anaplastic thyroid carcinoma

CONTROVERSY Ramon M Esclamado, MD, Section Editor ANAPLASTIC THYROID CARCINOMA Consultants: Askok Shaha, MD,1 Maisie Shindo, MD,2 Robert Sofferman, MD3 Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, New York Division of Otolaryngology – Head & Neck Surgery, SUNY Stony Brook, Stony Brook, New York Division of Otolaryngology, Fletcher Allen Health Care, Burlington, Vermont Accepted 16 April 2005 Published online 30 August 2005 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/hed.20277 A 48-year-old woman is seen for evaluation of a slowly enlarging lower neck mass Three months previously, she had symptoms consistent with an upper respiratory tract infection that resolved within to days, then noticed a lump in her lower neck just to the left of midline She was treated with two courses of antibiotics, but the mass continued to enlarge She had leftsided otalgia develop but no hoarseness, dysphagia, weight loss, fever, chills, or night sweats Evaluation before referral included the normal thyroid-stimulating hormone (TSH) level and two fine-needle aspirations (FNAs) that were nondiagnostic Ultrasound examination revealed a 2.9-cm  2.8-cm complex, thick-walled cyst adjacent to, but not clearly involving, the lower pole of the left lobe of the thyroid gland A CT scan of the neck and upper mediastinum was obtained and is shown in Figure Her medical history was significant in that she had no history of kidney stones, bone pain, de- Readers are invited to submit interesting or difficult cases to Ramon M Esclamado, MD, Section Editor, Head and Neck Institute, The Cleveland Clinic, 9500 Euclid Avenue (A71), Cleveland, OH 44195 B 2005 Wiley Periodicals, Inc 1102 Anaplastic Thyroid Carcinoma pression, constipation, or prior radiation to the neck She was an otherwise healthy nonsmoker, nondrinker There was no family history of thyroid or parathyroid disease Physical examination was remarkable for a thin, healthy-appearing woman with an approximately 3-  3-cm mass to the left of the trachea above the sternal notch The mass was firm, nontender, and elevated superiorly with swallowing There was no lymphadenopathy on either side of the neck, and vocal fold mobility was normal bilaterally The remainder of her head and neck examination was completely normal What is your differential diagnosis at this point in the evaluation? Dr Shaha: Based on the history and clinical examination, the patient seems to have a left thyroid mass, and even though the clinical examination revealed this to be a well-defined mass, radiologically it appears to be quite ill defined with a central cystic area There appears to be considerable involvement of the surrounding soft tissue based on the CT scan, which extends in the region of the superior mediastinum and suprasternal notch Unless proved otherwise, this is to HEAD & NECK December 2005 Dr Sofferman: Despite the fact that the ultrasound is somewhat equivocal, one still has to consider that this is of thyroid origin and may represent a benign adenoma, cystic multinodular component of a goiter, or a malignancy of all known varieties Additional differential diagnostic considerations would be a thymic cyst, parathyroid cyst, cystic degeneration of a parathyroid adenoma, cystic degeneration of a parathyroid carcinoma, or a metastatic lymph node from some other origin Both thymic cysts and parathyroid cysts usually have a thinner wall, and those would be lower on my differential diagnostic list FIGURE Axial CT scan with contrast be taken as malignant pathology originating in the left lobe of the thyroid I am concerned if this is a locally aggressive cancer or a poorly differentiated variety Dr Shindo: Irrespective of the ultrasound report, the clinical examination (moves with swallowing) and the CT findings are highly suggestive of a cystic thyroid mass, either a cystic papillary carcinoma or, less likely, a benign thyroid cyst I would be more suspicious of the former because of the surrounding soft tissue reaction The second possibility is a metastatic lesion to the thyroid or a paratracheal node (ie, laryngeal or hypopharyngeal malignancy) Other rare possibilities are cystic parathyroid adenoma and a thymic cyst Anaplastic Thyroid Carcinoma What is the next appropriate diagnostic step(s)? Dr Shindo: The next appropriate diagnostic step would be to obtain the slides from prior FNAs to see why it was nondiagnostic Was it due to insufficient cells? I would repeat the FNA at this time under ultrasound guidance with immediate analysis of cytologic content to ensure that the same is adequate Dr Sofferman: I would assume that that means after the two FNAs have been completed At this time, we still not know whether this is a malignant process, and the diagnosis is still in question One would like to know whether the fineneedle aspirate was obtained by the clinician in the office or whether it was done with ultrasound guidance With two failed needle aspirations, I would probably try to obtain a fine-needle aspirate with ultrasound guidance, and I usually this in the office setting I would also ask the pathologist to be on site and would continue to sample different areas in the solid wall of the mass until representative tissue was obtained If that effort would not yield results, an ultrasound-guided core biopsy would be my next preference I generally would not proceed to an open biopsy, unless my hands were forced to the limit Dr Shaha: Because the CT scan and clinical evaluation reveal what appears to be a tumor originating in the left lobe of the thyroid, I would consider this to be a malignant problem and proceed with a FNA biopsy of the left thyroid mass Even though a core biopsy would be of help, I would not consider a core biopsy without the results of the FNA biopsy being available At the time of FNA biopsy, I would also like to know whether there is cystic fluid or a solid component of the thyroid mass Because the mass can be felt very easily, an FNA biopsy could be performed in HEAD & NECK December 2005 1103 the office; however, an ultrasound-guided FNA biopsy also should be considered The cytologist should consider a thyroglobulin stain to confirm that the primary tumor originates in the thyroid Serum parathyroid hormone (PTH) and ionized calcium levels were normal An FNA was performed and read as ‘‘atypical cells suspicious for malignancy.’’ What would you recommend at this time? Dr Sofferman: Again, in question three, if the aspiration demonstrated atypical cells suspicious for malignancy, I think it is entirely possible to obtain more information with a core sample, and certainly a calcitonin level would be a basic requirement given the suspicion for malignancy Dr Shaha: On the basis of the clinical, radiologic, and FNA biopsy, the diagnosis is essentially confirmed for malignancy originating in the left lobe of the thyroid Metastatic tumors to the thyroid are quite rare, and unless there is an obvious primary tumor elsewhere in the body, I would not consider that as a differential diagnosis The serum PTH and calcium are normal, so the question of parathyroid carcinoma does not come up However, it should be remembered that parathyroid cancers are very rare, and this should be considered a thyroid carcinoma However, I would caution, based on the CT scan, that this seems more likely to be locally aggressive thyroid carcinoma such as poorly differentiated thyroid carcinoma, and there should be extensive discussion with the patient and family, including hoarseness of voice and recurrent laryngeal nerve sacrifice Dr Shindo: I would obtain the slides for review What did the atypical cells look like? If necessary, perform necessary stains to help classify the category of malignant cells (ie, stains for thyroglobulin, keratin) If still indeterminate, I would recommend left thyroidectomy and isthmusectomy with frozen section, possible total thyroidectomy, and paratracheal node dissection With the soft tissue reaction around the overlying strap muscles, I would be prepared to resect them if necessary An open, incisional biopsy was performed Intraoperatively there was an intense inflammatory response around the mass with edema and fibrosis of the overlying strap muscles The intraoperative frozen section was read as ‘‘poorly differ- 1104 Anaplastic Thyroid Carcinoma entiated carcinoma.’’ What would you at this time? Dr Shaha: Whenever a thyroid is explored for surgical resection, if the previous FNA biopsy has not given the diagnosis of carcinoma, and the clinical suspicion strongly favors malignant tumor, I would explore the thyroid bed and be prepared to perform appropriate surgical intervention, which in this case will require wide excision of the left thyroid lobe along with surrounding strap muscles and total thyroidectomy The inflammatory response is probably more related to desmoplastic reaction to aggressive malignant tumor The surrounding strap muscles need to be sacrificed The surgical procedure should encompass all extrathyroid extension of the tumor Because we not have a definite diagnosis of malignancy, I would consider incisional or core biopsy at the time of surgery to confirm the malignant diagnosis On the basis of the intraoperative frozen section of poorly differentiated carcinoma, I would proceed with radical resection of this tumor if this is feasible Even with a differential diagnosis of anaplastic carcinoma in the back of my mind, because I have opened the neck, I would make every effort to resect the tumor as necessary and as possible Dr Shindo: On the frozen section, was there any evidence that this carcinoma was metastatic in a lymph node? If not, did the mass appear to be arising from the thyroid on visual inspection? If so, I would proceed with total thyroidectomy at this time If the mass is clearly separate from the thyroid, this could possibly be a metastatic node, and I would close up and proceed with triple endoscopy Dr Sofferman: If an open biopsy were to be accomplished, other than proceeding with two of the steps in question five, I would not anything further at that juncture until a diagnosis was definitively established on permanent section The incision was closed and direct laryngoscopy, bronchoscopy, and flexible esophagoscopy were performed, which did not reveal a primary head and neck malignancy Is any additional workup indicated? Dr Shindo: I am assuming that the final pathology on the incisional biopsy was also read as poorly differentiated carcinoma With this diagnosis, I would again make sure special stains are performed to further classify the tissue of origin I suspect that in this tissue, some of the HEAD & NECK December 2005 cells will probably stain with thyroglobulin if the tumor is of thyroid origin If the diagnosis is still poorly differential carcinoma of indeterminate origin with a negative endoscopy, I would proceed with imaging studies to look for a primary tumor Whether a whole-body positron emission tomography (PET) scan is preferred over CT of chest/ abdomen/pelvis with contrast for searching for an unknown primary tumor is debatable My preference in this specific setting would be to obtain a PET, because I would want to avoid using iodine contrast at this time The reason for this is that in the event that this eventually turns out to be poorly differentiated thyroid cancer, the patient may still benefit from 131I treatment, and the load of iodine contrast may delay this treatment Dr Sofferman: Certainly a direct laryngoscopy, absolute requirement for bronchoscopy, and a rigid esophagoscopy would be those things I would at the primary anesthetic if it were performed under general anesthesia If the open biopsy were done under local anesthesia, these other elements would have to be accomplished on an outpatient basis by respective services of Pulmonary Medicine and Gastrointestinal Medicine In addition, to get much better definitive information about the local extent of disease, an MRI scan with contrast would be a very good approach, as well as a PET scan As an aside, in anything potentially thyroid malignant in nature, one would prefer not to use a CT scan with contrast as was done in this case A large iodine load can delay the use of radioactive iodine by several months Dr Shaha: Going back to the previous question, I would have considered radical resection of the tumor the first time rather than closing the wound and bringing the patient back to the operating room, unless the patient was not informed of these possibilities This is radiologically and clinically a primary aggressive tumor originating in the thyroid gland and does not appear as a metastatic tumor An FNA biopsy was suspicious for malignancy A thyroglobulin stain could have been performed on the FNA biopsy specimen initially I not think any addition workup is indicated at this time; however, one may consider doing a PET scan or CT scan of the chest to rule out pulmonary metastasis or distant disease Because the patient had an open biopsy of the thyroid mass, I would be interested in a detailed evaluation from the pathologist and appropriate immunohistochemistry testing Anaplastic Thyroid Carcinoma CT scans of the chest, abdomen, and pelvis showed no evidence of a primary malignancy or metastatic disease What are your treatment recommendations? Dr Shindo: With a negative result on the imaging studies, I would then proceed with the operation that was outlined under this section Dr Sofferman: I agree completely with all of the steps that were performed in this patient to include the aggressive management of the manubrium, resection of the medial aspects of ribs one and two, and the performance of the mediastinal node dissection Certainly the fortuitous requirement to remove the cartilaginous and manubrial structures allows a much better dissection of the anterior mediastinum Because no skin removal was required, a myogenous flap is all that is required In addition, it appears that the tumor is closely adherent to the trachea If there is any question about this, it is possible to resect the cartilaginous areas beneath the tumor mass without violating the mucosa Certainly resection of the strap muscles and even omohyoids are not issues at all in the resection process However, the real problems would occur with trying to determine how much of the trachea to resect, whether the recurrent laryngeal nerve should be removed, and even involvement of the esophageal serosa and muscularis layer might require careful consideration Again, this case is quite unusual in that the disease does appear to be separated from all of the important structures When lesions of this sort are on the left side, there is often fixation in the tracheoesophageal groove, and the esophagus itself is often involved Dr Shaha: The treatment recommendations at this time are to consider surgical exploration with a diagnosis of poorly differentiated carcinoma If the pathologist confirms this to be anaplastic thyroid carcinoma, then the surgeon has to make a decision whether technically this is a resectable disease or not However, it seems that this is a resectable disease, and I would consider surgical resection as performed here However, I am not sure the resection of the manubrium and the clavicular heads are necessary, obviously, on the basis of the previous exploration, there may be considerable inflammatory reaction, and this may be more confusing The surgeon has to make a personal decision regarding the resectability of the tumor and what additional structures need to be resected However, every attempt should be made to resect all gross HEAD & NECK December 2005 1105 disease The final pathology report showing anaplastic thyroid carcinoma is not unexpected in this case on the basis of the radiologic picture of the CT scan Also, this anaplastic thyroid cancer is originating into the papillary carcinoma There are three types of anaplastic thyroid carcinomas seen: Rapidly growing thyroid mass in the form of a fulminating anaplastic thyroid carcinoma, where surgical resection is unlikely to be satisfactory, and most of the time, all gross tumor cannot be removed Most of the time such patients are seen with a large thyroid mass, vocal cord paralysis, and frozen and fixed central compartment of the neck A patient with previously known papillary carcinoma of the thyroid that transforms itself into anaplastic thyroid carcinoma Most of these are surgically resectable lesions, and every attempt should be made to resect the tumor if feasible, both on the basis of the CT evaluation and the clinical findings A long-standing goiter transforming itself into anaplastic thyroid carcinoma This is quite rare except in endemic goitrous regions If clinically this appears to be surgically resectable, every attempt should be made to resect this tumor However, it must be added, most anaplastic carcinomas that we see are generally not a surgical problem Most of them are rapidly growing, invading the surrounding structures, invariably with paralysis of the recurrent laryngeal nerve In this case, the fact that the nerve was functioning is a good sign and may be a consideration for surgical intervention The patient underwent a total thyroidectomy, bilateral paratracheal and central compartment node dissection, and resection of the mass with the overlying strap muscles Both recurrent laryngeal nerves and superior parathyroid glands were preserved, and all macroscopic tumor was removed from the trachea However, the strap muscles were grossly involved on the left side at their origins from the manubrium and first rib Therefore, a manubrial resection, along with resection of the clavicular heads and the costochondral portions of ribs and 2, was performed in conjunction with an upper mediastinal node dissection and reconstruction with a left pectoralis myogenous flap All final intra- 1106 Anaplastic Thyroid Carcinoma FIGURE Final histopathology of the thyroid mass operative frozen section margins were negative The final pathology was read as anaplastic thyroid cancer (Figure 2A) arising from a papillary thyroid cancer (Figure 2B) There was no metastatic cancer in any of 45 lymph nodes examined Do you recommend further adjuvant therapy? Dr Sofferman: In terms of adjuvant therapy, there has been some promise with anaplastic carcinoma in the use of radioactive iodine, external beam radiation therapy in accelerated fractions (ie, twice daily), and the concomitant use of doxorubicin, which is also a potent radiosensitizer DeCrevoisier and his coworkers have described a management profile in 30 patients with anaplastic carcinoma This series combines surgery, two cycles of doxorubicin and cisplatinum, and then four cycles of radiation therapy The overall survival rate in this series at years was 27%, which is more promising than any previous articles that I have been able HEAD & NECK December 2005 to review Helpful prognostic factors were complete macroscopic tumor resection, and negative features were tracheal invasion and distant metastatic disease Dr Shaha: Absolutely, yes This patient has a very aggressive tumor The final pathology report revealed this to be anaplastic thyroid carcinoma There was gross extrathyroidal extension of the disease that required radical resection of the tumor Even if the lymph nodes are negative, the tumor is quite aggressive I would strongly recommend postoperative chemoradiation therapy The classical chemotherapy used is Adriamycin, 100 mg/m2 along with external radiation therapy and hyperfractionation toward the conclusion of radiation therapy However, recently, we have been using intensity modulated radiation therapy (IMRT), and the role of taxol, although undefined, seems to be quite promising Despite this, I am quite concerned about the aggressive nature of this disease and the final diagnosis of anaplastic thyroid carcinoma The patient needs to be closely observed and followed for any evidence of either local recurrence or distant disease Follow-up should include careful clinical evaluation with evaluation of the vocal cord function and appropriate imaging studies such as CT scan and PET scan Dr Shindo: I would recommend postoperative external radiation therapy for anaplastic carcinoma DISCUSSION This case presentation of an anaplastic thyroid carcinoma arising from a preexisting papillary thyroid carcinoma in a young patient is both a diagnostic and therapeutic challenge; the consultants have given valuable insight The differential diagnosis includes a cystic thyroid carcinoma, an infected benign cyst of the thyroid, and thymus or parathyroid or metastatic lymphadenopathy Laboratory evaluation includes TSH, thyroglobulin, PTH, ionized calcium, and calcitonin levels In view of two prior nondiagnostic FNAs, the importance of reviewing the outside pathology, and/or repeating the FNA Anaplastic Thyroid Carcinoma under ultrasound guidance to sample the wall was critical in the evaluation Open biopsy was recommended only after failure of these diagnostic efforts The timing of the definitive surgical ablative procedure is controversial Dr Shaha appropriately emphasizes that the definitive surgical procedure should be preformed at the time of open biopsy, and the surgeon should be prepared and the patient counseled regarding the potential extent of the surgery Dr Shindo makes the important point that if this mass is clearly within the thyroid gland and is malignant, that total thyroidectomy and paratracheal node dissection be performed at the time of exploration Both Dr Shindo and Dr Sofferman concurred with this patient’s management of deferring definitive treatment until a diagnosis was established on permanent section Although unusual, metastatic squamous cell carcinoma was considered in the differential diagnosis, which may have altered the treatment strategy In view of the diagnosis of anaplastic thyroid carcinoma, all consultants agreed that aggressive surgical management should be attempted if the tumor was determined to be potentially resectable Dr Shaha makes the important point of differentiating between three types of anaplastic carcinoma of the thyroid In this case, this histologically was arising from a previously existing papillary thyroid cancer, which made attempt at resection more feasible The importance of adjuvant therapy was agreed on by all the consultants, and the relative rarity of this disease was reflected in the variety of adjuvant therapies recommended In summary, this case illustrates an unusual presentation of anaplastic thyroid carcinoma and the need for careful diagnostic evaluation and treatment planning Anaplastic thyroid cancer, although generally associated with a dismal prognosis, can be resected with attempt for cure when it arises from a papillary thyroid cancer Whether this approach will ultimately benefit the patient in terms of long-term survivorship will require review of a large or multiinstitutional series HEAD & NECK December 2005 1107 ... papillary carcinoma There are three types of anaplastic thyroid carcinomas seen: Rapidly growing thyroid mass in the form of a fulminating anaplastic thyroid carcinoma, where surgical resection is... external radiation therapy for anaplastic carcinoma DISCUSSION This case presentation of an anaplastic thyroid carcinoma arising from a preexisting papillary thyroid carcinoma in a young patient... intra- 1106 Anaplastic Thyroid Carcinoma FIGURE Final histopathology of the thyroid mass operative frozen section margins were negative The final pathology was read as anaplastic thyroid cancer