Advances in Anatomic Pathology:
Poorly Differentiated Thyroid Carcinoma: A Cytologic-histologic Review
Bongiovanni, Massimo MD*; Sadow, Peter M. MD, PhD†; Faquin, William C. MD, PhD†
*Pathologie Clinique, Hôpitaux Universitaires de Genève, Geneva, Switzerland
†Department of Pathology, Massachusetts General Hospital, Boston, MA
Reprints: William C. Faquin, MD, PhD, Department of Pathology, WRN 219, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 (e-mail: WFaquin@Partners.org).
The term poorly differentiated thyroid carcinoma (PDTC) was first proposed in the 1980s, but it was not definitively recognized as a distinct pathologic entity until the most recent classification of endocrine tumors by the World Health Organization in 2004. More recently, as a result of discussions in Turin, Italy, in 2006, diagnostic criteria were made more specific by a consensus of expert thyroid pathologists. The histologic and cytologic aspects are detailed with particular attention to key features helpful in the diagnosis of PDTC, both in surgical pathology and in cytology-based studies. Histologically, insular, solid, and/or trabecular architecture, along with at least one of the following: convoluted nuclei, mitotic activity (>3/10 HPF), or tumor necrosis, are required for a diagnosis of PDTC. Cytologically, the combination of insular, solid, or trabecular cytoarchitectural pattern, single cells, high nuclear to cytoplasmic (N/C) ratio, and severe crowding are highly suggestive of PDTC. Most PDTCs are immunohistochemically positive for thyroglobulin and thyroid transcription factor 1 (TTF-1), and a subset is also positive for p53. On the molecular level, ras mutations are the most common finding. PDTCs are managed aggressively by total thyroidectomy, 131I, and in some cases, external beam radiotherapy.
Poorly differentiated thyroid carcinoma (PDTC) is an infrequent and clinically aggressive thyroid cancer of follicular cell origin that has distinct clinical, histologic and biologic characteristics. It may arise de novo1 or associated with well-differentiated thyroid carcinomas (WDTC; papillary carcinoma, follicular carcinoma).2 PDTC accounts for 4% to 7% of all thyroid cancers,2 but the overall prevalence is difficult to establish due to regional variations. PDTC seems to be more frequent in iodine deficient areas such as northern Italy or the alpine European region and less frequent in North America.3 PDTC usually occurs in older individuals, with a mean age of 55 years and a slight female predominance (up to 2 times more frequent).1,2,4–9 Recently, we studied a series of 38 PDTCs that were evaluated by fine-needle aspiration biopsy (FNAB), and found an average age of 62 years (ranging from 31 to 86 y) with a slight female predominance (22 women and 16 men).10 Cases of PDTC in the pediatric population are rare.11–14
PDTC has an aggressive clinical behavior intermediate between that of WDTCs and undifferentiated (anaplastic) thyroid carcinomas.6,8,15–17 Even when PDTCs are present as a minor component of an otherwise WDTC, some studies suggest an increased likelihood that the tumor will behave aggressively,18 although other authors have found no correlation between the quantity of insular component and tumor stage at diagnosis or tumor progression at follow-up.19 Clinically, PDTCs often present at an advanced stage with extra thyroidal extension and a propensity for local recurrence and frequent relapse.20 These tumors tend to metastasize to regional lymph nodes, lung, and bones, but other sites such as liver and brain have also been observed.10 The current mean 5-year survival of patients with PDTC is approximately 50%2 but longer survival has also been documented.3 The majority of studies reporting and prognosticating outcomes for PDTC are based upon traditional findings in previously called “insular carcinomas”; however, the newly established criteria based upon the Turin proposal may shift our understanding of PDTC.21
PDTC has also been known as “insular carcinoma” due to the original observation by Langhans in 1907,22 who described the “wuchernde struma” (proliferating struma), a locally aggressive tumor with a peculiar architecture composed of tumor cells arranged in large, round-to-oval formations, the so-called “insulae.” During the following decades, recognition of these tumors as a distinct entity was neglected, and instead several different, largely histomorphologic terms were used to describe it. Pathologists have considered PDTC to be a morphologic variant of follicular thyroid carcinomas (FTC), and due to its rarity, especially in North America, many have found it difficult to recognize.
In October 1994, the International Workshop on Thyroid Tumor Pathology was held in San Miniato, Italy. There, the existence and recognition of a class of thyroid neoplasms with a microscopic appearance and natural history intermediate between WDTC and undifferentiated (anaplastic) carcinoma was proposed. The unique consensus achieved at this meeting was that these lesions are poorly differentiated carcinomas and portend a more severe prognosis than their well-differentiated counterparts; classical papillary thyroid carcinomas (PTC) and FTC.23 Two publications appeared that year describing these lesions. Under the monicker of “poorly differentiated” were a broad group of tumors displaying a peculiar growth pattern (solid, trabecular, or “scirrhous” architectures) and uncertain prognosis (including PTC variants such as tall cell variant, diffuse sclerosing variant, columnar cell variant, and solid variant).6 Also included were those having an “insular” growth pattern4 with high-grade features (necrosis and mitotic activity) and a comparably poorer prognosis compared with their well-differentiated counterparts.
At this point, the pathology community divided its loyalties between these 2 visions of PDTC. Moreover, the different approaches used in defining these tumors (one based on the architectural pattern and the other on the architecture and high-grade features) explains why there are so many articles in the literature using different inclusion criteria for defining a neoplasm as a PDTC.
An advance toward a more uniform definition of PDTC came in 2004 at the annual meeting of the Endocrine Pathology Society, where a consensus on the criteria defining PDTC was proposed. In the same year, the World Health Organization (WHO) Classification of Tumors of Endocrine Organs recognized PDTC as a separate entity, defined on the basis of architectural and high-grade features.2 The 2006 Turin (Italy) consensus conference, attended by an internationally recognized quorum of thyroid pathologists7, agreed to a unified series of diagnostic criteria and terminology, and a diagnostic algorithm for PDTC.
RECENT CLASSIFICATION CRITERIA (WORLD HEALTH ORGANIZATION AND TURIN ALGORITHM)
As defined by the 2004 WHO classification2 and now more clearly specified by the 2006 Turin consensus meeting,7 PDTC is defined by a combination of architectural and cytomorphologic features. By definition, tumors diagnostic of papillary, follicular and medullary carcinoma are excluded from this classification.
Three histomorphologic patterns including insular, solid, and trabecular, are recognized. So-called insular carcinoma, traditionally defined by its cellular nests falls under the umbrella of PDTC. Trabecular or solid patterns may coexist with insular growth patterns and are generally more frequent than a purely insular growth. However, insular, solid, and trabecular histomorphologic patterns are not sufficient for a diagnosis of PDTC. They are often encountered as features of benign thyroid nodules and in follicular variants of papillary carcinoma and follicular carcinoma.24–26 The WHO volume on “Pathology and Genetics of Tumors of Endocrine Organs” states that the majority of the tumor should have an insular, solid, or trabecular pattern, but the definition of majority, in this case, is unclear.2 For some authors, only a small percentage of this architecture (<20% of the tumors) should be present,24 and for others, the presence of more than 50% of these architectures is needed for a diagnosis of PDTC.27
In addition to the architectural patterns described, one of the following features should also be present: convoluted nuclei, mitotic activity (>3/10 HPF), or tumor necrosis. Necrosis and mitoses are discernible features of malignancy and their presence generally correlates with a less favorable prognosis.8,9,28 Nevertheless, they can also be present in well-differentiated tumors,19 such us widely invasive FTC or the solid variant of PTC7 where their exact significance remains to be defined. Even benign thyroid lesions, including previously biopsied nodules, may show focal necrosis, and it is not unheard of to see occasional mitoses within an adenoma or adenomatous nodule. More difficult is the concept of convoluted nuclei and its differential from the enlarged, pale, grooved nuclei of papillary carcinoma. As specified by Volante et al,7,28 convoluted nuclei are smaller and darker than the nuclei of classic PTC. The convoluted nuclei of PDTC are more compact and “raisinoid”; the nuclear membrane is irregular as in classic PTC, but only occasional grooves are seen and there are no nuclear pseudoinclusions. The presence of convoluted nuclei is considered a sign of dedifferentiation of a preexisting papillary carcinoma. Even if the tumor has one of the 3 architectural patterns of PDTC, with or without necrosis or mitotic activity, the tumor still would not be classified as a conventional PDTC if the nuclei are those of classic PTC. The significance of this latter group of thyroid carcinomas has yet to be well defined.
PDTCs are usually large at presentation, often showing extensive vascular invasion, infiltrative borders, and extrathyroidal extension.8,20 The average size of the resected PDTC often exceeds 5 cm in greatest dimension5 and in our series, the tumors ranged in size from 1.5 to 8.5 cm with an average size of 4.2 cm.10 On gross examination, they are firm, solid lesions with a gray-white cut surface and with focal soft areas corresponding to necrosis (Fig. 1).
An insular growth pattern is a common histologic feature of PDTC, and it is readily appreciated microscopically at low magnifications (Fig. 2A). This pattern reflects the presence of well-defined nests (insulae) outlined by a thin fibrovascular border. The cells within these insular groups seem round to oval and are separated from each other by optically empty spaces due to artifactual retraction of the stroma. Up to 50% of PDTC cases are composed almost exclusively of an insular pattern. In other PDTCs, the cells form solid areas or trabecular structures, and often, these patterns are variably admixed with the insular pattern in the same tumor (Fig. 2B). Mitotic activity (Fig. 2C) and necrosis (Fig. 2D) are often present, and the latter may manifest as a peritheliomatous appearance of the viable tumor cells clustered about central blood vessels with necrosis within the intervening stroma.5 A subset of microfollicles can also be seen. PDTCs often will show lymphovascular invasion (Fig. 2E) and extrathyroidal extension. The cells of PDTCs are a uniform population of follicular cells with scant cytoplasm (sometimes plasmacytoid) and a high nuclear/cytoplasmic (N/C) ratio with variable nuclear atypia and inconspicuous nucleoli. As mentioned, some cases will have nuclei with a convoluted appearance (Fig. 2F), but they should not exhibit conventional nuclear features of PTC.
According to the authors of the chapter of the WHO volume on “Pathology and Genetics of Tumors of Endocrine Organs” on PDTC,2 the diagnosis of PDTC can be made only on histology. This statement reflects the paucity of published studies evaluating diagnostic cytologic features of PDTC. Depending upon whether a well-differentiated component is also present, FNAB samples can contain microfollicles and nuclei with grooves and pseudoinclusions, thus overlapping with follicular neoplasms and PTC. It is not surprising that in a majority of cases, such fine-needle aspirates are diagnosed as “suspicious for a follicular neoplasm” or “suspicious for PTC.”
One of the first cytologic descriptions of PDTCs was a report of 6 cases by Pietribiasi et al in 1990,29 followed by 4 cases in 1992 by Sironi et al,30 6 cases in 1999 by Guiter et al,31 5 cases in 2001 by Nguyen et.32 and 40 cases by our group in 2009.10 In addition to these series, a limited number of published case reports are also available33–41 but only a few FNAB cases have prospectively recognized the tumors as PDTC.42,43
Table 1 summarizes the cytomorphologic features of PDTC. Usually, the aspirates are highly cellular with a bloody background, scant colloid, and rare necrosis. The cells are arranged in loosely cohesive solid or trabecular clusters or in insular groups measuring 0.2 to 0.4 mm in diameter (Fig. 3A,B).36,37 The proportion of isolated cells versus clusters varies from case-to-case (Fig. 3C). The cell population consists of isolated small to medium-size cells with scant cytoplasm, round nuclei, inconspicuous nucleoli, and high N/C ratio. At low magnification, they have a monomorphic appearance, but at higher magnification, variable degrees of atypia can be found with occasional mitoses and apoptotic nuclei.
In our FNAB series10 of 40 histologically proven cases of PDTC, 32 cytomorphologic features were evaluated. Only 13 (32.5%) of the cases were prospectively recognized as “poorly differentiated carcinoma” by FNAB, whereas the majority of cases (42.5%) was diagnosed as “suspicious for a follicular neoplasm.” Using stepwise logistic regression analysis, a combination of insular, solid, or trabecular cytoarchitectural patterns, single cells, high N/C ratio, and severe crowding were found to be the most useful in combination for predicting PDTC.
At present, no specific immunohistochemical or molecular markers exclusively expressed in PDTCs have been identified.24 High-molecular–weight cytokeratins, thyroglobulin, thyroid transcription factor 1 (TTF-1), HBME-1, galectin-3, CD44v6, p3, PAX8-PPARγ1, and Bcl-2 may be found, but these markers do not distinguish between WDTC and PDTC (Fig. 3D).24,44 If there is a role for immunohistochemistry to play, it is probably, its use in distinguishing PDTC from other entities in the differential diagnosis such as medullary carcinoma or metastatic disease.
PDTCs are immunohistochemically negative for calcitonin and carcinoembryonic antigen, and are usually negative for neuroendocrine markers such as chromogranin and synaptophysin. They are also negative for E-cadherin and hematopoietic markers such as leukocyte common antigen (LCA), CD19, CD20, and plasma cells markers such as CD138.45
Studies investigating p16 expression in PDTCs are variable. A study by Ball et al46 showed a contradictory loss of expression in 25% of cases and a high level of expression in another 25%. In the same study, the authors showed Cyclin A to be uniformly increased in insular carcinomas. Martyniak and Nosé47 affirm that positive p53 immunostains and MIB-1 >15% might be a helpful complement in cases with the PDTC architecture but lacking convoluted nuclei, mitoses and necrosis. Cell cycle markers (cyclins A, B1, E) were found to be elevated in more than 70% of tumors.17
The molecular biology of PDTCs is not well understood,48 in part, because of the inclusion and exclusion criteria for PDTC has varied considerably among authors as the histologic features used to define PDTC have been revised and refined.
Analysis of TP53 with both immunohistochemistry and molecular biology techniques (polymerase chain reaction, single stranded conformational polymorphism) has identified protein alterations in different proportions of PDTC cases49 that range from 17% to 38%. Although it is difficult to compare these results, as they may represent different groups of PDTCs based upon different histologic inclusion criteria,50–53 there, does seem to be a role for TP53 gene inactivation in tumor progression from WDTC to PDTC.
A high prevalence of ras mutations ranging from 18% to 63% has been found in PDTC.1,49,54–56 In some studies, ras mutations were associated with a poor prognosis,55,56 and inversely correlated with thyroglobulin expression.54 The ras point mutations were similarly limited to the N-ras gene at codon 611,54 or to the K-ras gene at codon 12 and 13.55 Interestingly, ras point mutations were the exclusive known genetic alteration found in studies by Soares et al57 and Nikiforova et al,58 that looked at a group of PDTCs lacking a WDTC component. Using strict criteria for including PDTCs and excluding aggressive variants of PTC, Soares found no BRAF mutations57 in 19 PDTCs, whereas Nikiforova et al58 found 2 BRAF mutations in PDTCs containing a tall cell papillary carcinoma component. In addition, no RET/PTC or PAX8/PPARγ rearrangements were found in PDTC cases without an associated PTC or FTC.59,60
Results concerning the expression of β catenin are unclear, perhaps reflecting the molecular heterogeneity of PDTCs.49 Rocha et al45 found negative immunoreactivity for E-cadherin in all cases, negative for β catenin immunostaining in 2 out of 17 PDTC cases, and neither mutations in the E-cadherin gene nor in the β catenin gene in 17 cases of PDTCs. In contrast, Garcia-Rostan et al61 showed β catenin immunostaining and/or gene mutation in 21.4% and 25% of 28 PDTCs, respectively. The thyroid stimulating hormone receptor (TSHR) pathway seems to be altered in poorly differentiated and anaplastic carcinomas in comparison with differentiated carcinomas.62,63
The differential diagnosis of PDTC includes some primary thyroid tumors and metastatic neoplasms. Cytologically, an isolated-cell pattern and plasmacytoid cell morphology, and histologically an organoid appearance, raise the possibility of medullary thyroid carcinoma (MTC). The nuclei of cells in PDTC lack the characteristic “salt and pepper” chromatin pattern of MTC. In addition, amyloid is absent, and the stroma is not hyalinized as in MTCs. Definitive distinction between PDTC and MTC is easily accomplished using a panel of immunohistochemical markers. PDTCs are negative for calcitonin, carcinoembryonic antigen, and neuroendocrine markers. PDTC is immunohistochemically positive for thyroglobulin; however, TTF-1 is generally not a useful marker as both PDTC and MTC could be positive.
Cytologically and histologically, PDTC can mimic a metastatic process. Both PDTC and secondary thyroid maligancies can be hypercellular with nuclear atypia and necrosis. Immunoreactivity of PDTCs for both thyroglobulin and TTF-1 helps to exclude metastatic disease.64 In cytologic samples, the single cell pattern and plasmacytoid appearance of some PDTC cases might suggest a lymphoproliferative disorder. However, this can easily be distinguished from PDTC by immunohistochemistry (negative reactivity for CD45, CD19, CD20, and CD138). Anaplastic thyroid carcinomas can display unusual cytomorphologic patterns together with necrosis and increased mitotic activity, but PDTCs lack the marked nuclear pleomorphism, high-grade atypia, and sarcomatoid features seen in undifferentiated carcinomas.
Accepted management guidelines for PDTCs include total thyroidectomy (or completion thyroidectomy) followed by 131I administration, and thyroxin suppression. In a subset of cases, FNAB can be a useful adjunct in the management of PDTCs. Although often diagnosed as “suspicious for a follicular neoplasm” followed by simple thyroid lobectomy, cases diagnosed prospectively by FNAB as PDTC could be prospectively treated with total thyroidectomy and neck dissection.20 Sanders et al3 suggest that in cases of PDTC, the preoperative evaluation of vocal cord function is important, due to a higher rate of local laryngeal invasion by these tumors and for the general assessment for extrathyroidal extension of the tumor.65
Concerning the use of 131I therapy postoperatively, data from the literature shows conflicting results. Sanders et al3 recommend using 131I therapy in all patients affected by PDTC after surgery. As with more aggressive WDTCs, external beam radiotherapy has been suggested for stage T3 PDTCs without distant metastases, and all T4 tumors and cases with regional lymph node involvement. For inoperable cases, Auersperg et al66 obtained a good response for tumor regression using chemotherapy and external beam radiotherapy.
With refinement of the diagnostic histologic criteria, the category of PDTC has evolved to include certain thyroid cancers exhibiting either insular, solid, or trabecular architecture. In addition, cytologic studies suggest that there may be a role for FNAB in the preoperative diagnosis of a subset of these tumors. In light of the recently published Turin criteria for PDTCs, a reevaluation of clinical cases will need to occur to more accurately stratify patients according to risk of an aggressive clinical course and improved prediction of clinical outcome and response to therapy. Additionally, as more advances are made on the molecular front, we may be able to provide stricter diagnostic criteria and better, more objective diagnostic markers for both cytologic and histologic specimens.
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International Journal of EndocrinologyComprehensive Literature Review: Recent Advances in Diagnosing and Managing Patients with Poorly Differentiated Thyroid CarcinomaInternational Journal of Endocrinology
thyroid; poorly differentiated carcinoma; FNAB; diagnosis
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