TITLE: Management of Invasive Thyroid Carcinoma
SOURCE: Grand Rounds Presentation, UTMB, Dept. of Otolaryngology
DATE: May 2, 2007
RESIDENT PHYSICIAN:
FACULTY PHYSICIAN: Vicente Resto, MD, PhD
SERIES EDITORS: Francis B. Quinn, Jr., MD and Matthew W. Ryan, MD
"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, completen=
ess,
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."
Introduction
Invasive thyroid carcinoma encompasses any malignant t= issue that protrudes beyond the capsule of the gland. Although rare, extrathyroid= al invasion is associated with a worse prognosis and increased risk of morbidi= ty. Management remains controversial, with some authors advocating conservative treatment with preservation of midline structures and others, aggressive extensive en bloc resection. = There are a number of prognostic factors to consider when evaluating thyroid nodu= les and thyroid cancer risk.
In addition to the standard TNM system (table below), a
number of systems have been developed to gauge risk-group classification.
Depending on variables pre= sent, patients can be categorized into one of three groups: high, intermediate, or low risk. The classifications focus on parame= ters that are well established in the literature as risk factors for a poorer prognosis. A parameter common to all scoring systems is age given that pati= ents over 45 years of age have a worse outcome than their younger counterparts. Larger primary tumor size and extension and the presence of metastases incr= ease a patient's stage and affect 5-year survival. For papillary carcinoma the 5-year relative survival rates by stage are 100% for stages I and II, 95.8%= for stage III, and 45.3% for stage IV.
For foll=
icular
carcinoma the 5-year relative survival rates are 100% for stages I and II,
79.4% for stage III, and 47.1% for stage IV(17).=
Specific prognostic factors are extremely important a=
nd include:
|
TNM staging for papillar=
y and
follicular carcinoma(17) |
|
Primary = tumor (T) TX Primary tumor cannot be asses=
sed Regional lymph nodes (= N) NX Regional nodes cannot be asse=
ssed Distant metastasis (M)= MX Distant metastasis cannot be
assessed Stage grouping (for pa= pillary and follicular carcinoma) Under 45 years of age Stage I Any T Any N Any M 45 years of age and older Stage I T1 N0 M0 |
Diagnosis
The most common diagnostic measures include needle bio= psy or aspiration, thyroid blood studies, and radiology imaging. Needle biopsy, a superior diagnostic technique, which provides accurate cytologic finding wi= th little to no morbidity, has become an incremental step in thyroid nodule workup. <= /p>
History and physical examination: a thorough history s= hould be obtained. Symptoms such as= pain, hoarseness, dysphagia, dyspnea, stridor, hemoptysis, and rapid enlargement = of the mass may occur with thyroid carcinomas, but are not necessarily to be t= he signs of malignancy. A history of irradiation, especially in childhood, is = an important risk for papillary carcinoma. External low dose irradiation is the treatment for some diseases, e.g. acne, tonsillar hypertrophy, enlarged thy= mus, cervical adenitis, sinusitis and malignant disease. Previous thyroid diseas= es such as goiter, Hashimoto’s disease and Grave’s disease can be = risk factors for thyroid cancer.
Physical exam includes the full head and neck examinat= ion. A benign thyroid nodule is usually well-circumscribed, soft, non-tender, and movable free to surrounding tissue. A malignant tumor is harder, can be gre= ater than 4 cm in diameter and may be fixed to the surrounding and underlying tissues. Neck examination can reveal palpable metastatic cervical lymph nod= es, especially in the anterior compartment (level III, IV, VI) and less common = in level V. Pre-operative laryngoscopy evaluates for vocal cord paralysis and should be documented in all patients to determine the function of the recur= rent laryngeal nerve and use for preoperative planning. If one cord is noted to be paralyz= ed, it is likely secondary to an invasive process until proven otherwise, and remo= val of the nerve can be planned in the future operative intervention.
Fine needle aspiration (FNA) is performed on a palpable = nodule or under guidance using ultrasonography. Fine needle biopsy is an accurate diagnostic procedure in papillary, medullary, metastatic, anaplastic cancer= s, and malignant lymphomas. Differentiation between follicular and Hurthle cell neoplasms is based on capsular or vascular invasion. A malignant specimen on fine needle aspiration is a strong indication for surgery; however, a negat= ive result cannot rule out cancer. There are some limitations of fine needle aspiration to differentiate (1) adenomatoid nodule vs. follicular neoplasm, (2) papillary carcinoma with cy= stic change and benign cystic nodules, (3) large multinodular goiters and present malignancy, (4) Hashimoto’s thyroiditis vs. oxyphilic cell (Hurthle) neoplasm, (5) multinodular goiter vs. Hurthle cell neoplasm, (6) Hashimoto’s vs. malignant lymphoma, (7) malignant melanoma.
Blood test: thyroid function tests include (1) thyroxin or T4, (2) triiodothyronine or T3, and (3) thyroid stimulating hormone or TSH. Ser= um calcium and phosphorous levels may indicate hyperfunction of parathyroid gland adenoma, which may be associated with thyroid gland malignancy. Thyroglobulin (Tg) is usually meas= ured as a baseline before and following up after surgery of well-differentiated thyroid carcinomas because it correlates with histologic types of tumors. Recurrent tumors are usually associated with high Tg level. Calcitonin is a useful test for diagnosis and screening in patients with medullary thyroid carcinoma and th= eir family members; however, it is not a work up test. Antimicrosomal and anti-Tg antibody titer are unrealistic tests= for screening or following up a thyroid cancer because of high cost and low-specificity
Imaging studies:
· Ultrasonography:= is one of the most sensitive and effective tests for differentiation a thyroid= and a non-thyroid nodule in more than 80% of cases. It provides an accurate tri-dimensional location, follows up the nodular size, and indicates nodular location for the fine needle aspiration. US can detect the nodules as small= as 2 to 3 mm and differentiate between solitary and multinodular diseases. I= t is however not useful in detecting invasive disease. If one suspect= s invasion based on physical examination findings, such as fixed nodal diseas= e or true vocal cord paralysis, then further imaging, such as CT or MRI is neces= sary. CT is useful in detecting tracheal invasion and evaluating for cervical met= astasis. One drawback to this test for thyr= oid cancer is that it may delay postoperative radioactive iodine treatment.
· Magnetic resonance imaging (MRI): is very us= eful to detect residual, recurrent and metastatic cancers. T2 imaging is useful = in differentiation between tumors and fibroses in an operated neck tissue, and detection of muscle invasion. MRI also shows tracheal displacement and vasc= ular relationship involved with large masses. Fat-saturation MRI can be used in suspected recurrent tumors, which are not identified by radioiodine scan. <= /p>
· Chest x-ray is helpful in detecting tracheal deviation, airway narrowing, and existent lung and bone metastasis. Pattern= s of calcification on chest x-ray are useful in identifying the types of cancer:= (1) rim or eggshell calcification suggests a benign lesion, (2) bilateral calcification in superolateral aspect of the thyroid gland indicates MTC and (3) extensive irregular calcification suggests a multinodular goiter.
.
Classification, Pathology, and Biology
Well-differentiated thyroid carcinomas (WDTC) - Papil= lary, Follicular, and Hurthle cell
Papillary, follicular, and Hurthle carcinomas are clas= sified as well-differentiated malignancies. Papillary and follicular carcinomas are the two most common malignancies found in the thyroid gland and occur 60-70% and 10% of the time, respectively Hurthle cell makes up about 3% of thyroid malignancies. All three of these cancers arise from the thyroid hormone producing follicular cells, however, their pathogenesis is largely unknown (15). Unlike medullary carcinoma, the= y do not have a definite genetic inheritance pattern. Only a small number are thought to occur in rare familial syndromes (15). Recent research has lead = to the identification of a few cancer-causing genes that may be responsible for the benign or malignant transformation of follicular cells. Specifically, R= ET proto-oncogene mutations have been implicated in papillary and medullary carcinoma but a definitive link has yet to be proven (14). Despite the uncertainty of these molecular events, certain clinical factors, such as exposure to radiation, increases the likelihood for developing thyroid canc= er, especially papillary carcinoma. In areas with endemic goiter, in populations that are iodine deficient and therefore have high level of TSH stimulation,= the incidence of follicular carcinoma is high. Although this relationship has b= een confirmed in the laboratory where follicular carcinoma can be induced by exposure to TSH after exposure to a mutagen, the exact mechanism for this is not known (16). This relationship has not been consistent with papillary or Hurthle cell carcinoma (16).
.Papillary and follicular carcinomas are more frequent= ly found in women. The mean age = of incidence of papillary carcinoma is 35, while follicular tends to occur at = an older age than papillary, with a mean age of 50 years (6). Lymph node involvement is relatively common in papillary carcinoma, with lymphatic spread being the m= ajor route of metastasis. In contrast to papillary carcinoma, follicular carcino= ma tends to metastasize via angioinvasion and hematogenous spread and has a hi= gher frequency of distant metastasis. When nodes are involved in follicular canc= er, however, outcome is usually poor. This probably relates to the fact that patients with lymph node involvement at the time of diagnosis are also like= ly to have significant local disease and visceral invasion (43). Bone is the m= ost common site of distant metastasis, with lung coming in second.
One of the most controversial and confusing neoplasms of the thyroid gland is the Hurthle cell carcinoma (HCC). This WDTC comprises approximately 3% of thyroid malignancies (6). These= cells are believed to be a derived from follicular cells and together form a vari= ant of a follicular neoplasm (6). A Hurthle cell ne= oplasm is defined as an encapsulated group of follicular cells with at least a 75%= Hurthle cell component. Like follicular carcinoma, HCC requires histologic proof of vascular and capsu= lar invasion to distinguish it from an adenoma. This makes diagnosis with either FNA or frozen section almost impossible, requiring permanent sections. Alth= ough classified as a WDTC carcinoma, HCC is more aggressive than follicular carcinoma. It also has a greater propensity for malignant transformation to= anaplastic carcinoma than any other WDTC.
Medullary Thyroid Carcinoma (MTC)
Medullary thyroid carcinoma accounts for approximately=
10%
of all thyroid cancers and has an incidence of approximately 1000 new cases=
, in
the
Sporadic MTC accounts for approximately 70%- of all MT= Cs (5,29). The mean age at presentation i= s 50 years (41). This form of MTC tends to occur unilaterally and unifocally and usually presents as an enlarging thyroid nodule. It is slightly more aggres= sive than familial MTC, which composes the remaining 30% of medullary thyroid carcinomas. The most common clinical presentation of sporadic and inherited MTC is a mass in the neck (= 36).
Anaplastic carcinoma (ATC)
Anaplastic carcinoma of the thyroid is a rare but high= ly lethal form of cancer with a median survival in most series of less than 8 months (22= ,23,25,27). It comprises 1%-10% of all thy= roid tumors and up to 30% of thyroid malignancies in patients older than 70 year= s (26,28,45). ATC usually occurs in the elderly with a mean age of presentation of 60 yea= rs and has a slight female predominance (23). The most common clinical symptom= is a rapidly enlarging mass and because of its aggressiveness, symptoms of invasion such as hoarseness, dysphagia, dyspnea, and superior vena cava syndrome are not uncommon.
Treatment Considerations
Wein and Weber (50) discussed a number of treatment considerations when evaluating thyroid cancer. These included:
When a follicular neoplasm's obtained on FNA, 80% beni= gn, 20% carcinoma. Of this 20%, u= p to 50% have the diagnosis of follicular variant of papillary carcinoma.
Management
The locally invasive presentation of
well-differentiated thyroid carcinoma occurs in less than 5% of all cases. =
The
most common pathology involved is papillary carcinoma. There is a male
predominance with patients presenting at a higher mean age than those with
noninvasive disease (31). Invasive
thyroid carc=
inoma
spreads by direct extension from the primary tumor or from extracapsular=
spread of pa=
ratracheal
nodal metastasis. Tumor at the primary site has the capacity for invasion
through the cricothyroid membrane or the thyroid
cartilage anteriorly or may extend posteriorly to wrap around the thyroid cartilage and
present in the region of the piriform sinus.
<= span style=3D'mso-bookmark:xref_r04001653048'>The goals of treatment for invasive thyroid carcinoma include prevention of hemorrhage and airway obstruction, preservation of a functional upper aerodigestive tract, prevention of locoregional recurrence, and long-term survival. Frequently t= he mandate for removing all gross disease is at odds with function-sparing surgery. Several authors have advocated a conservative approach of shaving = the tumor (24,31,32,33) off the tracheal wall, but other authors advocate more aggressive approaches to accomplish a complete removal of tumor (11,21). Few disagree that the goal in treating invasive thyroid carcinoma<= /span> is to remove all macroscopic disease noted at the time of surgery. The controversy lies in the degree of resection required to accomplish this res= ult. For individuals with limited tracheal deficits but gross intraluminal sprea= d of tumor, window and sleeve resections are necessary. For larger defects, up to one third the circumference of the tracheal, use of sternocleidomastoid and pectoralis major myoperiosteal flaps over T-tubes has been described (12). = For larger defects, tracheal resection with re-anastomosis with release procedu= res while preserving at least one recurrent laryngeal nerve has been described = with favorable results (19). McCaffrey et al (31) retrospectively compared three gr= oups of patients undergoing surgery for thyroid carcinoma with limited tracheal invasion. These groups included individuals undergoing complete surgical excision (group I), shave resection with the potential for microscopic resi= dual disease (group II), and incomplete resection with macroscopic residual dise= ase remaining (group III). The overall 5-year survival was 79%. No significant = difference was noted in survival between groups I and II, whereas survival in group III was the lowest. The authors concluded that for selected patients shave resection is a viable option that allows preservation of upper aerodigestive tract anatomy without compromising survival. The importance of postoperative RAI therapy and possible external beam radiation were also stressed.=
E= sophageal invasion, when present, tends to invade only the outer muscular layers of t= he esophagus. Because achieving wide tumor-free margins is less of an issue wi= th thyroid carcinoma than with squamous cell carcinoma, limited resection with= out intraluminal entry is possible. When limited intraluminal invasion is encountered, primary closure of the defect after resection is an option when closure does not predispose to stricture formation. When extensive resectio= ns of the esophagus are required, options for reconstruction with pedicled and free tissue transfer parallel those described in the literature for the treatment of squamous cell carcinoma (13).
<= span style=3D'mso-bookmark:xref_r04001653056'>When a patient presents for thyroidectomy and the preoperative examination indicates paralysis of the recurrent laryngeal nerve, attempts to save the nerve at the time of surgery should not be pursued. Primary thyroplasty may be considered in this scenar= io. When the recurrent laryngeal nerve is noted to be functional preoperatively, attempts should be made to preserve the nerve if possible. Falk and McCaffr= ey (10) retrospectively compared patients who had a functional recurrent laryn= geal nerve sacrificed at the time of thyroidectomy with those with nerve preservation and noted that complete resection of tumor and nerve sacrifice offered no survival benefit over potentially incomplete resection of tumor = and nerve preservation.
<= span style=3D'mso-bookmark:xref_r04001653056'>Laryngeal invasion requires the su= rgeon to be aware of the various options in conservation laryngeal surgery if the goal of avoiding total laryngectomy is possible. Vertical partial laryngect= omy may be appropriate for patients with unilateral disease, whereas a supracri= coid partial laryngectomy may be considered for extensive anterior invasion (13)= . The indications for total laryngectomy include extensive laryngeal spread beyond the scope of organ-preservation surgery and involvement of more than= one third of the cricoid ring (32).
In a recent article by Segal et al (43) they per= formed a retrospective review of 1200 pts with diagnosis of well-differentiated thyroid carcinoma. 49 pts (5%) showed involvement of an adjacent structure (larynx, trachea, esophagus) - 30 female, 19 male. The type of surgery, radiation tre= atment radioiodine treatment, and patient demographics were evaluated. Most common pathologic finding was papillary carcinoma (43 pts, 88%). Follicular carcinoma, including Hurthle = cell carcinoma was noted in 6 pts (12%). Anaplastic tumors were excluded.&nb= sp; All patients underwent total thyroidectomy and central neck dissection. Eighteen also had functional neck dissection (37%). &nb= sp; For extrathyroidal involvement, two main approaches were used - radi= cal surgery to excise all microscopic disease, with or without adjuvant therapy (n=3D16) = and surgery for macroscopic disease only, followed by iodine and radiation treatment for microscopic residual disease (n=3D33). Overall 5 year survival for invasi= ve carcinoma was 78%, compared to 93% of noninvasive disease. The only statistically significant factor was large tumor size. = They concluded that conservative procedures followed by radioiodide treatment we= re associated with similar survival rates as aggressive techniques, with less perioperative mortality and lower overall mortality.
There is little consensus regarding surgical management of invasive, well-differentiated thyroid carcinoma. The conserva= tive school recommends preservation of the midline structures by shaving carcino= ma from the larynx, trachea, and esophagus, which potentially leaves behind microscopic disease requiring radioiodine and radiation treatment. (7) The aggressive school recommends extensive en bloc resection of the tumor, including partial or total laryngectomy, pharyngectomy, or tracheal resecti= on, as necessary, to obtain clear margins. (19)
Undifferentiated Anaplastic Carcinoma
These tumors are usually unresect= able. Tracheotomy is considered when airway is compressed. Diagnosis is made by F= NA and usually by open biopsy for completed cell study. A combination treatmen= t of surgery, radiation or chemotherapy may help to control the tumors.
Medulla= ry Thyroid Cancer
Cervical metastasis at the time of diagnosis is observ= ed in 50% of cases. Surgical resection includes the anterior compartment node dissection, which removes the lymphatics and ad= ipose tissue from the hyoid bone to the sternal notch= and laterally to the internal jugular vein. The lymph node groups removed are pre-tracheal, paratracheal, pre-cricoid, Delphian and perithyroidal= nodes. With N(+) cervical lymph nodes, a selecti= ve lateral neck dissection of zones II, III, IV can be included.
Adjuvant therapy:
Post-op radioiodine (RAI): with appropriate dose, radiation t= herapy is safe in both children and adults. When patients have significant hypothyroidism (TSH>50 mU/L), 4 to 5 mCi of 131-I is given and the total body is scanned t= o look for residual thyroid tissue or metastasis. The scan and treatment are repea= ted until the scan is negative. Patient will receive follow up annually for sev= eral years. For the rest of life, patient’s TSH should be held in low norm= al range by maintaining T4 level in high normal range. According to Attie et al (2), RAI uptake scanning is an essential indication after a thyroidectomy to determine t= he completeness of the surgical procedure and to detect residual or metastatic disease.
Another controversial complementary treatment is exter= nal beam radiation. Some earlier reports recommend the use of external beam rad= iotherapy in all cases of aggressive disease because it improves local disease contro= l, (20) even though there is no proof that it changes the survival rate. By contrast, others found no improvement in either local con= trol or disease-free survival.(3,42) E= xternal beam radiation is thought to be useful in advanced loc= oregional WDTC whether superficial excision is complete or incomplete, if the tumor no longer picks up radioiodine, and in post-op adjuvant therapy for palliation= of unresectable bone metastasis.
Surgical complications
Surgical complications can include injuries to the sup= erior laryngeal nerve or recurrent laryngeal nerve, hemorrhage, airway obstructio= n, pneumothorax, chyle leak, hypothyroidism and hypocalcemia.
Postoperative treatment and follow up
Studies have demonstrated the usefulness of postoperative RAI in decreasing the local recurrence and mortality rates in patients with stage II and stage III well-differentiated thyroid carcinoma. For this reason, the routine use of postoperative RAI and thyroid hormone suppression has been advocated for patients with primary tumors larger than 1.5 cm (30,42). Radiation is also a postoperative consideration for tumors that do not respond to RAI and for management of d= istant metastasis.
Conclusion
The goal of management for invasive thyroid cancer is = to remove all gross disease, especially in medullary carcinomas and Hurthle cell, which are less responsive to postoperative radioactive iodine administration. There is still a debate regarding optimal techniques and extent of surgical resection to perform when dealing with invasive disease. There = are a number of techniques which can be performed to complete dissection, however= minimally a total thyroidectomy and central neck dissecti= on should be performed for invasive disease.&= nbsp; It is also important to remember that the type of cancer and risk grouping can affect both prognosis and influence treatment decisions.
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