Abstract
Medullary thyroid carcinoma (MTC) comprises approximately 1–2% of thyroid malignancies and occurs in sporadic and heritable forms. Hereditary forms include multiple endocrine neoplasia (MEN) type 2A, familial medullary thyroid carcinoma (FMTC), and MEN type 2B. Most cases of MTC demonstrate characteristic cytomorphology and a distinctive immunophenotype, but MTC can show a wide variety of cell shapes, nuclear and cytoplasmic features, and growth patterns. This morphologic heterogeneity leads to significant diagnostic challenges in the histologic and cytologic evaluation of this neoplasm. Characteristic features include a dispersed, noncohesive cell pattern, plasmacytoid and/or spindled cell shapes, finely granular chromatin, inconspicuous nucleoli, intranuclear pseudoinclusions, cytoplasmic granularity, and amyloid. Immunocytochemistry is helpful for distinguishing MTC from its cytologic mimics. Additional ancillary tests include measurement of calcitonin levels in needle washout fluid from FNA of thyroid nodules, thyroidectomy beds, and/or lymph nodes, particularly in patients with elevated serum calcitonin levels and/or with FNA findings that are inconclusive for MTC. Surgical treatment is usually total thyroidectomy and central lymph node dissection, with consideration of lateral cervical lymph node dissection depending on imaging studies and serum calcitonin levels.
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Keywords
- Medullary thyroid carcinoma
- Cytopathology
- Immunocytochemistry
- Calcitonin
- Multiple endocrine neoplasia
- Rearranged during transfection
Background
According to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, medullary thyroid carcinoma (MTC) comprises approximately 1–2% of thyroid carcinomas; this value is lower than previous estimates because of the relative increase in the incidence of papillary thyroid carcinoma (PTC) over the past several decades [1]. Looking ahead, the recent reclassification of the noninvasive follicular variant of PTC as “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” (i.e., not a malignancy) will undoubtedly increase the proportion of thyroid malignancies comprised of MTC in the future [2].
MTC occurs in sporadic and heritable forms . Sporadic MTC (70–80% of cases) typically presents as a solitary thyroid nodule in adults. In contrast, patients with hereditary MTC usually develop multifocal bilateral thyroid tumors, and the age of presentation varies with the syndrome. Hereditary syndromes include multiple endocrine neoplasia (MEN) type 2A, familial medullary thyroid carcinoma (FMTC) , and MEN type 2B. Table 9.1 summarizes the clinical and pathologic features of the sporadic and hereditary forms of MTC.
MEN2 syndromes and FMTC show an autosomal dominant mode of inheritance and are associated with pathogenic germline mutations of the RET gene, encoded on chromosome 10, that result in constitutive activation of the RET receptor tyrosine kinase. Mutations in the extracellular domain of RET (e.g., codons 609, 611, 618, 620, and 634) result in kinase activation via ligand-independent receptor dimerization, and mutations in the catalytic domain of RET (e.g., codon 918) result in kinase activation independent of ligand or receptor dimerization. There is a strong correlation between specific pathogenic mutations and phenotype, vis-à-vis MEN2 subtype , aggressiveness of MTC , and association with other manifestations such as Hirschsprung disease and cutaneous lichen amyloidosis [1, 3]. Somatic RET mutations have been identified in up to 50% of sporadic MTC [4, 5]. Among larger series, between 1 and 7% of patients with presumed sporadic MTCs are found to have hereditary disease, underscoring the importance of germline RET mutation testing in all patients diagnosed with MTC [1, 6, 7].
Most cases of MTC demonstrate characteristic cytomorphology, a distinctive immunophenotype, and variable stromal amyloid deposition (Table 9.2). Nevertheless, MTC can show a wide variety of cell shapes, cytoplasmic features, and growth patterns, leading to the description of a large number of MTC variants: papillary (or pseudopapillary), follicular, giant cell, spindle cell, small cell and neuroblastoma-like, paraganglioma-like, oncocytic, clear cell, angiosarcoma-like, squamous cell, melanin producing, and amphicrine (mucin producing) [8]. Recognizing and reporting any specific variant of MTC is not important for clinical management. This morphologic heterogeneity, however, leads to significant diagnostic challenges in the morphologic evaluation of this neoplasm (Table 9.3) [9].
Definition
MTC is a malignant neuroendocrine neoplasm derived from the parafollicular cells (C cells) of the thyroid gland.
Criteria
Aspirates show moderate to marked cellularity.
Numerous isolated cells alternate with syncytium-like clusters in variable proportions.
Cells are plasmacytoid, polygonal, round, and/or spindle-shaped. Long cell processes are seen in some cases.
The neoplastic cells usually show only mild to moderate pleomorphism.
Rare bizarre giant cells may be seen; they can be numerous in the giant-cell variant.
Nuclei are round, oval, or elongated and often eccentrically placed, with finely or coarsely granular (“salt and pepper”) chromatin.
Binucleation is common. Multinucleation is less often observed.
Nucleoli are usually inconspicuous but can be prominent in some cells.
Nuclear pseudoinclusions are occasionally noted. Nuclear grooves are rare or absent.
Cytoplasm is granular and variable in quantity. Small red-purple granules are seen with Romanowsky stains in some cases. Rare cases show cytoplasmic melanin pigment.
Amyloid is often present and appears as dense, amorphous material that resembles thick colloid.
With liquid-based preparations, fine cytoplasmic vacuolization can be prominent.
Cells are typically strongly immunoreactive for calcitonin, CEA, neuroendocrine markers (chromogranin, synaptophysin), and TTF1. Immunoreactivity for PAX8 is variable. Cells are negative for thyroglobulin (aberrant results occasionally occur).
Explanatory Notes
Cytologic preparations from MTC are usually moderately or highly cellular and composed of a mixture of noncohesive cells (Fig. 9.1) and crowded, syncytium-like aggregates (Fig. 9.2) [8,9,10,11,12]. Occasionally, rosette-forming, follicular, and pseudopapillary architecture can be seen. Most aspirates show a mixture of cell morphologies, including polygonal, round, and plasmacytoid shapes (all with round to ovoid nuclei) (Fig. 9.3), as well as spindled cells with elongated nuclei (Fig. 9.4). Tumor cells have a variable amount of cytoplasm, sometimes replete with red-purple granules after Romanowsky-type staining of air-dried smears (Fig. 9.5). A minority of cases demonstrate cytoplasmic vacuoles, melanin-like pigment (Fig. 9.6), and intracytoplasmic lumina (Fig. 9.7) [8]. With liquid-based preparations, fine cytoplasmic vacuolization can be prominent (see Fig. 9.6). Typically, most of the tumor cells demonstrate only mild to moderate nuclear pleomorphism, with occasional cells showing markedly enlarged or bizarre-appearing nuclei [8, 10]. Binucleation is common [8, 10]. Intranuclear pseudoinclusions (indistinguishable from those seen in papillary thyroid carcinoma) are seen in a limited number of cells in ~20–50% of cases (Fig. 9.8) [8, 10, 13]. Nuclear grooves are rare [13]. Rare cases show scant cytoplasm and nuclear molding, resembling small-cell carcinoma (Fig. 9.9). Amyloid is identified in approximately one-third to one-half of MTC aspirates (Figs. 9.10 and 9.11) [8, 10, 14]. It is virtually indistinguishable from colloid without the cellular context and is not diagnostic of MTC by itself, since amyloid may be present in papillary thyroid carcinoma (rarely) and amyloid goiter [15, 16]. Colloid is present in about 30% of MTC aspirates and is more frequent in medullary thyroid microcarcinoma, likely due to incidental colloid sampling from surrounding thyroid follicles [10, 17]. Calcifications (including psammoma bodies) have been reported in approximately 3% of MTC [8, 10].
Diagnosing MTC by FNA can be challenging given its diverse appearances and cytologic overlap with other tumors. Although the sensitivity of FNA for a definitive and specific diagnosis of MTC has been reported to be as high as 89% in a single-institution study, a meta-analysis revealed a substantially lower sensitivity of 56% (range 12–88%), thus highlighting the challenge that MTC poses to the cytologist [10, 18]. Immunocytochemistry (ICC) is extremely helpful for distinguishing MTC from its cytologic mimics (Table 9.2). Most MTCs are immunoreactive for “C-cell markers” (calcitonin , CEA), neuroendocrine markers (synaptophysin, chromogranin) [19,20,21,22,23,24,25], and TTF1 [19, 21, 26,27,28] and are negative for thyroglobulin (Fig. 9.12) [22, 29]. Staining for PAX8 varies considerably among studies (0–75%), with positive cases generally showing only focal immunoreactivity [27, 30,31,32]. Therefore, TTF1 and PAX8 are not helpful for distinguishing MTC from follicular cell-derived thyroid neoplasms. A Congo red stain can confirm the presence of amyloid, which supports the diagnosis of MTC in the context of characteristic malignant cells. The measurement of calcitonin levels in needle rinsings (washout fluid) from FNAs of thyroid nodules, thyroidectomy beds, and/or lymph nodes, can be helpful. This is particularly true in patients with elevated serum calcitonin levels and/or when FNA findings are inconclusive for MTC, e.g., when confirmation by ICC is not possible given limited material or equivocal staining results [1, 33]. Overall, this test is reliable, inexpensive, and associated with fast turnaround time. In order to avoid repetition of the FNA for this purpose, calcitonin measurement in FNA washout fluid should be anticipated in all clinically suspected cases of MTC and for all patients with MEN2. The Afirma Gene Expression Classifier (Veracyte, Inc., South San Francisco, CA), in common use for nodules interpreted as atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS) or follicular neoplasm (FN)/suspicious for follicular neoplasm (SFN), includes an MTC classifier that is effective in identifying the MTCs hidden in the substantial population of nodules with indeterminate cytology [34, 35].
The differential diagnosis of MTC includes the full spectrum of follicular cell-derived thyroid tumors (Table 9.2). Aspirates of Hürthle-cell (oncocytic) neoplasms often yield noncohesive cells with abundant granular cytoplasm, resembling some MTCs (Fig. 9.13). Papillary thyroid carcinoma (PTC) and hyalinizing trabecular tumor (HTT) can also mimic MTC by virtue of their intranuclear pseudoinclusions [36]. In particular, certain variants of PTC (tall cell, oncocytic) can have elongated or abundant cytoplasm, similar to that of some MTC cells [37]. Poorly differentiated thyroid carcinoma (PDTC) can resemble MTC; both have similar cytoarchitecture (crowded insular/nested groups and/or noncohesive cells), variable binucleation and chromatin granularity, and occasional plasmacytoid shape (Fig. 9.14) [38]. Like MTC, cells of undifferentiated (anaplastic) thyroid carcinomas (UTC) can have a multitude of appearances, including epithelioid, plasmacytoid, spindled, and giant-cell forms (Fig. 9.15) [39]. Increased mitotic activity, apoptosis, and necrosis should raise concern for PDTC or UTC rather than MTC. For each of the above possibilities, a panel of immunostains (calcitonin, CEA, synaptophysin, chromogranin) helps distinguish MTC from follicular cell-derived thyroid neoplasms.
Additional mimics of MTC include other neuroendocrine lesions in the head and neck, such as paraganglioma and parathyroid adenoma , both of which resemble MTC morphologically, and all are immunoreactive for synaptophysin and chromogranin. Additional immunostains help discriminate MTC (CEA+, calcitonin+, cytokeratin [CK]+) from paraganglioma (CEA-, calcitonin-, CK-, S100-protein+ sustentacular cells) and parathyroid neoplasms/hyperplasia (CEA-, calcitonin-, PTH+, GATA3+) [40, 41]. Metastatic neuroendocrine tumors to the thyroid gland or cervical lymph nodes mimic MTC and can be associated with elevated serum calcitonin levels [42]. In particular, moderately differentiated neuroendocrine carcinomas (atypical carcinoid) of the larynx are frequently positive for calcitonin and/or CEA. In contrast to MTC, however, most laryngeal atypical carcinoids are negative for TTF1 [19]. Correlation with clinical and radiographic findings plays a critical role in distinguishing MTCs from extra-thyroidal neuroendocrine tumors. Of other tumors metastatic to the thyroid, melanoma is a noteworthy mimic of MTC: the variable cell shape, frequent binucleation, nuclear pseudoinclusions, and dispersed cell pattern of many melanomas are features shared by many MTCs. In a patient with a history of melanoma, MTCs can be recognized by their immunoreactivity for cytokeratins and C-cell markers, the lack of staining for melanocytic markers (HMB45, S100-protein, Melan-A, SOX10), and the absence of macronucleoli. MTCs with a prominent spindle-cell pattern resemble mesenchymal lesions; immunoreactivity for CK, calcitonin , and neuroendocrine markers can be used to confirm the diagnosis of MTC in this setting [43]. Finally, plasma cell neoplasms resemble MTC because a dispersed cell pattern, “plasmacytoid” morphology, and amyloid deposition are shared by both tumors. Plasmacytomas of the thyroid are exceptionally rare but have been described [44]. Expression of CD138 and immunoglobulin light chain restriction favor a plasma cell neoplasm, whereas expression of C-cell and neuroendocrine markers supports a diagnosis of MTC.
Management
Following a cytologic diagnosis of MTC, preoperative studies should include a neck ultrasound and measurement of serum calcitonin and CEA. Systemic imaging studies may be indicated for patients with clinical or laboratory evidence of metastatic disease. Genetic testing for germline RET mutations should also be performed, and patients with hereditary MTC should be evaluated for pheochromocytoma and hyperparathyroidism prior to thyroid surgery [1]. For patients with pheochromocytoma, alpha/beta-adrenergic blockade and resection of the adrenal tumor should precede thyroidectomy for MTC. Surgical treatment of MTC is usually total thyroidectomy and central lymph node dissection, with consideration of lateral cervical lymph node dissection depending on imaging studies and serum calcitonin levels. For patients with advanced, progressive MTC , tyrosine kinase inhibitors such as vandetanib (targeting RET, EGFR, VEGFR) and cabozantinib (targeting RET, c-MET, VEGFR) can be used as single-agent first-line systemic chemotherapy [1].
Sample Reports
The general category “MALIGNANT” is used whenever the cytomorphologic features are conclusive for malignancy. If an aspirate is interpreted as MALIGNANT, it is implied that the sample is adequate for evaluation (an explicit statement of adequacy is optional). Descriptive comments that follow are used to subclassify the malignancy as an MTC and summarize the results of special studies, if any. If the findings are suspicious but not conclusive for malignancy, the general category “SUSPICIOUS FOR MALIGNANCY” should be used (see Chap. 7).
Example 1
MALIGNANT.
Medullary thyroid carcinoma.
Note: A Congo red stain is positive for amyloid. Immunocytochemistry performed on cell block/cytocentrifuge/liquid-based preparations (choose one) shows that the malignant cells are immunoreactive for calcitonin, CEA, chromogranin, and TTF1 and negative for thyroglobulin.
Example 2
MALIGNANT.
Consistent with medullary thyroid carcinoma.
Note: Cytomorphologic features are characteristic of medullary thyroid carcinoma, but tissue is insufficient for confirmatory immunocytochemical studies. Serum chemistry for calcitonin and CEA and/or repeat FNA for calcitonin measurement in the washout fluid warrant clinical consideration.
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Nishino, M., Pusztaszeri, M.P., Pitman, M.B. (2018). Medullary Thyroid Carcinoma. In: Ali, S., Cibas, E. (eds) The Bethesda System for Reporting Thyroid Cytopathology. Springer, Cham. https://doi.org/10.1007/978-3-319-60570-8_9
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