multiple studies have shown that this did not improve patie= nt survival, and only increased patient morbidity. Another procedure that used to be per= formed in this scenario was a diagnostic laparoscopy with liver biopsies looking f= or disease. However, this is no longer recommended for two main reasons. = First, when negative, the previously recommended treatment involved extensive neck= and mediastinal dissections which have already been proven to not be beneficial= in overall survival. Second, the imag= ining studies that are available today are much more reliable at detecting disease than they were in the past, thus diagnostic, invasive procedures would like= ly not reveal new information, and would just increase patient morbidity.
Radiation:
The role of radiation therapy in the treatment o= f MTC has also been studied. In these st= udies, it has been shown that the addition of external beam radiotherapy (EBRT) to= the treatment of MTC has improved the relapse rate. However, it has not improved overall survival. Brierley et al used EBRT in patients wi= th microscopic residual disease, cases where local soft tissue involvement occurred, and in cases with nodal positive disease. They found that the relapse rate was 86= % at 10 years in patients treated post-operatively with EBRT compared to 52% in patients who were not treated with EBRT. In a smaller study, Chow et al treated patients with nodal positive disease with EBRT. Of the 4 patien= ts who received post-operative EBRT, all were noted to have 10 year locoregional control. Of the 3 who did not rece= ive EBRT, 1 had 10 year locoregional control. Because of these findings, the ATA has recommended that all patients with microscopic, nodal positive, or small amounts of macroscopic disease undergo post-operative treatment with EBRT. It is not recommended that patients with elevated calcitonin levels = who are negative for nodal disease and had negative surgical margins undergo EBRT. This is because the exact lo= cation of disease is not known, and could potentially be at a different site than = what would be irradiated. At this time, chemotherapy does not have a role in the treatment of MTC as these tumors h= ave persistently shown to have a poor response the chemotherapeutic agents.
Conclusion:
MTC is = a rare, but potentially fatal malignancy. = It is very important that this disease is recognized and treated early as distant metastasis caries a poor prognosis. In addition, the presence of a RET mutation needs to be determined as it will = help to guide further work-up and treatment as well as trigger screening examinations for family members. Surgery is the primary treatment of MTC= with EBRT being used in cases of residual and nodal disease to improve disease relapse rate. However, EBRT is not a subst= itute for proper oncologic resection as it has not been shown to improve survival= .
Sources:
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3. Papaparaskeva K, Nagel H, Droese M. Cytologic diagnosi of medullary carcinoma of the thyroid gland. Diagn Cytopathol 2000;22:351–358.
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7. Modigliani E, Cohen R, Campos JM, et al. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. T= he GETC Study Group. Groupe d’e´tude des tumeurs a` calcitonine. Clin Endocrin= ol 2008;48:265–273.
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Medullary Thyroid Cancer
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