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6 Differentiated Thyroid Cancer
47
Cross-Sectional Imaging
• Indications of advanced disease may include clinically apparent or bulky cervi-
cal lymphadenopathy and concern for invasion of the primary tumor into local
structures.
• Preoperative use of cross-sectional imaging with IV contrast (CT or MRI) is
recommended as an adjunct to US for patients with clinical suspicion for
advanced disease [6], as cross-sectional imaging can facilitate surgical planning
in these circumstances.
– Clinical indications of invasive disease include progressive dysphagia, respi-
ratory compromise, hemoptysis, signicant voice changes or vocal cord
paralysis, and rapid enlargement or xation of the tumor mass.
– Concern about the ability to assess for extent of disease (e.g., extension into
mediastinum), or nodal metastases not easily detectable by bedside ultrasound (e.g., to levels IIb, V, and VII) should also prompt evaluation with
cross-sectional imaging.
– Of note, the iodine load associated with contrast may delay the administration
of radioactive iodine for ablation and a urine sodium level can help determine
the timing for ablative therapy.
• Routine use of pre-operative 18FDG-PET CT scan in cytologically conrmed
DTC is not indicated.
Staging andPrognosis
– Overall, the prognosis for differentiated thyroid carcinoma is favorable, with
10-year survival rates for papillary and follicular DTCs of 98% and 92%, respectively [8].
– Prognosis of DTC varies by stage and patient age, and is delineated in the
American Joint Committee on Cancer-Union for International Cancer Control
(AJCC- UICC) guidelines (Fig.6.1) [9].
– Because survival for DTCs is generally excellent, prevention of recurrence and
long-term prognosis is critical to management of DTCs. The American Thyroid
Association guidelines provide criteria for risk of recurrence based on the clinicpathologic features (Fig.6.2) [6].
48
Primary tumor (T)
Lymph node status (N)
N1a: metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal or
Distant metastasis (M
Prognostic stage group
o
Tx: primary tumor cannot be assessed
T0: no evidence of primary tumor
T1: tumor <= 2cm in greatest dimension, limited to thyroid
T2: tumor >2 cm but <=4 cm in greatest dimension, limited to thyroid
T3: tumor >4cm, l limited to thyroid or gross extrathyroidal extension invading only
T4: includes gross extrathyroidal extension into major neck structures
M0: no distant metastasis
M1: distant metastasis
R. L. Williams-Karnesky and D. F. Schneider
o
T1a: tumor <=1cm in greatest dimension, limited to thyroid
o
T1b: tumor >1cm but <=2cm in greatest dimension, limited to thyroid
strap muscles
o
T3a: tumor >4cm limited to the thyroid
o T3b: gross extrathyroidal extension invading only strap muscles (sternohyoid,
sternothyroid, thyrohyoid or omohyoid) from a tumor of any size
o T4a: gross extrathyroidal extension invading subcutaneous tissues, larynx,
trachea, esophagus, or recurrent laryngeal nerve from a tumor of any size
o T4b: gross extrathyroidal extension invading prevertebral fascia or encasing
carotid artery, or mediastinal vessels from a tumor of any size
NX: regional nodes cannot be assessed
N0: no evidence of regional lymph node metastasis
N1: metastasis to regional lymph nodes
o
Delphian or upper mediastinal) lymph nodes. This nodal metastasis can be
unilateral or bilateral
o N1b: metastasis to unilateral, bilateral, or contralateral lateral lymph nodes
(level I, II, III, IV and V) or retropharyngeal lymph nodes
<55 years old at diagnosis
o Stage I: any T, any N, and M0
o Stage II: any T, any N, and M1
>=55 years old at diagnosis
o Stage I: T1 or T2, N0 or NX, and M0
o Stage II: T1 or T2, N1 and M0
o Stage II: T3, any N and M0
o Stage III: T4a any N and M0
o Stage IVA: T4b, any N and M0
Stage IVB: any T, any N and M1
)
s
Fig. 6.1 AJCC-UICC 8th edition guidelines for staging of differentiated thyroid cancer
6 Differentiated Thyroid Cancer
Fig. 6.2 American Thyroid Association risk stratication system for disease recurrence in patients
without structurally identiable disease after initial therapy. FTC follicular thyroid cancer, FV follicular variant, LN lymph node, PTMC papillary thyroid microcarcinoma, PTC papillary thyroid
cancer. (Figure from the 2015 American Thyroid Association management guidelines for adult
patients with thyroid nodules and differentiated thyroid cancer. Modied from [6])
49
Treatment
– Options for management of DTC include active surveillance, lobectomy, and
total thyroidectomy with or without lymphadenectomy, as well as the use of
post-operative adjuncts such as radioactive iodine ablation and thyroid hormone
suppression (Fig.6.3).
– Optimization for treatment of DTC requires surgeons to balance the potential for
higher risk of recurrent disease associated with a less aggressive primary surgery
with the potential risks of complications from more aggressive surgery (e.g.,
recurrent laryngeal nerve injury, hypoparathyroidism) [4].
– In addition to tumor biology, additional factors to consider in pre-operative
decision- making include patient preference and patient ability to remain compliant with active surveillance protocols or thyroid hormone supplementation.
– Quality of life concerns, such as the need for potential hormone supplementation
(following lobectomy) versus replacement (with total thyroidectomy), should be
discussed with the patient during operative planning.
50
Fig. 6.3 Treatment options for patients with differentiated thyroid cancer. Shaded areas indicate
tissue left in-situ
R. L. Williams-Karnesky and D. F. Schneider
Surveillance
– Papillary thyroid microcarcinoma is dened as a thyroid cancer <=1cm.
– While discussion is ongoing, surveillance of these microcarcinomas and other
DTCs that are deemed low-risk cancers based on the ATA guidelines [4] may be
considered.
– If active surveillance is pursued, timing subsequent imaging studies to monitor
progression of disease should be discussed and the patient must be able to comply with appropriate follow-up.
Lobectomy
– For low-risk DTCs >1cm and <4cm, either unilateral lobectomy or total thy-
roidectomy may be appropriate, as increasing evidence suggests that extent of
initial surgery does not impact overall long-term survival [6, 10].
– Patients who elect to pursue lobectomy should be counseled about the need for
ongoing surveillance of the contralateral thyroid lobe, as well as the potential
need for completion of lobectomy in the future.
– Generally, lobectomy is not appropriate for patients that need radioactive iodine
ablation (RAI).
– Lobectomy does not preclude the use of serial serum Tg for the detection of
disease recurrence, though it becomes more difcult to interpret.
Total Thyroidectomy
– Total thyroidectomy with gross removal of all tumor is recommended for
DTC >4cm.
– Total thyroidectomy is also recommended for tumors with high-risk features,
gross extrathyroidal extension, with metastatic disease to lymph nodes (clinical
N1), or with metastases to distant sites (clinic M1) [6].
6 Differentiated Thyroid Cancer
– Total thyroidectomy should be performed when post-operative treatment with
RAI is planned.
– Serum Tg levels following total thyroidectomy can be used to evaluate for
both completion of resection as well as for monitoring for disease recurrence.
Lymphadenectomy
– The most common site of lymph node metastasis in DTC is the central neck (cer-
vical level VI). Less commonly involved nodal compartments include the lateral
neck (compartments II–V), the anterior mediastinum (level VII), and level I.
– Prophylactic central neck lymph node dissection should be considered for can-
cers >4cm.
– Therapeutic lymphadenectomy should be performed in patients with clinically
positive lymph nodes, and extent of dissection should be determined by location of
positive nodes as this may reduce the risk of recurrence and improve survival [2, 6].
Long-Term Management
Post-Operative Adjuncts
51
– Because TSH receptors are expressed in DTC, thyroxine (T4) supplementation
to suppress TSH is frequently used to reduce the risk of recurrence [2, 6].
– Radioactive iodine ablation may be used in more advanced cases such as the
presence of signicant lymph node metastasis, invasion, large cancers, or unfavorable subtypes.
– External beam radiation may play a limited role in reducing locoregional recur-
rence in incomplete resection due to locally invasive DTC (e.g., with aerodigestive involvement), but generally plays no role in the management of DTC [11].
Metastatic Disease
– Unlike many tumor types, metastatic disease in DTC does not preclude the
patient from surgical resection of the primary tumor. Metastatic disease may
respond to RAI, so removal of the thyroid as well as the primary tumor and accessible locoregional disease is an important component of initial management [6].
Surveillance
– Most recurrences of DTC occur in the rst 3years after initial treatment [12].
– Post-operative, neck ultrasound and serum Tg and Tg antibody levels should be
monitored every 6 to 12months for patients with DTC [2, 6].
52
R. L. Williams-Karnesky and D. F. Schneider
Conclusion
Differentiated thyroid carcinoma is a highly treatable form of thyroid cancer with
good long-term survival. Overall prognosis is generally good, and depends on tumor
biology, patient factors, and therapeutic approach. Depending on stage, treatment
options for DTC range from active surveillance to surgical intervention with additional post-operative medical therapies, necessitating the involvement of a multidisciplinary team of providers. Shared decision-making between the physician and
patient is critical in the successful management of DTC.
References
1. Lloyd R, Osamura R, Klöppel G, Rosai J, editors. WHO classication of Tumours of endocrine organs, vol. 10. 4th ed. Lyon: International Agency for Research on Cancer; 2017.
2. Patel KN, Yip L, Lubitz CC, Grubbs EG, Miller BS, Shen W, etal. The American Association
of Endocrine Surgeons Guidelines for the denitive surgical management of thyroid disease in
adults. Ann Surg. 2020;271(3):e21.
3. Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, etal. 2016 American
Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other
causes of thyrotoxicosis. Thyroid. 2016;26(10):1343–421.
4. Wang TS, Sosa JA.Thyroid surgery for differentiated thyroid cancer—recent advances and
future directions. Nat Rev Endocrinol. 2018;14(11):670–83.
5. Sherman SI.Thyroid carcinoma. Lancet. 2003;361(9356):501–11.
6. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, etal. 2015
American Thyroid Association management guidelines for adult patients with thyroid nodules
and differentiated thyroid cancer: the American Thyroid Association guidelines task force on
thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;26(1):1–133.
7. McLeod DSA, Cooper DS, Ladenson PW, Ain KB, Brierley JD, Fein HG, etal. Prognosis of
differentiated thyroid cancer in relation to serum thyrotropin and thyroglobulin antibody status
at time of diagnosis. Thyroid. 2014;24(1):35–42.
8. Gilliland FD, Hunt WC, Morris DM, Key CR.Prognostic factors for thyroid carcinoma. A
population-based study of 15,698 cases from the surveillance, epidemiology and end results
(SEER) program 1973-1991. Cancer. 1997;79(3):564–73.
9. Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK, Washington MK, etal. AJCC
cancer staging manual. 8th ed. 2017, Corr. 3rd printing 2018 edition. Chicago, IL: Springer;
2016. p.1049.
10. Adam MA, Pura J, Gu L, Dinan MA, Tyler DS, Reed SD, etal. Extent of surgery for papillary thyroid cancer is not associated with survival: an analysis of 61,775 patients. Ann Surg.
2014;260(4):601–5; discussion 605–607.
11. Fussey JM, Crunkhorn R, Tedla M, Weickert MO, Mehanna H.External beam radiotherapy in differentiated thyroid carcinoma: a systematic review. Head Neck. 2016;38(Suppl
1):E2297–305.
12. Ross DS, Litofsky D, Ain KB, Bigos T, Brierley JD, Cooper DS, etal. Recurrence after treatment of micropapillary thyroid cancer. Thyroid. 2009;19(10):1043–8.
Chapter 7
Medullary Thyroid Cancer
JesseE.Passman andHeatherWachtel
Overview [1–4]
• Medullary thyroid cancer (MTC) is a tumor of the calcitonin-producing parafol-
licular C-cells in the thyroid.
• 25% of MTC is hereditary and associated with multiple endocrine neoplasia
(MEN) 2A or 2B (RET mutations). It is critical to determine if patients have
sporadic or hereditary MTC prior to initiating treatment.
• MTC is typically treated with total thyroidectomy with central neck lymph node
dissection. Lateral neck lymph node dissection is added if there is evidence of
lymphatic spread.
• Surgery is the only potentially curative treatment for MTC.Systemic therapies
are generally of limited efcacy.
Denition [2, 4, 5]
• Medullary thyroid cancer (MTC) is a neuroendocrine cancer of the calcitonin-
producing parafollicular C-cells in the thyroid.
J. E. Passman
Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
e-mail: Jesse.Passman@pennmedicine.upenn.edu
H. Wachtel (*)
Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
e-mail: heather.wachtel@pennmedicine.upenn.edu
Switzerland AG 2024
R. M. Gartland, J. A. Lee (eds.), Endocrine Surgery Clerkship, Contemporary
Surgical Clerkships, https://doi.org/10.1007/978-3-031-62091-1_7
53© The Author(s), under exclusive license to Springer Nature
54
MEN1 MEN2AMEN2B
J. E. Passman and H. Wachtel
Epidemiology [2, 4–7]
• MTC accounts for 1–2% of all thyroid cancers. 60% of patients with MTC
are female.
• 75% of MTC is sporadic; 25% is familial and associated with MEN 2A and
2B.Presentation varies between sporadic and inherited forms.
• Sporadic MTC typically occurs between the fourth and sixth decades of life.
• MTC is a dening feature of MEN2A and MEN2B, with virtually all RET muta-
tion carriers developing MTC at a young age. Patients with MEN2A typically
develop MTC in their 30s; MTC occurs even earlier in MEN2B and is aggressive
(see Fig.7.1).
Pathogenesis/Behavior [3–5]
• MTC is caused by cancerous growth of parafollicular C-cells of the thyroid.
• C-cells are responsible for the production of calcitonin. Serum calcitonin levels
often correlate with tumor mass and differentiation and serve as the tumor marker
for MTC.
• Hereditary MTC is caused by germline mutations in the RET proto-oncogene
leading to MEN.
• 60% of sporadic MTC tumors have somatic mutations in RET.
• Sporadic MTC usually presents as a solitary thyroid nodule.
• Hereditary MTC most commonly presents as bilateral, multifocal disease within
the thyroid or with metastatic spread.
• MTC has a high likelihood of metastasis. 75% of patients will have metastatic
disease at time of diagnosis, primarily to the cervical lymph nodes (lymphatic
spread). 5–10% will have distant metastases primarily to liver, lung, and bones
(hematogenous spread). Rarely, MTC will spread to the brain or skin.
• MTC produces several hormones and tumor markers, primarily calcitonin and
carcinoembryonic antigen (CEA). Rarely, MTCs may produce ACTH, chromogranin, or somatostatin.
Parathyroid hyperplasiaParathyroid hyperplasia
Pituitary adenoma Medullary thyroid cancer Medullary thyroid cancer
Pancreac tumors Pheochromocytoma Pheochromocytoma
Fig. 7.1 Summary of clinical characteristics of multiple endocrine neoplasia (MEN) syndromes [7]
Marfanoid body habitus and
mucosal neuromas
7 Medullary Thyroid Cancer
55
Evaluation
History [1, 3, 4]
• MTC may present as thyroid nodule(s) or abnormal cervical lymphadenopathy.
• Local invasion or compression may cause dysphagia or hoarseness in a minority
of patients (approximately 15%).
• Patients with hereditary tumors may present with other manifestations of MEN,
such as hypercalcemia due to primary hyperparathyroidism (MEN2A), or hypertension and tachycardia due to pheochromocytoma (MEN2A, 2B), or mucosal
neuromas and marfanoid body habitus (MEN2B).
• Very rarely, secretion of calcitonin or calcitonin gene-related peptide can lead to
diarrhea or ushing in patients with advanced disease.
• Special attention should be paid to family history given the association with
MEN2A and 2B.
Physical Exam [3]
• Most MTCs present as a solitary thyroid nodule with or without cervical lymph-
adenopathy, or as a dominant nodule within a multinodular goiter.
• A physical exam of the neck should be performed in all patients.
Laboratory Studies [1, 3, 4]
• Thyroid function tests (TSH) should be performed.
• Baseline calcitonin and CEA values should be obtained.
• Calcitonin acts as a tumor marker for size of the tumor as well as differentiation.
Poorly differentiated tumors generally do not produce calcitonin, but will
secrete CEA.
• If produced by the tumor, calcitonin and CEA can be measured sequentially to
determine response to therapy or surveil for recurrence. Doubling times of CEA
and calcitonin correlate with progression and aggressiveness.
• All patients with conrmed MTC require genetic testing to assess for germline
RET proto-oncogene mutation.
• Prior to surgery, all patients should have serum calcium level and plasma meta-
nephrines evaluated to screen for primary hyperparathyroidism and pheochromocytoma or paraganglioma. Missed diagnoses of pheochromocytoma or
paraganglioma can lead to life-threatening cardiovascular complications.
56
J. E. Passman and H. Wachtel
Imaging Studies [1, 3]
• Ultrasound of the central and lateral neck is performed to characterize thyroid
nodule(s) and regional lymph nodes.
• Patients with preoperative calcitonin levels >500pg/mL require cross-sectional
imaging including neck computed tomography (CT), chest CT, and contrastenhanced CT or MRI of the liver to assess for metastatic disease and complete
staging evaluation.
Diagnosis [1, 3, 4]
• Diagnosis is made based on ne needle aspiration (FNA) biopsy, as is standard
for thyroid nodules. FNA biopsy is 50–80% sensitive for MTC.
• For indeterminate histocytology, molecular testing of FNA specimens has a high
degree of accuracy in diagnosing MTC.A calcitonin level may also be assessed
on FNA washout but has a low degree of sensitivity and is not widely available.
• Diagnosis may also be made on surgical pathology for indeterminate or inciden-
tal lesions.
• Surgical pathology shows spindle-shaped, pleomorphic cells without follicles.
Immunohistochemistry may be positive for calcitonin and CEA without the presence of thyroglobulin.
• Evidence of c-cell hyperplasia on tumor histopathology is suggestive of heredi-
tary MTC.
Special Considerations forHereditary MTC [4]
• Patients who test positive for RET proto-oncogene germline mutations (or
patients with unknown status) need to be evaluated for pheochromocytoma and
primary hyperparathyroidism prior to any surgical intervention.
• If pheochromocytoma is present, adrenalectomy should be performed before
thyroidectomy to avoid precipitating a hypertensive crisis.
• If primary hyperparathyroidism is present, parathyroidectomy should be per-
formed at the time of total thyroidectomy.
• Genetic counseling should be provided for patients with conrmed RET muta-
tions, and cascade genetic testing offered to family members.