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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0000000000000004
Review Articles

Update on the Cytologic and Molecular Features of Medullary Thyroid Carcinoma

Pusztaszeri, Marc P. MD*; Bongiovanni, Massimo MD; Faquin, William C. MD, PhD‡,§

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Author Information

*Department of Pathology, Geneva University Hospital, Geneva

Institute of Pathology, Locarno, Switzerland

Department of Pathology, Massachusetts General Hospital

§Harvard Medical School, Boston, MA

All figures can be viewed online in color at

The authors have no funding or conflicts of interest to disclose.

Reprints: Marc P. Pusztaszeri, MD, Service de Pathologie Clinique, Hôpitaux Universitaires de Genève, 1 rue Michel-Servet, 1211 Genève 14, Switzerland (e-mail:

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Medullary thyroid carcinoma (MTC) accounts for only 5% to 10% of all thyroid carcinomas, but it is the most aggressive form of well-differentiated thyroid carcinoma, being responsible for 8% to 15% of all thyroid cancer-related deaths. MTC is frequently diagnosed at a locally advanced or metastatic stage, and 10-year survival rates in these cases are <20%. Fine-needle aspiration biopsy of the thyroid gland is an accurate method to diagnose MTC, having a high sensitivity and specificity. The cytologic features of MTC are characteristic and the cytologic diagnosis of classic MTC is often straightforward, especially when combined with immunocytochemistry. However, because of its morphologic heterogeneity and overlap with other tumors, the differential diagnosis of MTC on cytology and on histology is broad with several potential pitfalls. Significant advances have been made over the last decade in understanding MTC. This concerns mainly the early detection of MTC, especially in familial forms (eg, multiple endocrine neoplasia type 2), and the identification of key molecular pathways and alterations which now offer promising targets for specific therapies in progressive MTC cases. Genetic testing (eg, RET mutation) has allowed for early detection in asymptomatic carriers and high-risk patients, with prophylactic thyroidectomy often being curative. Targeted therapies with multityrosine-kinase inhibitors (eg, vandetanib or cabozantinib) have emerged as promising new treatments for recurrent or metastatic MTC. In this review article, we discuss the cytologic features of MTC and its variants, its differential diagnosis, the role of ancillary studies, and the salient molecular features of MTC.

Medullary thyroid carcinoma (MTC) accounts for 5% to 10% of all thyroid carcinomas.1,2 It is a well-differentiated neuroendocrine carcinoma arising from the C-cell, and is associated with secretion of calcitonin. MTC can also secrete other hormones such as carcinoembryonic antigen (CEA), adreno cortico trophic hormone, and somatostatin which may be responsible for paraneoplastic syndromes, and nonhormonal substances including mucin and melanin. MTC is the most aggressive form of well-differentiated thyroid carcinoma, being responsible for 8% to 13.5% of total deaths attributable to thyroid cancer,3 with an overall 5-year survival of approximately 70%.4 The stage and age at diagnosis are the most important prognostic factors. Therefore, early detection and diagnosis of this tumor is very important, and fine-needle aspiration biopsy (FNAB) of the thyroid gland and of lymph nodes plays a major role in the diagnosis of primary or metastatic MTC. In this review, we discuss the cytologic features of MTC and its variants, the differential diagnosis, the role of ancillary studies, and the salient molecular features of MTC.

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Familial Medullary Thyroid Carcinoma

In approximately 25% to 30% of cases, MTC is part of a familial syndrome known as multiple endocrine neoplasia (MEN) type 2, encompassing MEN2A, MEN2B, and familial MTC (FMTC) (Table 1). The various hereditary forms of MTC are caused by germline mutations of the RET gene involving different exons (Table 1), and are all autosomal dominant with high penetrance and variable expression patterns of inheritance.2 MTCs in MEN2 syndromes are often multifocal and are associated with C-cell hyperplasia. MTC typically occurs in the fifth decade in sporadic cases and in FMTC, which is the least aggressive form of MEN2. In contrast, MTC occurs at a younger age in patients with MEN2A and MEN2B, especially in MEN2B where most occur before adolescence. Current recommendations suggest that family members of MEN type 2 syndromes including FMTC should have genetic screening early in life, and affected members should have prophylactic thyroidectomy in childhood.4–6 The recommended age of surgery varies according to the type of MEN2 and especially to the specific type of RET protooncogene mutation (Table 1). MEN2A, which accounts for 90% to 95% of childhood MTC cases, is most commonly due to mutations in codon 634 of RET. MEN2B is almost always due to the Met918Thr mutation of RET,7 and is associated with the most aggressive clinical presentation of MTC. Since, metastatic cases have been described in MEN2B patients within the first year of life,8 patients affected with MEN2B usually undergo surgery even earlier than patients with MEN2A or FMTC.7,9 Therefore, measurement of serum calcitonin (with or without pentagastrin stimulation), and analysis of RET mutations to identify high-risk codons are the most common methods used to identify MTC10 and/or the precursor lesion C-cell hyperplasia at a potentially curable stage of the disease (eg, microcarcinoma).11 When these recommendations are followed, thyroid FNAB for the evaluation of a thyroid nodule is rarely performed in this population as most lesions are small. Therefore, most MTCs identified in familial cases are now microcarcinomas, and most of them are diagnosed in resection specimens.11,12

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Sporadic Medullary Thyroid Carcinoma

The majority of MTC cases (70% to 75%) are sporadic.1,2 Without calcitonin screening, patients with sporadic MTC usually present clinically with a cold solitary thyroid nodule. Most are solid, firm, and nonencapsulated, and occur in the lateral mid portion or upper half of the thyroid gland, corresponding to areas with greater numbers of C cells. In up to two thirds of patients, lymph node metastases are already present at the time of diagnosis, and curative surgery rarely can be achieved.13,14

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The cytologic features of MTC have been extensively studied15–27 since their original description by Ljungberg in 197228 and Söderström in 1975.15 The reported sensitivity of FNAB for a specific diagnosis of MTC is approximately 89% (range, 63% to 94%),15,26,29–31 and the positive predictive value ranges from 85% to 100%.26,30,31

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Classic Features of Medullary Thyroid Carcinoma

Aspirates from MTC are generally cellular and have a variable appearance. The most important cytologic criteria of MTC on FNAB are: dispersed to loosely cohesive patterns of epithelioid, plasmocytoid, polygonal, or spindled cells, eccentrically placed round nuclei with coarse granular (salt-and-pepper) chromatin, azurophilic cytoplasmic granules [May-Grünwald-Giemsa (MGG) stain], and background amyloid (Figs. 1A, B).15,18,26,27,32

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When this typical constellation of findings is present, the diagnosis of MTC is generally straightforward but should still be confirmed with a calcitonin immunostain and/or with documentation of elevated serum calcitonin levels, because of the broad differential diagnosis and the implications of diagnosing MTC for both the patient’s management and family members.1,17,32–34

Although epithelioid, plasmocytoid, or spindle cells are the most common form of tumor cells found in MTC, their proportion varies from 1 case to another.27 Most cases show a mixed cellular population but a pure spindle-cell population may be seen in up to 45% of cases (Fig. 1C).19,26,27 Moreover, many other types of tumor cells may be encountered on cytology, reflecting the many different variants of MTC that are recognized histologically (Table 2).1,2 These include ovoid or small cells, giant cells or bizarre cells, clear cells, squamoid, oncocytic, melanotic, and mucinous cells (Figs. 1D–F).35 Fortunately most of these MTC variants are uncommon.

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Binucleated or multinucleated cells are frequent, being found in approximately 78% (range, 46% to 100%)16,22,23,26,27 and 45% to 78% of cases,16,24,26 respectively, and may serve as a minor criteria for MTC diagnosis. Although an isolated or weakly cohesive pattern of cells is seen in the majority (>90%) of FNAB cases,26 other architectural patterns may occasionally be seen including: rosette, follicular, papillary-like, and trabecular.26 Rarely, a cohesive pattern with rectangular cells may be found.36

Nuclei are generally round and regular but can vary greatly in size (endocrine-related nuclear atypia). Intranuclear cytoplasmic inclusions are present in a limited number of cells in 19% to 58% of MTC (Figs. 1G, H)16,20,26,34,37; however, they are quantitatively less frequent than in PTC. In contrast to PTC, nuclear grooves are not a feature of MTC.1 Azurophilic cytoplasmic granules are helpful when present on MGG staining. Bose et al20 reported the presence of cytoplasmic granules in 85% of their 38 cases. However, according to the experience of many other authors, cytoplasmic granularity is considered an inconsistent finding.18,22,23,27,34,38

Amyloid is found in variable amounts in 34% to 80% of MTC on cytology18,20,27 and may mimic thick (chewing-gum) colloid or hyalinized stroma (Fig. 1B). Amyloid appears translucent or weakly orangeophilic to pink on Papanicolaou staining (Fig. 1B), pale blue to pink on Romanowsky staining, and blue gray to purple on MGG.15 Unlike colloid, amyloid does not show the typical cracking artifact on MGG, it may have a fibrillar appearance, and cells may appear to be embedded within its matrix. Congo Red and/or calcitonin staining may be useful to confirm the presence of amyloid. Although the presence of amyloid is very suggestive of MTC, it is not specific as it may be seen in other conditions such as amyloid goiter.39 Rarely calcifications including psammoma bodies can be seen in MTC (3% of cases).

Colloid is present in 31% of cases and is more frequent in medullary thyroid microcarcinoma (MTMC) (discussed below).

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MTC is known cytologically and histologically as a “mimicker” reflecting the many variants of this cancer. Recognizing a variant of MTC on cytology is generally not important for clinical management. However, some variants of MTC may mimic other tumors and have a specific differential diagnosis as outlined in Table 2. Among these variants of MTC, the spindle-cell variant and the oncocytic variant are the most common. The spindle-cell variant consists of elongate cells present singly and in loose clusters (Fig. 1C). It can be misinterpreted in FNAB samples as anaplastic carcinoma; however, it lacks the nuclear pleomorphism, mitotic activity, and necrosis of the latter. The oncocytic variant of MTC (Fig. 1F) consists of a dispersed population of polygonal cells with abundant granular cytoplasm. This pattern closely mimics a Hürthle cell neoplasm, and as such, MTC should be considered in the differential diagnosis of any thyroid Hürthle cell neoplasm. Cytologic features favoring MTC include the paucity of macronucleoli and presence of amyloid. Three additional variants of MTC that merit special attention include the small cell variant, microcarcinoma variant, and mixed medullar-follicular carcinoma variant.

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Small Cell Variant

The small cell variant of MTC is a very unusual tumor which behaves more aggressively than typical MTC.1 It may be impossible on morphologic examination to distinguish this variant from metastatic small cell carcinoma of the lung or of another site (eg, bladder) (Fig. 1D). Other small cell tumors such as lymphoma, neuroblastoma, and primitive neuroectodermal tumor also enter into the differential diagnosis.40,41 Moreover, amyloid may be absent and immunoreactivity for calcitonin can be negative in this variant,1,42 which is why some authors may arguably consider it as a primary small cell carcinoma of the thyroid or as an undifferentiated form of MTC.43–45 However, CEA will often be positive as in other types of MTC (88% to 100% of cases).1 Positivity for CEA supports a diagnosis of MTC even in the absence of calcitonin and other neuroendocrine marker immunoreactivity in the setting of MEN2. Consequently, a panel of antibodies consisting of calcitonin, CEA, PAX-8, chromogranin, cytokeratin, and leukocyte common antigen is useful for the correct diagnosis. Thyroid transcription factor-1 is not helpful as it will often also be positive in metastatic small cell carcinoma from the lung or from other sites.46,47 In difficult cases, the distinction may rely only on the clinical history.

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MTMCs are defined as tumors measuring 1 cm or less.2,12,48 They account for approximately 20% of all MTCs and their incidence has increased over time.48 This is likely the result of the improved detection of subclinical disease because of widespread use of ultrasonography, FNAB of thyroid nodules, and screening of patients with inherited disease. In contrast to papillary thyroid microcarcinomas which are generally indolent, MTMCs may have an increased risk of metastasis.48 Kazaure et al48 reported that 31% were multifocal, 7.8% had extrathyroid extension, and 37% and 5% of patients had lymph node metastases and distant metastases, respectively. Etit et al,11 however, found a very low risk of metastasis in their series of MTMCs in which most of their cases were <0.5 cm. Most MTMCs are found at prophylactic thyroidectomy in high-risk patients.12 On cytology, MTMCs may be misdiagnosed as a follicular lesion as a result of the small size of the lesion and the sampling of surrounding colloid-filled follicles. Colloid was present in almost half of FNAB cases in the series from Yang et al12 (4 of 9). Moreover, there was a more frequent occurrence of a round cell type together with the less frequent occurrence of plasmacytoid, spindle and giant cells, and amyloid.12

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Mixed Medullary-Follicular Carcinoma

Mixed medullary-follicular carcinoma of thyroid is a very rare tumor, characterized by coexistence of morphologic and immunohistochemical features of both medullary carcinoma and follicular (or papillary) carcinoma.1 This rare variant is somewhat controversial as it can be mimicked by the presence of entrapped benign follicular cells within a MTC. Often, the tumor will be diagnosed as MTC on FNAB, and microscopic examination of the follow-up total thyroidectomy specimen with the aid of immunocytochemical studies will detect minor component of follicular-derived carcinoma in addition to MTC. However, although specific identification of mixed medullary-follicular carcinoma by FNAB may be difficult and is largely influenced by sampling and the respective amount of both components, it should be emphasized that adequate sampling in conjunction with the proper immunostaining panel may highlight the different aspects of the mixed tumor. The size of the tumor is also important as FNAB of MTMC as discussed previously may contain both normal thyroid follicular cells with colloid and tumor cells of MTC.49,50

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The differential diagnosis of MTC is broad and depends upon the predominant type of cell present and/or upon the variant of MTC (Table 2). It includes other primary thyroid tumors and metastasis. On histology and cytology, MTC is known as the great mimicker in a similar manner as metastatic melanoma.

MTC can mimic a follicular neoplasm.26,51 Tumor cells of MTC may be arranged in small follicular clusters resembling a follicular neoplasm. A microfollicular pattern was present in 13 of 38 cases (34.2%) of MTC in the study by Bose et al.20 This pattern may even be prominent in some cases.26 Conversely, in some follicular neoplasms, cell dissociation and the presence of polymorphic cells may occur, resembling MTC.

Similar to MTC, Hürthle cell neoplasms often present as hypercellular, discohesive single cells with eccentric nuclei (plasmacytoid cells), and granular cytoplasm.23,38 However, rather than a salt–and-pepper chromatin, most cells of a Hürthle cell neoplasm have a prominent red macronucleolus. In contrast, macronucleoli are identified only in a minority of cells in typical MTC (4.4%).26,27 However, as mentioned previously, an oncocytic variant of MTC has been recognized where most tumor cells may be of the oncocytic type.52,53 Therefore, in difficult cases, immunocytochemistry with calcitonin, CEA, and thyroglobulin will solve the diagnostic dilemma.

When nuclear pseudoinclusions (Figs. 1G, H), papillary structures, and/or psammoma bodies are identified, MTC can be confused with PTC.54,55 Amyloid may also be confused with the thick “chewing-gum-like” colloid of PTC.54 Some variants of PTC such as the columnar or the oncocytic variant, in which the typical nuclear features of PTC are not well developed, may also enter into the differential diagnosis. The presence of papillary structures or even of true papillae with fibrovascular cores is not specific for PTC as it may also be found in the papillary or pseudopapillary variant of MTC.17,26,54 On rare occasion, PTC and MTC may coexist in the same gland.56

Poorly differentiated carcinoma, especially the insular type, may be extremely difficult to distinguish from MTC. Sometimes, a more differentiated follicular component with microfollicles and colloid will also be present. Immunocytochemistry will also be very helpful in this differential diagnosis.

Hyalinizing trabecular tumor (HTT) can also be confused with MTC because of the presence of amyloid-like hyaline stromal fragments and intranuclear cytoplasmic inclusions on cytology. Moreover, although extremely rare, an HTT-like and a paraganglioma-like variant of MTC have been described histologically.1,57–61 These variants are morphologically indistinguishable from HTT and paraganglioma, respectively. However, positivity for thyroglobulin and negativity for calcitonin and CEA should resolve the diagnostic dilemma between HTT and HTT-like MTC.1,57,59 Distinction between paraganglioma and paraganglioma-like MTC is more problematic as some paraganglioma may be positive for calcitonin.58,62 Moreover, MTC may contain S100-positive “sustentacular cells,” a typical feature of paraganglioma, in almost 30% of cases.63 However, whether these S100-positive cells in MTC represent true sustentacular cells or an alternative S100-positive type of cell such as tumor-infiltrating dendritic cells remains an unsolved question.60 In contrast to MTC, paragangliomas are negative for cytokeratins. True primary thyroid paraganglioma are extremely rare.64

C-cell hyperplasia, a precursor for MTC, cannot be differentiated from MTMC on cytology, but can be separated on ultrasound in a subset of cases. Both MTMC and C-cell hyperplasia can present as a nodular lesion. Both lesions can be seen in prophylactic thyroidectomy specimens in patients with MEN2.11

Other differential diagnoses include plasmacytoma65 and metastases from: neuroendocrine tumors (NETs) including carcinoid and small cell carcinoma,45 sarcoma, melanoma, and renal cell carcinoma. In primary thyroid plasmacytoma, discohesive plasmacytoid cells and amyloid/amyloid-like materials, which are major features of MTC, may all be seen. However, the tumor cells of MTC are generally larger than plasma cells. The pigmented variant of MTC and the clear cell variant of MTC can mimic melanoma or renal clear cell carcinoma, respectively. Finally, MTC with a pure or predominant spindle-cell component as discussed previously can mimic spindle-cell sarcoma, melanoma, or sarcomatoid/anaplastic carcinoma.27 Clinical correlation and immunocytochemistry are crucial in avoiding pitfalls in these situations.

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Because of its wide range of cytologic appearances, as well as its cytologic overlap with other tumors as discussed above, the diagnosis of MTC often requires the use of ancillary techniques for confirmation, including immunocytochemistry or calcitonin measurement in the blood or in the wash-out fluid from the FNAB of a thyroid nodule or of a lymph node.

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The most useful marker for the diagnosis of MTC is calcitonin, with a reported sensitivity of 74% to 100% on cytology.16,26 Sporadic cases of MTC may be less frequently immunoreactive (74% to 79%) than familial cases (100%).20,66 Although calcitonin is also the most specific marker for MTC, a nonspecific reaction of the antibodies can occur with oncocytic neoplasms, possibly leading to a misdiagnosis of MTC. However, if immunochemistry for thyroglobulin and CEA are performed, MTC cells should be negative in contrast to follicular-cell–derived oncocytic neoplasms. CEA is also very sensitive (80% to 100%) for MTC but is less specific than calcitonin.

Some pulmonary and extrapulmonary NETs including pulmonary carcinoid or moderately differentiated neuroendocrine carcinoma/atypical carcinoid of the larynx can also be positive for calcitonin67 and/or CEA.68 However, in contrast to MTC, pulmonary (but not laryngeal) carcinoid should be negative for CEA, whereas extrapulmonary (but not pulmonary) carcinoid should be negative for thyroid transcription factor-1.47,67

The amyloid in MTC often stains for calcitonin,1,16 likely because the amyloid protein represents a precursor of calcitonin that cross-reacts with the antibody.1,69 When feasible (eg, cellblock), a panel of antibodies comprising calcitonin, CEA, chromogranin, cytokeratin, and thyroglobulin should be used.20,33,42

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Calcitonin and Carcinoembryonic Antigen Measurements in the Blood

In most cases of MTC including MTMC, the serum levels of calcitonin and CEA will be markedly elevated (>500 pg/mL).6 The levels of calcitonin and CEA are proportional to tumor burden and differentiation. This may be particularly useful when the FNAB does not yield sufficient material for ancillary studies to confirm the suspicion of MTC. Conversely, if the blood levels of calcitonin are normal, other diagnoses should be considered before making a definitive diagnosis of MTC, especially given that patients are typically treated with a total thyroidectomy with cervical lymph node dissection. However, there may be some overlap with patients who have C-cell hyperplasia only, or other medical conditions such as renal insufficiency, acute pancreatitis, or hypergastrinemia. In addition, other nonthyroid tumors can also secrete calcitonin resulting in elevated serum levels. Examples include several other NET (eg, small cell lung cancer, pheochromocytoma, bronchial carcinoid, and pancreatic NET), melanoma, breast cancer, and colorectal cancer.70–75 The administration of pentagastrin or calcium infusions, which stimulates secretion of calcitonin by tumors but not other conditions, may be used to confirm abnormal levels of calcitonin and to select patients for surgery.76,77 Although calcitonin screening for the detection of patients with MTC before surgery is controversial, it should be considered before performing surgery for nodular goiter. Calcitonin levels as well as CEA levels are also routinely monitored after surgery to help identify patients with recurrent or metastatic disease. When calcitonin and CEA normalize after surgery, the prognosis is generally excellent.

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Calcitonin Measurement in Thyroid Fine-Needle Aspiration Biopsy Wash-Out

A recent study comparing the sensitivity of calcitonin measurements in thyroid FNAB wash-out fluid and thyroid FNAB cytology for detecting MTC, showed that confirmed MTC cases that have been classified by FNAB cytology alone as benign, inadequate, or indeterminate were correctly identified as MTC by calcitonin measurement in FNAB wash-out fluid (with a threshold >39.6 pg/mL). This method reached 100% accuracy and can also be a valuable tool in cases that have scant material for ancillary studies.78,79

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Calcitonin Measurement in Lymph Nodes

Because of its tendency to metastasize to regional lymph nodes at an early stage, MTC is occasionally diagnosed initially by FNAB of an enlarged cervical lymph node. It will show the same morphologic features as described previously for MTC. However, metastatic MTC may lose the ability to express calcitonin while retaining CEA positivity, which can still be useful in confirming metastatic MTC in cases with consistent cytomorphology.27 In addition, calcitonin levels can also be measured in the wash-out fluid from the FNAB of neck masses in patients with metastatic MTC.80 The reported sensitivity and specificity of calcitonin for MTC in metastatic lymph nodes is 100%, whereas the reported sensitivity and specificity of cytology alone is 61.9% and 80%, respectively.80

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Role of RET Protooncogene and Targeted Therapies

The major signaling pathways and molecular alterations involved in the pathogenesis of MTC are illustrated in Figure 2. RET oncogene plays a major role in the tumorigenesis of MTC and has been characterized extensively.81RET encodes a tyrosine kinase receptor expressed mainly in neuroendocrine cells (including thyroid C cells and adrenal medullary cells), neural cells (including parasympathetic and sympathetic ganglion cells), urogenital tract cells, and testis germ cells.82 RET signaling leads to the activation of the RAS/mitogen-activated protein kinase and the phosphatidylinositol 3′ kinase (PI3K)/Akt pathways, and has key roles in cell growth, differentiation, and survival. Activating point mutations of RET affecting different codons have been reported in nearly all hereditary cases of MTC (Table 1). There is a genotypic/phenotypic correlation between the type of RET mutation and clinical features. Somatic RET mutations are also found in approximately 60% of sporadic MTCs, with a wide range (12% to 100%) depending on the reported series.83–85 The mutational profile of sporadic MTC is shown in Figure 3. Germline mutations in the RET protooncogene are therefore responsible for inherited MTC, whereas somatic RET mutations are responsible for a subset of sporadic MTC.86 MEN2B is almost always associated with the M918T mutation (exon 16) and represents the most aggressive clinical presentation of MTC during childhood. In sporadic cases, the M918T somatic mutation is also the most common, and it has been shown to be a negative predictor of cancer remission and survival.84,87,88 The recent findings of H-RAS and K-RAS mutations in 56% and 12% of RET-negative sporadic MTC (Fig. 3),83,85,89,90 and the activation of the mammalian target of rapamycin intracellular signaling pathway in hereditary MTC91 suggests that additional or alternative genetic events can play a role in MTC pathogenesis. In contrast, common abnormalities found in other cancers, such as TP53, RB1, PIK3CA, and BRAF gene mutations, are extremely uncommon or absent in MTC.83,92–95

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Taken together, these data provide a strong rationale for targeting RET signaling pathways in the selective therapy of MTC. Moreover, although cytotoxic treatments and radiotherapy have been shown to have limited efficacy for MTC, targeted molecular therapies have shown distinct advantages with regard to rates of disease response and control.96 In April 2011, vandetanib (ZD6474), a multi-targeted kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR 3, epidermal growth factor receptor and RET, became the first targeted therapy drug to be approved by US Food and Drug Administration for the treatment of patients with locally advanced or metastatic MTC.84 This was followed by the approval of cabozantinib (XL184), an inhibitor of RET, MET, and VEGFR2, in November 2012. In ZETA and EXAM trials, vandetanib improved progression-free survival from 19.3 to 30.5 months compared with placebo in patients with metastatic disease, whereas cabozantinib improved progression-free survival from 4.0 to 11.2 months in a population with more aggressive disease.96–98 However, improvement in overall survival was not demonstrated in these 2 trials. A subset of patients without RET mutations also benefit from vandetanib/cabozantinib and had clinical responses.96–98 The exact mechanism by which these drugs are effective, and the impact of different types of RET mutations on the clinical response remain uncertain. Furthermore, important resistances to TKIs can occur over time, which limit the long-term efficacy of these treatments. The assessment of RET and/or RAS mutation status in sporadic RET-negative MTC may prove useful in selecting target therapies with TKIs83; however, more data are needed before these tests are routinely performed. Several other multi-TKIs including sorafenib,99,100 sunitinib,101 axitinib,102 and motesanib103 are currently under clinical trial and may yield additional treatment options, alone or in combination, for patients with advanced MTC or who acquired resistance to vandetanib/cabozantinib.104,105

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MicroRNAs (miRNAs) are involved in the pathogenesis of most if not all human cancers including MTC, and may serve as diagnostic or prognostic biomarkers, and as potential therapeutic targets. miRNAs are significantly deregulated in MTC, and this deregulation is probably an early event in C-cell carcinogenesis.106,107 However, very few studies have analyzed miRNAs in MTC. Nikiforova et al108 investigated miRNA expression profiling in 2 FNAB samples from MTC, and found a subset of 10 specific upregulated miRNAs. Although calcitonin immunochemistry is very sensitive and specific for confirming MTC diagnosis, in difficult cases, miRNA analysis of FNA samples may represent an additional diagnostic tool. Abraham et al107 studied a series of 45 patients with MTC using miRNA microarray analysis and found that a combination of three miRNAs (miR-183, miR-375, and miR-9*) could distinguish hereditary forms of MTC from sporadic forms. Moreover, overexpression of miR-183 and miR-375 was also significantly associated with residual disease, distant metastases, and mortality in their series. Conversely, miR-224 upregulation may represent a prognostic biomarker associated with a better outcome in MTC patients.106

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Significant advances have been made over the last decade in the diagnosis and treatment of MTC. This includes the early detection of MTC, especially in familial forms, and the identification of key molecular pathways and alterations which now offer promising targets for specific therapies in progressive MTC cases. MTC has now definitely joined the growing list of cancers for which targeted therapies with TKIs are available. Therefore, in the near future it is likely that molecular analysis on cytologic and/or resection specimen of MTC will be part of the routine practice for the surgical pathologist and cytopathologist, to stratify patients for targeted therapies.

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thyroid; medullary carcinoma; fine-needle aspiration; cytology; immunocytochemistry; calcitonin; multiple endocrine neoplasia; molecular; rearranged during transfection; targeted therapy

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